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http://www.ncbi.nlm.nih.gov/pubmed/23225386 | 1. Muscle Nerve. 2012 Dec;46(6):951-3. doi: 10.1002/mus.23529.
Patient-identified disease burden in facioscapulohumeral muscular dystrophy.
Johnson NE(1), Quinn C, Eastwood E, Tawil R, Heatwole CR.
Author information:
(1)Department of Neurology, University of Rochester, 601 Elmwood Avenue, P.O.
Box 673, Rochester, New York 14642, USA. Nicholas_johnson@urmc.rochester.edu
INTRODUCTION: The multitude of symptoms associated with facioscapulohumeral
muscular dystrophy (FSHD) disease burden are of varying importance. The extent
of these symptoms and their cumulative effect on the FSHD population is unknown.
METHODS: We conducted interviews with adult FSHD patients to identify which
symptoms have the greatest effect on their lives. Each interview was recorded,
transcribed, coded, and analyzed using a qualitative framework technique,
triangulation, and a three-investigator consensus approach.
RESULTS: One thousand three hundred seventy-five quotes were obtained through 20
patient interviews. Two hundred fifty-one symptoms of importance were identified
representing 14 themes of FSHD disease burden. Symptoms associated with mobility
impairment, activity limitation, and social role limitation were most frequently
mentioned by participants.
CONCLUSIONS: There are multiple themes and symptoms, some previously
underrecognized, that play a key role in FSHD disease burden.
Copyright © 2012 Wiley Periodicals, Inc.
DOI: 10.1002/mus.23529
PMCID: PMC4097080
PMID: 23225386 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30414142 | 1. Methods Mol Biol. 2019;1890:29-40. doi: 10.1007/978-1-4939-8900-3_3.
Identification of Transcription Factor-Binding Sites in the Mouse FOXO1
Promoter.
Cardozo CP(1)(2).
Author information:
(1)Center for the Medical Consequences of Spinal Cord Injury, James J Peters
Medical Center, Bronx, NY, USA. christopher.cardozo@mssm.edu.
(2)Icahn School of Medicine at Mount Sinai, New York, NY, USA.
christopher.cardozo@mssm.edu.
One critical determinant of levels of gene expression is binding of
transcription factors to cognate DNA sequences in promoter and enhancer regions
of target genes. Transcription factors are DNA-binding proteins to which
transcriptional co-regulators are bound, ultimately resulting in histone
modifications that change chromatin structure to regulate transcription.
Examples of transcription factors include hormone-activated transcription
factors such as the glucocorticoid receptor, transcription factors regulated by
cell surface receptors such as FOXO1 and Smad2/Smad3, and many others. Promoter
regions typically contain multiple, diverse transcription factor-binding sites.
Binding sites for cell-type-specific transcription factors involved in cell fate
determination such as Runx2, MyoD, or myogenin are frequently observed. Promoter
regions are located within ~2 kb upstream of the transcriptional start site,
whereas enhancers may be located at some distance from promoter sequences and
exert long-range effects. Here, we will discuss classical and emerging
technologies by which one can understand the role of binding of specific
transcription factors in regulation of transcription of FOXO genes.
DOI: 10.1007/978-1-4939-8900-3_3
PMID: 30414142 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35020192 | 1. Muscle Nerve. 2022 Apr;65(4):415-421. doi: 10.1002/mus.27493. Epub 2022 Jan
25.
Systemic manifestations and symptom burden of facioscapulohumeral muscular
dystrophy in a referral cohort.
Kelly CR(1), Saw JL(1), Thapa P(2), Mandrekar J(2), Naddaf E(1).
Author information:
(1)Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
(2)Department of Internal Medicine-Biomedical Statistics and Informatics, Mayo
Clinic, Rochester, MN, USA.
INTRODUCTION/AIMS: The full spectrum of the clinical phenotype of
facioscapulohumeral muscular dystrophy (FSHD), beyond skeletal muscle weakness,
remains poorly characterized. In this study, we describe systemic manifestations
and symptom burden in a large series of FSHD patients.
METHODS: We performed a retrospective chart review of FSHD patients seen at our
institution between 2000 and 2017. We reviewed patients' responses to a
comprehensive review of symptoms and the results of diagnostic testing for
sensorineural hearing loss, cardiac disease, dysphagia, ocular abnormalities,
and respiratory insufficiency. We assessed the association between disease
manifestations and age of onset, genetic profile, and disease duration.
RESULTS: We identified 87 patients with FSHD. The most common reported symptoms
included pain (71%), difficulty sleeping (41%), headaches (27%), and altered
mood (24%). When tested, 7 of 16 (44%) patients had sensorineural hearing loss,
20 of 60 (33%) had cardiac arrhythmias or conduction defects, 17 of 45 (38%) had
echocardiogram abnormalities, 12 of 25 (48%) had reduced forced vital capacity,
and 4 of 10 (40%) had oropharyngeal dysphagia. However, patients with these
abnormalities represented 8%, 23%, 20%, 14%, and 5% of total number of patients,
respectively, as uniform screening was lacking. Ocular pathology attributable to
FSHD was not detected.
DISCUSSION: FSHD demonstrates a broad clinical phenotype. Increased vigilance
among neurologists to screen for systemic manifestations of the disease is
warranted. More uniform screening and future population-based studies are needed
to compare findings in FSHD patients with the general population.
© 2022 Wiley Periodicals LLC.
DOI: 10.1002/mus.27493
PMID: 35020192 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15050443 | 1. J Neurol Sci. 2004 Apr 15;219(1-2):89-93. doi: 10.1016/j.jns.2003.12.010.
FSHD-like patients without 4q35 deletion.
Yamanaka G(1), Goto K, Ishihara T, Oya Y, Miyajima T, Hoshika A, Nishino I,
Hayashi YK.
Author information:
(1)Department of Neuromuscular Research, National Institute of Neuroscience,
National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-higashi,
Kodaira, Tokyo 187-8502, Japan.
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive
weakness and wasting of facial, shoulder-girdle and upper arm muscles. Despite
of the characteristic clinical features, the diagnosis of FSHD is sometimes
difficult because clinical symptoms are extremely variable including facial
sparing type, limb-girdle type, and distal myopathy type. Most of the FSHD
patients have a deletion in the subtelomeric region of chromosome 4q35
(FSHMD1A), however the linkage analysis in some families suggested genetic
heterogeneity. In the present study, we identified 40 patients without a
deletion in the 4q35 region (non-4q35del) among 200 Japanese patients who were
clinically suspected to have FHSD. All non-4q35del patients had shoulder-girdle
weakness and 75% also had facial weakness. Eight patients showed clinical
features that were indistinguishable from FSHD, but two of them had Becker
muscular dystrophy. FSHD is clinically, and most likely genetically, as well,
variable. Other forms of muscular dystrophy can also mimic FSHD.
DOI: 10.1016/j.jns.2003.12.010
PMID: 15050443 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22907234 | 1. Muscle Nerve. 2012 Sep;46(3):421-5. doi: 10.1002/mus.23358.
Focal and other unusual presentations of facioscapulohumeral muscular dystrophy.
Hassan A(1), Jones LK Jr, Milone M, Kumar N.
Author information:
(1)Department of Neurology, Mayo Clinic College of Medicine, 200 First Street
SW, Rochester, Minnesota 55905, USA.
INTRODUCTION: Facioscapulohumeral dystrophy (FSHD) presents classically with
facial and shoulder-girdle weakness. We report focal atypical presentations of
FSHD. Our aim was to identify focal/unusual phenotypes in genetically confirmed
FSHD cases.
METHODS: We undertook a retrospective review of an academic center database of
the period from 1996 to 2011. Of 139 FSHD cases, 7 had atypical genetically
confirmed disease. Clinical data were abstracted.
RESULTS: Seven cases (4 men) had a mean age of 37 years at onset (range 18-63
years) and mean 43 years at diagnosis (range 20-74 years). Presenting symptoms
were monomelic lower limb (n = 3) or upper limb (n = 2) atrophy, or axial
weakness (n = 2). Five patients had focal weakness on examination. CK was normal
to borderline high. Two patients had a relative with FSHD. Coexistent unusual
features included dyspnea (n = 1), S1 radicular pain with calf atrophy (n = 2),
and peripheral neuropathy (n = 1). Almost all patients had myopathic EMG
changes. DNA analysis showed a D4Z4 EcoRI fragment size ranging from 20 to 37
kilobases.
CONCLUSIONS: FSHD may present with focal weakness, dyspnea and myopathic EMG
changes. These findings should raise the possibility of FSHD.
Copyright © 2012 Wiley Periodicals, Inc.
DOI: 10.1002/mus.23358
PMID: 22907234 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34675094 | 1. Neurology. 2021 Nov 23;97(21):e2103-e2113. doi: 10.1212/WNL.0000000000012882.
Epub 2021 Oct 21.
Natural History of Facioscapulohumeral Dystrophy in Children: A 2-Year
Follow-up.
Dijkstra JN(1), Goselink RJM(1), van Alfen N(1), de Groot IJM(1), Pelsma M(1),
van der Stoep N(1), Theelen T(1), van Engelen BGM(1), Voermans NC(1), Erasmus
CE(2).
Author information:
(1)From the Departments of Neurology (J.N.D., N.v.A., B.G.M.v.E., N.C.V.) and
Rehabilitation (I.J.M.d.G., M.P.), Donders Centre of Neuroscience, Department of
Pediatric Neurology (J.N.D., C.E.E.), Amalia Children's Hospital, and Department
of Ophthalmology (T.T.), Radboud University Medical Centre, Nijmegen, the
Netherlands; Department of Neurology (R.J.M.G.), Jönköping, Region Jönköping
County, and Department of Biomedical and Clinical Sciences (R.J.M.G.), Linköping
University, Linköping, Sweden; and Department of Clinical Genetics (N.v.d.S.),
Leiden University Medical Centre, the Netherlands.
(2)From the Departments of Neurology (J.N.D., N.v.A., B.G.M.v.E., N.C.V.) and
Rehabilitation (I.J.M.d.G., M.P.), Donders Centre of Neuroscience, Department of
Pediatric Neurology (J.N.D., C.E.E.), Amalia Children's Hospital, and Department
of Ophthalmology (T.T.), Radboud University Medical Centre, Nijmegen, the
Netherlands; Department of Neurology (R.J.M.G.), Jönköping, Region Jönköping
County, and Department of Biomedical and Clinical Sciences (R.J.M.G.), Linköping
University, Linköping, Sweden; and Department of Clinical Genetics (N.v.d.S.),
Leiden University Medical Centre, the Netherlands corrie.erasmus@radboudumc.nl.
BACKGROUND AND OBJECTIVES: Data on the natural history of facioscapulohumeral
dystrophy (FSHD) in childhood are limited and critical for improved patient care
and clinical trial readiness. Our objective was to describe the disease course
of FSHD in children.
METHODS: We performed a nationwide, single-center, prospective cohort study of
FSHD in childhood assessing muscle functioning, imaging, and quality of life
over 2 years of follow-up.
RESULTS: We included 20 children with genetically confirmed FSHD who were 2 to
17 years of age. Overall, symptoms were slowly progressive, and the mean FSHD
clinical score increased from 2.1 to 2.8 (p = 0.003). The rate of progression
was highly variable. At baseline, 16 of 20 symptomatic children had facial
weakness; after 2 years, facial weakness was observed in 19 of 20 children.
Muscle strength did not change between baseline and follow-up. The most
frequently and most severely affected muscles were the trapezius and deltoid.
The functional exercise capacity, measured with the 6-minute walk test,
improved. Systemic features were infrequent and nonprogressive.
Weakness-associated complications such as lumbar hyperlordosis and dysarthria
were common, and their prevalence increased during follow-up. Pain and fatigue
were frequent complaints in children, and their prevalence also increased during
follow-up. Muscle ultrasonography revealed a progressive increase in
echogenicity.
DISCUSSION: FSHD in childhood has a slowly progressive but variable course over
2 years of follow-up. The most promising outcome measures to detect progression
were the FSHD clinical score and muscle ultrasonography. Despite this disease
progression, an improvement on functional capacity may still occur as the child
grows up. Pain, fatigue, and a decreased quality of life were common symptoms
and need to be addressed in the management of childhood FSHD. Our data can be
used to counsel patients and as baseline measures for treatment trials in
childhood FSHD.
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on
behalf of the American Academy of Neurology.
DOI: 10.1212/WNL.0000000000012882
PMCID: PMC8610619
PMID: 34675094 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32008231 | 1. Ther Innov Regul Sci. 2020 Jan;54(1):144-150. doi: 10.1007/s43441-019-00038-w.
Epub 2020 Jan 6.
Updating the Clinical Picture of Facioscapulohumeral Muscular Dystrophy:
Ramifications for Drug Development With Potential Solutions.
Huml RA(1), Uspenskaya-Cadoz O(2), Dawson J(3), Slifer Z(4).
Author information:
(1)IQVIA, Durham, North Carolina, 27703, USA. Raymond.huml@iqvia.com.
(2)IQVIA, Durham, North Carolina, 27703, USA.
(3)Consultant, Durham, NC, USA.
(4)North Carolina State University's College of Veterinary Medicine, Raleigh,
North Carolina, USA.
BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a complex,
inheritable, and rare muscle disease that affects the entire body. The major
symptom of FSHD is progressive weakening and loss of skeletal muscles. The usual
location of these weaknesses at onset is the origin of the name: face (facio),
shoulder girdle (scapulo), and upper arms (humeral). FSHD appears to have
varying molecular and genetic determinants with commensurate differences in
disease progression.
METHODS: Facioscapulohumeral muscular dystrophy (MD) is probably the most
prevalent form of MD but has neither disease-modifying treatments nor a cure. As
the mechanism of action becomes further elucidated, more biopharmaceutical
companies are investing capital into finding treatments for patients with FSHD.
Sponsors of treatments for FSHD patients should be aware of some of the common
misconceptions associated with FSHD drug development with the goal of optimizing
the chance to prove safety and efficacy for each potential treatment for FSHD in
the clinical trial setting.
RESULTS: Four major topics with potential clinical manifestations for patients
with FSHD will be discussed related to muscle weakness, respiratory issues,
animal models and prevalence.
CONCLUSION: The authors offer multiple solutions to help counteract
misconceptions with each scenario during clinical trial drug development.
DOI: 10.1007/s43441-019-00038-w
PMID: 32008231 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31409737 | 1. Neurology. 2019 Sep 17;93(12):e1180-e1192. doi: 10.1212/WNL.0000000000008123.
Epub 2019 Aug 13.
Patient-Reported Symptoms in Facioscapulohumeral Muscular Dystrophy
(PRISM-FSHD).
Hamel J(1), Johnson N(2), Tawil R(2), Martens WB(2), Dilek N(2), McDermott
MP(2), Heatwole C(2).
Author information:
(1)From the Department of Neurology (J.H., R.T., W.B.M., N.D., M.P.M., C.H.) and
Department of Biostatistics and Computational Biology (M.P.M.), University of
Rochester Medical Center, NY; and Department of Neurology (N.J.), Virginia
Commonwealth University, Richmond. johanna_hamel@urmc.rochester.edu.
(2)From the Department of Neurology (J.H., R.T., W.B.M., N.D., M.P.M., C.H.) and
Department of Biostatistics and Computational Biology (M.P.M.), University of
Rochester Medical Center, NY; and Department of Neurology (N.J.), Virginia
Commonwealth University, Richmond.
OBJECTIVE: To determine the frequency and relative importance of the most
meaningful symptoms in facioscapulohumeral muscular dystrophy (FSHD) and to
identify the demographic and clinical features that are associated with the
greatest disease burden in this population.
METHODS: We performed a cross-sectional study involving 328 participants with
FSHD. Collectively, participants reported the prevalence and relative importance
of 274 symptoms and 15 symptomatic themes. We assessed the association between
symptomatic theme prevalence and participants' age, sex, disease duration, pain
level, employment status, and education.
RESULTS: Participants answered >48,000 questions regarding their disease burden.
The symptomatic themes with the highest prevalence in our sample were problems
with shoulders or arms (96.9%), limitations with activities (94.7%), core
weakness (93.8%), fatigue (93.8%), limitations with mobility and walking
(93.6%), changed body image due to the disease (91.6%), and pain (87.7%).
Problems with shoulders and arms and limitations with mobility and walking had
the greatest effect on participants' lives. Employment status and the report of
pain had the most extensive association with the prevalence of symptoms, with
employment being associated with 8 of 15 of the symptomatic themes and pain
being associated with 7 of 15 of the symptomatic themes. Men and women with FSHD
experienced a similar prevalence of all symptomatic themes.
CONCLUSIONS: Adults with FSHD experience a variety of symptoms that play an
important role in their disease burden. These symptoms have a variable
prevalence and importance in the FSHD population and are associated with disease
duration, employment status, and pain level.
© 2019 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000008123
PMCID: PMC6808532
PMID: 31409737 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27530735 | 1. BMC Neurol. 2016 Aug 17;16:138. doi: 10.1186/s12883-016-0664-6.
Facioscapulohumeral dystrophy in children: design of a prospective,
observational study on natural history, predictors and clinical impact (iFocus
FSHD).
Goselink RJ(1), Schreuder TH(2), Mul K(2), Voermans NC(2), Pelsma M(3), de Groot
IJ(3), van Alfen N(2), Franck B(4), Theelen T(5), Lemmers RJ(6), Mah JK(7), van
der Maarel SM(6), van Engelen BG(2), Erasmus CE(2).
Author information:
(1)Department of Neurology, Donders Center for Neuroscience, Radboud University
Medical Center, Nijmegen, The Netherlands. Rianne.Goselink@radboudumc.nl.
(2)Department of Neurology, Donders Center for Neuroscience, Radboud University
Medical Center, Nijmegen, The Netherlands.
(3)Department of Rehabilitation, Donders Center for Neuroscience, Radboud
University Medical Center, Nijmegen, The Netherlands.
(4)Department of Clinical audiology, Radboud University Medical Center,
Nijmegen, The Netherlands.
(5)Department of Op Ophthalmology, Radboud University Medical Center, Nijmegen,
The Netherlands.
(6)Department of Human Genetics, Leiden University Medical Center, Leiden, The
Netherlands.
(7)Department of Paediatric Neurology, Alberta Children's Hospital, Calgary,
Canada.
BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD; OMIM 158900 & 158901)
is a progressive skeletal muscle dystrophy, characterized by an autosomal
dominant inheritance pattern. One of the major unsolved questions in FSHD is the
marked clinical heterogeneity, ranging from asymptomatic individuals to severely
affected patients with an early onset. An estimated 10% of FSHD patients have an
early onset (onset before 10 years of age) and are traditionally classified as
infantile FSHD. This subgroup is regarded as severely affected and
extra-muscular symptoms, such as hearing loss and retinopathy, are frequently
described. However, information on the prevalence, natural history and clinical
management of early onset FSHD is currently lacking, thereby hampering adequate
patient counselling and management. Therefore, a population-based prospective
cohort study on FSHD in children is highly needed.
METHODS/DESIGN: This explorative study aims to recruit all children (aged 0-17
years) with a genetically confirmed diagnosis of FSHD in The Netherlands. The
children will be assessed at baseline and at 2-year follow-up. The general aim
of the study is the description of the clinical features and genetic
characteristics of this paediatric cohort. The primary outcome is the motor
function as measured by the Motor Function Measure. Secondary outcomes include
quantitative and qualitative description of the clinical phenotype, muscle
imaging, genotyping and prevalence estimations. The ultimate objective will be a
thorough description of the natural history, predictors of disease severity and
quality of life in children with FSHD.
DISCUSSION: The results of this population-based study are vital for adequate
patient management and clinical trial-readiness. Furthermore, this study is
expected to provide additional insight in the epigenetic and environmental
disease modifying factors. In addition to improve counselling, this could
contribute to unravelling the aetiology of FSHD.
TRIAL REGISTRATION: clinicaltrials.gov NCT02625662.
DOI: 10.1186/s12883-016-0664-6
PMCID: PMC4988042
PMID: 27530735 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22796148 | 1. Free Radic Biol Med. 2012 Sep 1;53(5):1068-79. doi:
10.1016/j.freeradbiomed.2012.06.041. Epub 2012 Jul 11.
Functional muscle impairment in facioscapulohumeral muscular dystrophy is
correlated with oxidative stress and mitochondrial dysfunction.
Turki A(1), Hayot M, Carnac G, Pillard F, Passerieux E, Bommart S, Raynaud de
Mauverger E, Hugon G, Pincemail J, Pietri S, Lambert K, Belayew A, Vassetzky Y,
Juntas Morales R, Mercier J, Laoudj-Chenivesse D.
Author information:
(1)Université Montpellier 1 et Université Montpellier 2, INSERM, U1046,
Montpellier, F-34000, France.
Facioscapulohumeral muscular dystrophy (FSHD), the most frequent muscular
dystrophy, is an autosomal dominant disease. In most individuals with FSHD,
symptoms are restricted to muscles of the face, arms, legs, and trunk. FSHD is
genetically linked to contractions of the D4Z4 repeat array causing activation
of several genes. One of these maps in the repeat itself and expresses the DUX4
(the double homeobox 4) transcription factor causing a gene deregulation
cascade. In addition, analyses of the RNA or protein expression profiles in
muscle have indicated deregulations in the oxidative stress response. Since
oxidative stress affects peripheral muscle function, we investigated
mitochondrial function and oxidative stress in skeletal muscle biopsies and
blood samples from patients with FSHD and age-matched healthy controls, and
evaluated their association with physical performances. We show that
specifically, oxidative stress (lipid peroxidation and protein carbonylation),
oxidative damage (lipofuscin accumulation), and antioxidant enzymes (catalase,
copper-zinc-dependent superoxide dismutase, and glutathione reductase) were
higher in FSHD than in control muscles. FSHD muscles also presented abnormal
mitochondrial function (decreased cytochrome c oxidase activity and reduced ATP
synthesis). In addition, the ratio between reduced (GSH) and oxidized
glutathione (GSSG) was strongly decreased in all FSHD blood samples as a
consequence of GSSG accumulation. Patients with FSHD also had reduced systemic
antioxidative response molecules, such as low levels of zinc (a SOD cofactor),
selenium (a GPx cofactor involved in the elimination of lipid peroxides), and
vitamin C. Half of them had a low ratio of gamma/alpha tocopherol and higher
ferritin concentrations. Both systemic oxidative stress and mitochondrial
dysfunction were correlated with functional muscle impairment. Mitochondrial ATP
production was significantly correlated with both quadriceps endurance (T(LimQ))
and maximal voluntary contraction (MVC(Q)) values (rho=0.79, P=0.003; rho=0.62,
P=0.05, respectively). The plasma concentration of oxidized glutathione was
negatively correlated with the T(LimQ), MVC(Q) values, and the 2-min walk
distance (MWT) values (rho=-0.60, P=0.03; rho=-0.56, P=0.04; rho=-0.93,
P<0.0001, respectively). Our data characterized oxidative stress in patients
with FSHD and demonstrated a correlation with their peripheral skeletal muscle
dysfunction. They suggest that antioxidants that might modulate or delay
oxidative insult may be useful in maintaining FSHD muscle functions.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.freeradbiomed.2012.06.041
PMID: 22796148 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10864616 | 1. J Neurol Neurosurg Psychiatry. 2000 Jul;69(1):114-6. doi:
10.1136/jnnp.69.1.114.
Extension of the clinical range of facioscapulohumeral dystrophy: report of six
cases.
van der Kooi AJ(1), Visser MC, Rosenberg N, van den Berg-Vos R, Wokke JH, Bakker
E, de Visser M.
Author information:
(1)Department of Neurology, Academic Medical Center, University of Amsterdam,
The Netherlands. a.j.kooi@amc.uva.nl
Consensual diagnostic criteria for facioscapulohumeral dystrophy (FSHD) include
onset of the disease in facial or shoulder girdle muscles, facial weakness in
more than 50% of affected family members, autosomal dominant inheritance in
familial cases, and evidence of myopathic disease in at least one affected
member without biopsy features specific to alternative diagnoses. Six patients
did not meet most of these criteria but were diagnosed as FSHD by DNA testing,
which showed small EcoRI fragments on chromosome 4q. Their clinical signs and
symptoms and results of auxiliary investigations are reported. The patients
presented with foot extensor, thigh, or calf muscle weakness. None of them had
apparent facial weakness, only one complained of weakness in the shoulders, none
had a positive family history. Expert physical examination, however, showed a
typical facial expression, an abnormal shoulder configuration on lifting the
arms, or scapular winging. This raised the suspicion of FSHD, whereupon DNA
analysis was done. In conclusion, the clinical expression of FSHD is much
broader than indicated by the nomenclature. The possibility to perform DNA tests
is likely to greatly expand the clinical range of FSHD.
DOI: 10.1136/jnnp.69.1.114
PMCID: PMC1737027
PMID: 10864616 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33096728 | 1. Int J Mol Sci. 2020 Oct 21;21(20):7783. doi: 10.3390/ijms21207783.
Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review.
Chen TH(1)(2)(3), Wu YZ(2), Tseng YH(2).
Author information:
(1)Section of Neurobiology, Department of Biological Sciences, University of
Southern California, Los Angeles, CA 90089, USA.
(2)Department of Pediatrics, Division of Pediatric Emergency, Kaohsiung Medical
University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
(3)School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical
University, Kaohsiung 80708, Taiwan.
Facioscapulohumeral muscular dystrophy (FSHD)-the worldwide third most common
inherited muscular dystrophy caused by the heterozygous contraction of a 3.3 kb
tandem repeat (D4Z4) on a chromosome with a 4q35 haplotype-is a progressive
genetic myopathy with variable onset of symptoms, distribution of muscle
weakness, and clinical severity. While much is known about the clinical course
of adult FSHD, data on the early-onset infantile phenotype, especially on the
progression of the disease, are relatively scarce. Contrary to the classical
form, patients with infantile FSHD more often have a rapid decline in muscle
wasting and systemic features with multiple extramuscular involvements. A rough
correlation between the phenotypic severity of FSHD and the D4Z4 repeat size has
been reported, and the majority of patients with infantile FSHD obtain a very
short D4Z4 repeat length (one to three copies, EcoRI size 10-14 kb), in contrast
to the classical, slowly progressive, form of FSHD (15-38 kb). With the
increasing identifications of case reports and the advance in genetic
diagnostics, recent studies have suggested that the infantile variant of FSHD is
not a genetically separate entity but a part of the FSHD spectrum. Nevertheless,
many questions about the clinical phenotype and natural history of infantile
FSHD remain unanswered, limiting evidence-based clinical management. In this
review, we summarize the updated research to gain insight into the clinical
spectrum of infantile FSHD and raise views to improve recognition and
understanding of its underlying pathomechanism, and further, to advance novel
treatments and standard care methods.
DOI: 10.3390/ijms21207783
PMCID: PMC7589635
PMID: 33096728 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23785297 | 1. PLoS Genet. 2013 Jun;9(6):e1003550. doi: 10.1371/journal.pgen.1003550. Epub
2013 Jun 13.
Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications
for the pathogenesis of facioscapulohumeral dystrophy.
Caruso N(1), Herberth B, Bartoli M, Puppo F, Dumonceaux J, Zimmermann A, Denadai
S, Lebossé M, Roche S, Geng L, Magdinier F, Attarian S, Bernard R, Maina F, Levy
N, Helmbacher F.
Author information:
(1)Aix-Marseille Université, CNRS, IBDML UMR 7288, Parc Scientifique de Luminy,
Case 907, Marseille, France.
Generation of skeletal muscles with forms adapted to their function is essential
for normal movement. Muscle shape is patterned by the coordinated polarity of
collectively migrating myoblasts. Constitutive inactivation of the protocadherin
gene Fat1 uncoupled individual myoblast polarity within chains, altering the
shape of selective groups of muscles in the shoulder and face. These shape
abnormalities were followed by early onset regionalised muscle defects in adult
Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre
reproduced muscle shape defects in limb but not face muscles, indicating a
cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly,
the topography of muscle abnormalities caused by Fat1 loss-of-function resembles
that of human patients with facioscapulohumeral dystrophy (FSHD). FAT1 lies near
the critical locus involved in causing FSHD, and Fat1 mutant mice also show
retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal
inner ear patterning, predictive of deafness, reminiscent of another burden of
FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was
observed in foetal FSHD1 cases. CGH array-based studies identified deletion
polymorphisms within a putative regulatory enhancer of FAT1, predictive of
tissue-specific depletion of FAT1 expression, which preferentially segregate
with FSHD. Our study identifies FAT1 as a critical determinant of muscle form,
misregulation of which associates with FSHD.
DOI: 10.1371/journal.pgen.1003550
PMCID: PMC3681729
PMID: 23785297 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/34964760 | 1. Medicine (Baltimore). 2021 Nov 24;100(47):e27907. doi:
10.1097/MD.0000000000027907.
A pediatric case report and literature review of facioscapulohumeral muscular
dystrophy type1.
Xiao T(1), Yang H(2), Gan S(2), Wu L(2).
Author information:
(1)Department of Pediatric Neurology, Xiangya Hospital, Central South
University, Changsha, Hunan, PR China.
(2)Department of Pediatric Neurology, Hunan Children's Hospital, Changsha,
Hunan, PR China.
RATIONALE: Early-onset facioscapulohumeral muscular dystrophy (FSHD) is defined
as facial weakness before the age of 5 and shoulder weakness before the age of
10. Early-onset facioscapulohumeral muscular dystrophy is relatively rare in the
clinic. This onset is relatively early, the symptoms are serious, and it is
likely to be accompanied by retinal vascular disease, sensorineural deafness,
epilepsy and other extramuscular multisystem diseases. We report the clinical
characteristics of 2 patients with early-onset facial and shoulder brachial
muscular dystrophy to improve clinicians' understanding of this particular
condition.
PATIENT CONCERNS: We report 2 pediatric patients with FSHD type 1. Patient 1 is
an 11-year-old boy with reduced facial expression for 9 years and proximal
muscle weakness for 6 years. Patient 2 is a 4-year and 6-month-old girl with
developmental delay for 3 years and facial weakness for 1 year.
DIAGNOSIS: According to the clinical manifestations and molecular genetic
testing (such as Southern blot analysis), the patients were diagnosed with
early-onset FSHD1.
INTERVENTIONS: The patients received cocktail therapy (vitamin B1 tablets,
vitamin B2 tablets, vitamin B6 tablets, vitamin C tablets, vitamin E tablets,
idebenone tablets, etc.) to improve their muscle metabolism.
OUTCOMES: Both patients' condition did not improve after being given cocktail
treatment. According to a recent follow-up, the symptoms of facial weakness and
proximal muscle weakness were aggravated.
LESSONS: Early-onset FSHD presents early and has frequent systemic features, and
it is a severe subtype of FSHD. Early identification and genetic diagnosis
should be performed to improve patient prognosis.
Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.
DOI: 10.1097/MD.0000000000027907
PMCID: PMC8615324
PMID: 34964760 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no conflicts of interests to
disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/11353419 | 1. Muscle Nerve. 2001 Mar;24(3):352-6. doi:
10.1002/1097-4598(200103)24:3<352::aid-mus1005>3.0.co;2-m.
Unusual clinical presentations in patients harboring the facioscapulohumeral
dystrophy 4q35 deletion.
Felice KJ(1), Moore SA.
Author information:
(1)Department of Neurology, University of Connecticut School of Medicine,
Farmington, Connecticut 06035-1840, USA. felice@nso.uchc.edu
Facioscapulohumeral dystrophy (FSHD) is a dominantly inherited myopathy usually
associated with a deletion at locus 4q35. Typically, FSHD patients present with
a recognizable constellation of signs including weakness of facial, shoulder and
pelvic girdle, humeral, and anterior foreleg muscles; preservation of some
muscles including the deltoids; and other characteristic features including
prominent scapular winging, anterior axillary folds, and horizontally positioned
clavicles. We performed clinical and FSHD genetic studies on four patients with
atypical clinical features who were cared for at a regional neuromuscular
center. The four patients, each harboring 4q35 deletions, presented with
atypical phenotypes including facial-sparing scapular myopathy, limb-girdle
muscular dystrophy, distal myopathy, and asymmetric brachial weakness. This
report demonstrates the expanding clinical heterogeneity in patients harboring
the 4q35 deletion.
Copyright 2001 John Wiley & Sons, Inc.
DOI: 10.1002/1097-4598(200103)24:3<352::aid-mus1005>3.0.co;2-m
PMID: 11353419 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32278354 | 1. Skelet Muscle. 2020 Apr 11;10(1):8. doi: 10.1186/s13395-020-00227-4.
Transgenic mice expressing tunable levels of DUX4 develop characteristic
facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity.
Jones TI(1), Chew GL(2)(3)(4), Barraza-Flores P(1), Schreier S(1), Ramirez M(1),
Wuebbles RD(1), Burkin DJ(1), Bradley RK(2)(3), Jones PL(5).
Author information:
(1)Department of Pharmacology, School of Medicine, University of Nevada, Reno,
Reno, NV, 89557, USA.
(2)Computational Biology Program, Public Health Sciences Division, Fred
Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
(3)Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA,
98109, USA.
(4)Current Address: The Cancer Science Institute of Singapore, National
University of Singapore, Singapore, Singapore.
(5)Department of Pharmacology, School of Medicine, University of Nevada, Reno,
Reno, NV, 89557, USA. peterjones@med.unr.edu.
BACKGROUND: All types of facioscapulohumeral muscular dystrophy (FSHD) are
caused by the aberrant activation of the somatically silent DUX4 gene, the
expression of which initiates a cascade of cellular events ultimately leading to
FSHD pathophysiology. Typically, progressive skeletal muscle weakness becomes
noticeable in the second or third decade of life, yet there are many individuals
who are genetically FSHD but develop symptoms much later in life or remain
relatively asymptomatic throughout their lives. Conversely, FSHD may clinically
present prior to 5-10 years of age, ultimately manifesting as a severe
early-onset form of the disease. These phenotypic differences are thought to be
due to the timing and levels of DUX4 misexpression.
METHODS: FSHD is a dominant gain-of-function disease that is amenable to
modeling by DUX4 overexpression. We have recently created a line of conditional
DUX4 transgenic mice, FLExDUX4, that develop a myopathy upon induction of human
DUX4-fl expression in skeletal muscle. Here, we use the FLExDUX4 mouse crossed
with the skeletal muscle-specific and tamoxifen-inducible line ACTA1-MerCreMer
to generate a highly versatile bi-transgenic mouse model with chronic, low-level
DUX4-fl expression and cumulative mild FSHD-like pathology that can be
reproducibly induced to develop more severe pathology via tamoxifen induction of
DUX4-fl in skeletal muscles.
RESULTS: We identified conditions to generate FSHD-like models exhibiting
reproducibly mild, moderate, or severe DUX4-dependent pathophysiology and
characterized progression of pathology. We assayed DUX4-fl mRNA and protein
levels, fitness, strength, global gene expression, and histopathology, all of
which are consistent with an FSHD-like myopathic phenotype. Importantly, we
identified sex-specific and muscle-specific differences that should be
considered when using these models for preclinical studies.
CONCLUSIONS: The ACTA1-MCM;FLExDUX4 bi-transgenic mouse model has mild FSHD-like
pathology and detectable muscle weakness. The onset and progression of more
severe DUX4-dependent pathologies can be controlled via tamoxifen injection to
increase the levels of mosaic DUX4-fl expression, providing consistent and
readily screenable phenotypes for assessing therapies targeting DUX4-fl mRNA
and/or protein and are useful to investigate certain conserved downstream
FSHD-like pathophysiology. Overall, this model supports that DUX4 expression
levels in skeletal muscle directly correlate with FSHD-like pathology by
numerous metrics.
DOI: 10.1186/s13395-020-00227-4
PMCID: PMC7149937
PMID: 32278354 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/31025273 | 1. Sleep Breath. 2019 Sep;23(3):899-906. doi: 10.1007/s11325-019-01843-1. Epub
2019 Apr 26.
Sleep-related breathing disorders in facioscapulohumeral dystrophy.
Runte M(#)(1), Spiesshoefer J(#)(1), Heidbreder A(1), Dreher M(2), Young P(3),
Brix T(4), Boentert M(5).
Author information:
(1)Department of Neurology, University Hospital Muenster,
Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
(2)Department of Pneumology and Intensive Care Medicine, University Hospital
RWTH Aachen, Aachen, Germany.
(3)Medical Park Klinik Reithofpark, Neurology, Bad Feilnbach, Germany.
(4)Institute of Medical Informatics, University of Muenster, Muenster, Germany.
(5)Department of Neurology, University Hospital Muenster,
Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.
matthias.boentert@ukmuenster.de.
(#)Contributed equally
Comment in
Sleep Breath. 2020 Jun;24(2):603-604. doi: 10.1007/s11325-019-01991-4.
Sleep Breath. 2020 Jun;24(2):675-676. doi: 10.1007/s11325-019-01992-3.
PURPOSE: Severe manifestations of facioscapulohumeral dystrophy (FSHD) may be
associated with sleep-disordered breathing (SDB), including obstructive sleep
apnea (OSA) and nocturnal hypoventilation (NH), but prevalence data are scarce.
In patients with respiratory muscle weakness, detection of NH can be facilitated
by transcutaneous capnometry, but respective data derived from FSHD patients
have not yet been published.
METHODS: We collected sleep studies and capnometry recordings from 31 adult
patients with genetically confirmed FSHD who were admitted to our sleep
laboratory for first-ever evaluation of sleep-related breathing. Indications for
admission included non-restorative sleep, morning headache, or excessive daytime
sleepiness. In addition, sleep studies were initiated if symptoms or signs of
respiratory muscle weakness were present. Thirty-one subjects with insomnia
served as controls for comparison of respiratory measures during sleep.
RESULTS: In the FSHD group, 17/31 (55%) patients showed OSA and 8 (26%) had NH.
NH would have been missed in 7/8 patients if only oximetry criteria of
hypoventilation had been applied. Capnography results were correlated with
disease severity as reflected by the Clinical Severity Score (CSS). Non-invasive
ventilation (NIV) was started in 6 patients with NH and 3 individuals with OSA.
Nocturnal continuous positive airway pressure was administered to 2 patients,
and positional therapy was sufficient in 4 individuals. In patients initiated on
NIV, nocturnal gas exchange already improved in the first night of treatment.
CONCLUSIONS: SDB is common in adult patients with FSHD complaining of
sleep-related symptoms. It may comprise OSA, NH, and most often, the combination
of both. Sleep-related hypercapnia is associated with disease severity.
Transcutaneous capnometry is superior to pulse oximetry for detection of NH.
DOI: 10.1007/s11325-019-01843-1
PMID: 31025273 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34559225 | 1. Hum Mol Genet. 2022 Mar 3;31(5):748-760. doi: 10.1093/hmg/ddab250.
High-resolution breakpoint junction mapping of proximally extended D4Z4
deletions in FSHD1 reveals evidence for a founder effect.
Lemmers RJLF(1), van der Vliet PJ(1), Granado DSL(1), van der Stoep N(2),
Buermans H(1), van Schendel R(1), Schimmel J(1), de Visser M(3), van Coster
R(4), Jeanpierre M(5), Laforet P(6), Upadhyaya M(7), van Engelen B(8), Sacconi
S(9), Tawil R(10), Voermans NC(8), Rogers M(7), van der Maarel SM(1).
Author information:
(1)Department of Human Genetics, Leiden University Medical Center, Leiden, 2333
ZA, The Netherlands.
(2)Department of Clinical Genetics, Leiden University Medical Center, Leiden,
2333 ZA, The Netherlands.
(3)Department of Neurology, Academic Medical Center, Amsterdam, 1105 AZ, The
Netherlands.
(4)Department of Pediatrics Neurology, Ghent University Hospital, Ghent, 9000,
Belgium.
(5)APHP-Hôpitaux de Paris, Université de Paris, Paris, 75400, France.
(6)Neurology Department, Raymond-Poincaré Hospital, Garches, 92380, France.
(7)Department of Medical Genetics, Cardiff University, Cardiff, CF10 3AT, UK.
(8)Department of Neurology, Donders Institute for Brain, Cognition and
Behaviour, Radboud University, Nijmegen, 6500 HB, The Netherlands.
(9)Centre de référence des Maladies neuromusculaires, Nice University Hospital,
Nice, 06000, France.
(10)Department of Neurology, University of Rochester Medical Center, Rochester,
NY, NY 14642, USA.
Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy
clinically characterized by weakness in the facial, shoulder girdle and upper a
muscles. FSHD is caused by chromatin relaxation of the D4Z4 macrosatellite
repeat, mostly by a repeat contraction, facilitating ectopic expression of DUX4
in skeletal muscle. Genetic diagnosis for FSHD is generally based on the sizing
and haplotyping of the D4Z4 repeat on chromosome 4 by Southern blotting (SB),
molecular combing or single-molecule optical mapping, which is usually straight
forward but can be complicated by atypical rearrangements of the D4Z4 repeat.
One of these rearrangements is a D4Z4 proximally extended deletion (DPED)
allele, where not only the D4Z4 repeat is partially deleted, but also sequences
immediately proximal to the repeat are lost, which can impede accurate diagnosis
in all genetic methods. Previously, we identified several DPED alleles in FSHD
and estimated the size of the proximal deletions by a complex pulsed-field gel
electrophoresis and SB strategy. Here, using the next-generation sequencing, we
have defined the breakpoint junctions of these DPED alleles at the base pair
resolution in 12 FSHD families and 4 control individuals facilitating a
PCR-based diagnosis of these DPED alleles. Our resultsshow that half of the DPED
alleles are derivates of an ancient founder allele. For some DPED alleles, we
found that genetic elements are deleted such as DUX4c, FRG2, DBE-T and myogenic
enhancers necessitating re-evaluation of their role in FSHD pathogenesis.
© The Author(s) 2021. Published by Oxford University Press. All rights reserved.
For Permissions, please email: journals.permissions@oup.com.
DOI: 10.1093/hmg/ddab250
PMCID: PMC8895739
PMID: 34559225 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36030628 | 1. Redox Biol. 2022 Oct;56:102450. doi: 10.1016/j.redox.2022.102450. Epub 2022
Aug 22.
ANT1 overexpression models: Some similarities with facioscapulohumeral muscular
dystrophy.
Arbogast S(1), Kotzur H(2), Frank C(2), Compagnone N(3), Sutra T(4), Pillard
F(5), Pietri S(6), Hmada N(1), Moussa DMA(7), Bride J(1), Françonnet S(1),
Mercier J(4), Cristol JP(4), Dabauvalle MC(2), Laoudj-Chenivesse D(8).
Author information:
(1)PhyMedExp, Université de Montpellier, INSERM, CNRS, Montpellier, France.
(2)Imaging Core Facility, Biocenter, University of Würzburg, Am Hubland, 97074,
Würzburg, Germany.
(3)Innovative Concepts in Drug Development (ICDD), Gemenos, France.
(4)PhyMedExp, Université de Montpellier, INSERM, CNRS, Montpellier, France; CHRU
de Montpellier, Montpellier, France.
(5)Sport Medicine Department, University Sport Clinic, Pierre Paul Riquet
University Hospital, Toulouse, France; Institute of Metabolic and Cardiovascular
Diseases, Joint Research Unit 1048 INSERM Adipolab Unit - Paul Sabatier
University, Toulouse, France.
(6)Aix Marseille Univ, CNRS, ICR, UMR, 7273, Marseille, France.
(7)IRMB, Univ Montpellier, INSERM (METAMONTP), Montpellier, France.
(8)PhyMedExp, Université de Montpellier, INSERM, CNRS, Montpellier, France; CHRU
de Montpellier, Montpellier, France. Electronic address:
dalila.laoudj-chenivesse@inserm.fr.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder
characterized by progressive muscle weakness. Adenine nucleotide translocator 1
(ANT1), the only 4q35 gene involved in mitochondrial function, is strongly
expressed in FSHD skeletal muscle biopsies. However, its role in FSHD is
unclear. In this study, we evaluated ANT1 overexpression effects in primary
myoblasts from healthy controls and during Xenopus laevis organogenesis. We also
compared ANT1 overexpression effects with the phenotype of FSHD muscle cells and
biopsies. Here, we report that the ANT1 overexpression-induced phenotype
presents some similarities with FSHD muscle cells and biopsies.
ANT1-overexpressing muscle cells showed disorganized morphology, altered
cytoskeletal arrangement, enhanced mitochondrial respiration/glycolysis, ROS
production, oxidative stress, mitochondrial fragmentation and ultrastructure
alteration, as observed in FSHD muscle cells. ANT1 overexpression in Xenopus
laevis embryos affected skeletal muscle development, impaired skeletal muscle,
altered mitochondrial ultrastructure and led to oxidative stress as observed in
FSHD muscle biopsies. Moreover, ANT1 overexpression in X. laevis embryos
affected heart structure and mitochondrial ultrastructure leading to cardiac
arrhythmia, as described in some patients with FSHD. Overall our data suggest
that ANT1 could contribute to mitochondria dysfunction and oxidative stress in
FSHD muscle cells by modifying their bioenergetic profile associated with ROS
production. Such interplay between energy metabolism and ROS production in FSHD
will be of significant interest for future prospects.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.redox.2022.102450
PMCID: PMC9434167
PMID: 36030628 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. |
http://www.ncbi.nlm.nih.gov/pubmed/14659411 | 1. Neuromuscul Disord. 2004 Jan;14(1):39-45. doi: 10.1016/j.nmd.2003.08.002.
Changes in motor cortex excitability in facioscapulohumeral muscular dystrophy.
Di Lazzaro V(1), Oliviero A, Tonali PA, Felicetti L, De Marco MB, Saturno E,
Pilato F, Pescatori M, Dileone M, Pasqualetti P, Ricci E.
Author information:
(1)Institute of Neurology, Università Cattolica, Largo A. Gemelli 8, Rome 00168,
Italy. vdilazzaro@rm.unicatt.it
Previous studies found that some patients with severe, early onset
facioscapulohumeral muscular dystrophy (FSHD) present epilepsy and mental
retardation. This suggests a functional involvement of central nervous system in
severe FSHD. It is unknown whether minor functional changes of central nervous
system are also present in less severe forms of FSHD. To investigate this, we
examined the excitability of neuronal networks of the motor cortex with a range
of transcranial magnetic stimulation paradigms in 20 FSHD patients with
heterogeneous clinical severity and compared the data with that from 20
age-matched healthy individuals and from 6 age-matched patients with other
muscle diseases. There was significantly less intracortical inhibition in FSHD
patients (mean responses +/- SD reduced to 58.1+/-43.5% of the test size) than
in controls (mean responses +/- SD reduced to 29.3+/-13.5% of the test size;
P=0.025) and in patients with other muscle diseases (mean responses +/-SD,
reduced to 30.6+/-11.7% of the test size; P=0.046). No significant difference
was found between the control group and patients with other muscle diseases
(P=0.970).
DOI: 10.1016/j.nmd.2003.08.002
PMID: 14659411 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23573589 | 1. Muscle Nerve Suppl. 1995;(2):S67-72.
Early onset facioscapulohumeral muscular dystrophy.
Brouwer OF(1), Padberg GW, Bakker E, Wijmenga C, Frants RR.
Author information:
(1)Department of Neurology, Leiden University, Leiden, The Netherlands.
We report 10 patients (5 familial, 5 sporadic) with facioscapulohumeral muscular
dystrophy (FSHD) with onset of facial and shoulder girdle weakness in early
infancy. They showed the same broad range of clinical signs and symptoms as can
be seen normally in FSHD. In 7 patients Southern blotting with p13E-11 was
performed which showed an abnormal EcoRI fragment (13-22 kb) in 6 of them. We
conclude that early onset FSHD does not differ from regular FSHD clinically or
genetically. However, the precise mechanisms involved in the extensive clinical
variability of the disease are still unknown.
PMID: 23573589 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1908258 | 1. No To Hattatsu. 1991 Jul;23(4):395-9.
[A case of facioscapulohumeral muscular dystrophy with infantile spasms,
sensorineural deafness and retinal vessel abnormality].
[Article in Japanese]
Akiyama C(1), Suzuki H, Nonaka I.
Author information:
(1)Department of Pediatrics, Ryokuseikai Seiikuen, Kodaira, Tokyo.
We report an 18-year-old female with facioscapulohumeral dystrophy (FSHD), who
had sensorineural deafness, retinal vessel abnormality, mental retardation, and
epilepsy. She had infantile spasms at 6 months of age. Muscle atrophy and
weakness of facial muscles were first noticed at 3 years of age. From 10 years
of age, she had rapidly progressive generalized muscle weakness especially of
facial, neck and truncal muscles with marked lordosis. Although mental
retardation is commonly complicated with FSHD, infantile spasms or epilepsy has
never been reported. Not only mental retardation but epilepsy may be one of the
central nervous system symptoms in a systemic disorder, FSHD.
PMID: 1908258 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35658005 | 1. N Engl J Med. 2022 Jul 14;387(2):120-131. doi: 10.1056/NEJMoa2204619. Epub
2022 Jun 3.
Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation.
Jänne PA(1), Riely GJ(1), Gadgeel SM(1), Heist RS(1), Ou SI(1), Pacheco JM(1),
Johnson ML(1), Sabari JK(1), Leventakos K(1), Yau E(1), Bazhenova L(1), Negrao
MV(1), Pennell NA(1), Zhang J(1), Anderes K(1), Der-Torossian H(1), Kheoh T(1),
Velastegui K(1), Yan X(1), Christensen JG(1), Chao RC(1), Spira AI(1).
Author information:
(1)From the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute
(P.A.J.), and Massachusetts General Hospital (R.S.H.) - both in Boston; the
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of
Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical
College (G.J.R.), and Perlmutter Cancer Center, New York University Langone
Health (J.K.S.), New York, and the Department of Medicine, Roswell Park
Comprehensive Cancer Center, Buffalo (E.Y.) - all in New York; the Henry Ford
Cancer Institute, Detroit (S.M.G.); the University of California Irvine School
of Medicine, Chao Family Comprehensive Cancer Center, Orange (S.-H.I.O.), the
University of California San Diego Moores Cancer Center, La Jolla (L.B.), and
Mirati Therapeutics, San Diego (K.A., H.D.-T., T.K., K.V., X.Y., J.G.C., R.C.C.)
- all in California; the Division of Medical Oncology, Department of Medicine,
University of Colorado Anschutz Medical Campus, Aurora (J.M.P.); Sarah Cannon
Research Institute at Tennessee Oncology, Nashville (M.L.J.); the Department of
Oncology, Mayo Clinic, Rochester, MN (K.L.); the University of Texas M.D.
Anderson Cancer Center, Houston (M.V.N.) and US Oncology Research, The Woodlands
(A.I.S.) - both in Texas; Cleveland Clinic Taussig Cancer Institute, Cleveland
(N.A.P.); the Division of Medical Oncology, Department of Internal Medicine, and
the Department of Cancer Biology, University of Kansas Medical Center, Kansas
City (J.Z.); and Virginia Cancer Specialists and NEXT Oncology Virginia - both
in Fairfax (A.I.S.).
Comment in
N Engl J Med. 2022 Jul 14;387(2):180-183. doi: 10.1056/NEJMe2207902.
N Engl J Med. 2022 Jul 14;387(2):184-186. doi: 10.1056/NEJMe2206831.
Nat Rev Clin Oncol. 2022 Nov;19(11):677-678. doi:
10.1038/s41571-022-00676-4.
N Engl J Med. 2022 Sep 29;387(13):1238-1239. doi: 10.1056/NEJMc2210539.
BACKGROUND: Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds
KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity
and had an acceptable adverse-event profile in the phase 1-1b part of the
KRYSTAL-1 phase 1-2 study.
METHODS: In a registrational phase 2 cohort, we evaluated adagrasib (600 mg
orally twice daily) in patients with KRASG12C -mutated non-small-cell lung
cancer (NSCLC) previously treated with platinum-based chemotherapy and
anti-programmed death 1 or programmed death ligand 1 therapy. The primary end
point was objective response assessed by blinded independent central review.
Secondary end points included the duration of response, progression-free
survival, overall survival, and safety.
RESULTS: As of October 15, 2021, a total of 116 patients with KRASG12C -mutated
NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously
received both chemotherapy and immunotherapy. Of 112 patients with measurable
disease at baseline, 48 (42.9%) had a confirmed objective response. The median
duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8),
and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As
of January 15, 2022 (median follow-up, 15.6 months), the median overall survival
was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously
treated, stable central nervous system metastases, the intracranial confirmed
objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related
adverse events occurred in 97.4% of the patients - grade 1 or 2 in 52.6% and
grade 3 or higher in 44.8% (including two grade 5 events) - and resulted in drug
discontinuation in 6.9% of patients.
CONCLUSIONS: In patients with previously treated KRASG12C -mutated NSCLC,
adagrasib showed clinical efficacy without new safety signals. (Funded by Mirati
Therapeutics; ClinicalTrials.gov number, NCT03785249.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2204619
PMID: 35658005 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35666594 | 1. Cancer Discov. 2022 Aug 5;12(8):OF1. doi: 10.1158/2159-8290.CD-NB2022-0042.
Adagrasib Response Remains Strong in NSCLC.
[No authors listed]
In the phase II KRYSTAL-1 trial, the KRASG12C inhibitor adagrasib yielded an
overall response rate of 43% and a disease control rate of 80% in patients with
previously treated KRASG12C-mutant non-small cell lung cancer. After a median
follow up of 12.9 months, overall survival was 11.7 months. The drug also shrank
brain metastases in 33% of patients who had them.
©2022 American Association for Cancer Research.
DOI: 10.1158/2159-8290.CD-NB2022-0042
PMID: 35666594 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35608481 | 1. Clin Cancer Res. 2022 Aug 2;28(15):3179-3181. doi:
10.1158/1078-0432.CCR-22-1137.
Trials, Tribunals, and Opportunities for Lung Cancer KRASG12C Brain Metastases.
Kommalapati A, Mansfield AS.
Comment on
Clin Cancer Res. 2022 Aug 2;28(15):3318-3328. doi:
10.1158/1078-0432.CCR-22-0383.
The activity of KRAS inhibitors against brain metastases is relatively
unexplored. The recent work on preclinical models and preliminary data from the
ongoing KRYSTAL-1 phase Ib clinical trial support the potential of adagrasib
(MRTX849) to penetrate the central nervous system and provide control of
KRASG12C brain metastases. See related article by Sabari et al., p. 3318.
©2022 American Association for Cancer Research.
DOI: 10.1158/1078-0432.CCR-22-1137
PMID: 35608481 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35938195 | 1. J Oncol Pharm Pract. 2023 Mar;29(2):422-430. doi: 10.1177/10781552221118848.
Epub 2022 Aug 8.
KRAS-targeted therapy in the treatment of non-small cell lung cancer.
Yun J(1), Nakagawa R(1), Tham K(1).
Author information:
(1)Pharmacy, 7284University of Washington/Fred Hutchinson Cancer Center,
Seattle, USA.
OBJECTIVE: KRAS mutations are one of the most common driver mutations in
non-small cell lung cancer. Though previously believed to be an undruggable
target, recent advances in therapeutics have seen new targeted agents against
KRAS mutations. The objective of this article is to review currently available
and upcoming KRAS-targeted treatments.
DATA SOURCES: Currently available trials examining KRAS-targeted therapy in
non-small cell lung cancer were examined by searching for the keyword "KRAS
inhibitors." The pivotal trials for sotorasib and adagrasib were reviewed for
this article.
DATA SUMMARY: Mutated KRAS can be challenging to target for a variety of
reasons. In 2021, the US Food and Drug Administration approved sotorasib for the
treatment of adult patients with locally advanced or metastatic non-small cell
lung cancer with KRAS G12C mutation as determined by a Food and Drug
Administration-approved test, who have received at least one prior systemic
therapy. A multicenter, single-group, open-label, phase 2 trial was able to
demonstrate that sotorasib was able to demonstrate objective response,
progression-free survival, and overall survival in this patient population. A
phase 3 trial comparing sotorasib to docetaxel in the subsequent-line treatment
of KRAS G12C non-small cell lung cancer is currently ongoing. There are other
KRAS-targeted agents currently under study, including adagrasib, with growing
interest in targeting KRAS downstream pathways.
CONCLUSION: Further trials need to be conducted in order to identify other
targeted agents for KRAS and the appropriate place in therapy among currently
approved treatments for non-small cell lung cancer.
DOI: 10.1177/10781552221118848
PMID: 35938195 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15189359 | 1. J Neurochem. 2004 Jun;89(6):1555-7. doi: 10.1111/j.1471-4159.2004.02544.x.
Endocannabinoids accumulate in spinal cord of SOD1 G93A transgenic mice.
Witting A(1), Weydt P, Hong S, Kliot M, Moller T, Stella N.
Author information:
(1)Department of Pharmacology, University of Washington, Seattle, WA, USA.
Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are caused by
mutations in the super oxide dismutase 1 (SOD1) gene and transgenic mice for
these mutations recapitulate many features of this devastating neurodegenerative
disease. Here we show that the amount of anandamide (AEA) and
2-arachidonoylglycerol (2-AG), two endocannabinoids that have neuroprotective
properties, increase in spinal cord of SOD1(G93A) transgenic mice. This increase
occurs in the lumbar section of spinal cords, the first section to undergo
neurodegeneration, and is significant before overt motor impairment. Our results
show that chronic neurodegeneration induced by a genetic mutation increases
endocannabinoid production possibly as part of an endogenous defense mechanism.
DOI: 10.1111/j.1471-4159.2004.02544.x
PMID: 15189359 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30509290 | 1. Mol Neurodegener. 2018 Dec 4;13(1):63. doi: 10.1186/s13024-018-0294-0.
Disease-modifying effects of metabolic perturbations in ALS/FTLD.
Jawaid A(1)(2), Khan R(3), Polymenidou M(4), Schulz PE(5).
Author information:
(1)Laboratory of Neuroepigenetics, Brain Research Institute, University of
Zurich (UZH)/ Swiss Federal Institute of Technology (ETH), Winterthurerstr. 190,
8057, Zurich, Switzerland. jawaid@hifo.uzh.ch.
(2)Syed Babar Ali School of Science and Engineering (SBASSE), Lahore University
of Management Sciences (LUMS), Lahore, Pakistan. jawaid@hifo.uzh.ch.
(3)Syed Babar Ali School of Science and Engineering (SBASSE), Lahore University
of Management Sciences (LUMS), Lahore, Pakistan.
(4)Institute of Molecular Life Sciences, University of Zurich, Zurich,
Switzerland.
(5)Department of Neurology, The McGovern Medical School of UT Health, Houston,
TX, USA.
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)
are two fatal neurodegenerative disorders with considerable clinical,
pathological and genetic overlap. Both disorders are characterized by the
accumulation of pathological protein aggregates that contain a number of
proteins, most notably TAR DNA binding protein 43 kDa (TDP-43). Surprisingly,
recent clinical studies suggest that dyslipidemia, high body mass index, and
type 2 diabetes mellitus are associated with better clinical outcomes in ALS.
Moreover, ALS and FTLD patients have a significantly lower incidence of
cardiovascular disease, supporting the idea that an unfavorable metabolic
profile may be beneficial in ALS and FTLD. The two most widely studied ALS/FTLD
models, super-oxide dismutase 1 (SOD1) and TAR DNA binding protein of 43 kDA
(TDP-43), reveal metabolic dysfunction and a positive effect of metabolic
strategies on disease onset and/or progression. In addition, molecular studies
reveal a role for ALS/FTLD-associated proteins in the regulation of cellular and
whole-body metabolism. Here, we systematically evaluate these observations and
discuss how changes in cellular glucose/lipid metabolism may result in abnormal
protein aggregations in ALS and FTLD, which may have important implications for
new treatment strategies for ALS/FTLD and possibly other neurodegenerative
conditions.
DOI: 10.1186/s13024-018-0294-0
PMCID: PMC6278047
PMID: 30509290 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: N/A.
CONSENT FOR PUBLICATION: The authors willfully consent for publication of this
article. COMPETING INTERESTS: The authors declare that they have no competing
interests. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/12402272 | 1. Ann Neurol. 2002 Nov;52(5):680-3. doi: 10.1002/ana.10369.
"True" sporadic ALS associated with a novel SOD-1 mutation.
Alexander MD(1), Traynor BJ, Miller N, Corr B, Frost E, McQuaid S, Brett FM,
Green A, Hardiman O.
Author information:
(1)Department of Neurology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland.
mikealexan@hotmail.com
Mutations in the Cu/Zn superoxide dismutase gene (SOD-1) are reported in 20% of
familial amyotrophic lateral sclerosis (ALS) cases, but no definite report of a
mutation in a "truly" sporadic case of ALS has been proved. We present the first
case of a novel SOD-1 mutation in a patient with genetically proven sporadic
ALS. This mutation (H80A) is believed to alter zinc ligand binding, and its
functional significance correlates well with the aggressive clinical course and
postmortem findings observed in this patient.
DOI: 10.1002/ana.10369
PMID: 12402272 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10624810 | 1. Neurosci Lett. 1999 Dec 3;276(2):135-7. doi: 10.1016/s0304-3940(99)00803-4.
A novel mutation (Cys6Gly) in the Cu/Zn superoxide dismutase gene associated
with rapidly progressive familial amyotrophic lateral sclerosis.
Kohno S(1), Takahashi Y, Miyajima H, Serizawa M, Mizoguchi K.
Author information:
(1)The First Department of Medicine, Hamamatsu University School of Medicine,
Japan. sato-kohno@mail.wbs.ne.jp
Autosomal-dominant familial amyotrophic lateral sclerosis (FALS) is associated
with mutation in the gene that encodes Cu/Zn superoxide dismutase (SOD1). We
identified a novel missense mutation of SOD-1 (Cys6Gly) in exon 1 in a Japanese
woman and her family. The illness showed rapid progression similarly to the FALS
with a mutation of Cys6Phe that was reported by Morita et al. (1996) (Morita,
M., Aoki, M., Abe, K., Hasegawa, T., Sakuma, R., Onodera, Y., Ichikawa, N.,
Nishizawa, M. and Itoyama, Y., A novel two-base mutation in the Cu/Zn superoxide
dismutase gene associated with familial amyotrophic lateral sclerosis in Japan.
Neurosci. Lett., 205 (1996) 79-82). Mutation of the cystein at amino acid 6
might be associated with the rapid progression of ALS.
DOI: 10.1016/s0304-3940(99)00803-4
PMID: 10624810 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24283821 | 1. Eur J Neurol. 1997 Jan;4(1):48-51. doi: 10.1111/j.1468-1331.1997.tb00298.x.
A novel mutation of SOD-1 (Gly 108 Val) in familial amyotrophic lateral
sclerosis.
Orrell RW(1), Habgood JJ, Shepherd DI, Donnai D, de Belleroche J.
Author information:
(1)Department of Biochemistry, Charing Cross and Westminster Medical School,
LondonNeuromuscular Unit, Charing Cross Hospital, LondonDepartment of Neurology,
North Manchester General Hospital, ManchesterRegional Genetic Service, St Mary's
Hospital, Manchester, UK.
A novel mutation of the SOD-1 gene which encodes the enzyme copper-zinc
superoxide dismutase was identified in a family manifesting amyotrophic lateral
sclerosis (ALS) in three generations. The mutation is a heterozygote point
mutation in exon 4, codon 108 (GGA to GTA), predicting the substitution of
valine for glycine. The mutation creates a new restriction site for the
endonuclease AccI. The mutation was demonstrated in two affected members of the
family, who show features of autosomal dominant inheritance of ALS, but variable
age at onset ranging from 48 to 72 years. Over 30 different mutations of SOD-1
have now been identified in families with ALS. The definition of the different
mutations causing human disease may allow further investigation of their
pathogenicity in transgenic animal models, and also offers insight into the
variable phenotypic disease expression both within and between genotypes.
1997 Lippincott Williams & Wilkins.
DOI: 10.1111/j.1468-1331.1997.tb00298.x
PMID: 24283821 |
http://www.ncbi.nlm.nih.gov/pubmed/11284995 | 1. Eur J Neurol. 2001 Mar;8(2):167-72. doi: 10.1046/j.1468-1331.2001.00186.x.
Sporadic ALS associated with the D90A Cu,Zn superoxide dismutase mutation in
Russia.
Skvortsova VI(1), Limborska SA, Slominsky PA, Levitskaya NI, Levitsky GN,
Shadrina MI, Kondratyeva EA.
Author information:
(1)Department of Neurology with Laboratory and Functional Diagnostics of Russian
State Medical University, Moscow. vskvor@sl.ru
Twenty blood samples from Russian patients (Moscow) with idiopathic motor
neurone disease were analysed for mutations in the Cu,Zn superoxide dismutase
(Cu,Zn SOD) gene. Two patients (10%) with the amyotrophic lateral sclerosis
(ALS) form of the disease were found to have a disease-related mutation. One
patient appears to have autosomal recessive adult-onset ALS associated with
homozygosity for D90A and presents the characteristic phenotype of very slowly
ascending paresis with both lower and upper motor neurone signs. Another
patient, heterozygous for D90A, presents ALS with lumbar onset and rapid
progression. This is the first report of a Cu,Zn SOD mutation in ALS in Russia.
DOI: 10.1046/j.1468-1331.2001.00186.x
PMID: 11284995 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10202988 | 1. J Neurol Sci. 1999 Jan 15;162(2):201-4. doi: 10.1016/s0022-510x(98)00237-8.
Heterogeneous distribution of amyotrophic lateral sclerosis patients with SOD-1
gene mutations: preliminary data on an Italian survey.
Malaspina A(1), Zaman R, Mazzini L, Camana C, Poloni E, Curti D, Ceroni M.
Author information:
(1)Institute of Neurology, Foundation Casimiro Mondino, Laboratory of
Neurogenetics, University of Pavia, Italy. rabc035@s1.cxwms.ac.uk
We report the absence of superoxide dismutase (SOD-1) gene mutations in 30
patients with amyotrophic lateral sclerosis (ALS) including individuals with a
confirmed family history of ALS (familial ALS/FALS), ALS with an unclear family
history (UFALS) and sporadic ALS (SALS). Single strand conformation polymorphism
(SSCP) and sequence analysis of the 5 SOD-1 gene exons were undertaken to
improve the accuracy of the mutation detection. Our preliminary data appear to
diverge from the results of studies by other groups using different populations.
We discuss the possible reasons for this disparity and the apparent
heterogeneous distribution of ALS with SOD-1 gene mutations among different
ethnic groups.
DOI: 10.1016/s0022-510x(98)00237-8
PMID: 10202988 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20385392 | 1. J Neurol Sci. 2010 Jun 15;293(1-2):112-5. doi: 10.1016/j.jns.2010.03.009. Epub
2010 Apr 10.
Severe familial ALS with a novel exon 4 mutation (L106F) in the SOD1 gene.
Battistini S(1), Ricci C, Lotti EM, Benigni M, Gagliardi S, Zucco R, Bondavalli
M, Marcello N, Ceroni M, Cereda C.
Author information:
(1)Department of Neuroscience, University of Siena, Siena, Italy.
battistinis@unisi.it
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease associated
with a positive familial history in 5-10% of ALS cases. Mutations in the
superoxide dismutase-1 (SOD1) gene have been found in 12%-23% of patients
diagnosed with familial ALS. Here we report a novel mutation in exon 4 of SOD1
gene in a 55-year-old ALS patient belonging to a large Italian family with ALS
first clinically described in 1968. In the family the clinical presentation was
characterized by relatively early age of onset, spinal onset with proximal
distribution weakness, bulbar involvement and a rapid disease course. Molecular
analysis showed a heterozygous mutation at codon 106 resulting in a substitution
of phenylalanine for leucine in the SOD1 protein (L106F). In analogy with the
previously reported L106V mutation, we propose that the L106F causes a relevant
destabilization of the protein chain around the mutation site, able to affect
the SOD1 monomer and dimer structures suggesting a pathogenic role for this
novel mutation.
Copyright 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jns.2010.03.009
PMID: 20385392 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9455977 | 1. J Neurol Sci. 1997 Dec 9;153(1):46-9. doi: 10.1016/s0022-510x(97)00181-0.
Familial ALS is associated with mutations in all exons of SOD1: a novel mutation
in exon 3 (Gly72Ser).
Orrell RW(1), Marklund SL, deBelleroche JS.
Author information:
(1)Department of Biochemistry, Charing Cross and Westminster Medical School,
Charing Cross Hospital, London, UK. rorrell@mail.neurology.rochester.edu
Mutations of the SOD1 gene, which encodes the enzyme copper/zinc superoxide
dismutase, are associated with familial amyotrophic lateral sclerosis (ALS).
SOD1 consists of five exons, and over 50 different mutations have been described
involving exons 1,2,4 and 5. The absence of mutations in exon 3 has been
attributed to a critical function of this exon, its integrity being necessary
for the toxic effect of mutant SOD1, and it has been suggested that such
mutations may be lethal rather than leading to adult onset disease. We
identified the heterozygote mutation Gly72Ser (exon 3) in a family with two
individuals affected by ALS. SOD enzyme activity was reduced by 45% when
measured in erythrocytes indicating reduced enzyme activity, or reduced
stability of the mutant protein. These findings indicate that exon 3 is not a
privileged region from mutation; that all five exons should be investigated when
seeking SOD1 mutations in human disease; and may help in a better understanding
of the pathogenicity of these mutations in ALS.
DOI: 10.1016/s0022-510x(97)00181-0
PMID: 9455977 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27297615 | 1. Neurobiol Aging. 2016 Sep;45:212.e1-212.e4. doi:
10.1016/j.neurobiolaging.2016.04.021. Epub 2016 May 3.
A novel 10-base pair insertion mutation in exon 5 of the SOD1 gene in a Chinese
family with amyotrophic lateral sclerosis.
Chen S(1), Li M(1), Zhu W(1), Mao F(2), Wang J(2), Sun Z(3), Huang X(4).
Author information:
(1)Department of Neurology, Chinese PLA General Hospital, Beijing, China.
(2)Beijing Institutes of Life Science Chinese Academy of Science, Beijing,
China; University of Chinese Academy of Science, Beijing, China.
(3)Beijing Institutes of Life Science Chinese Academy of Science, Beijing,
China; University of Chinese Academy of Science, Beijing, China. Electronic
address: zsunusa@yahoo.com.
(4)Department of Neurology, Chinese PLA General Hospital, Beijing, China.
Electronic address: lewish301@sina.com.
Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive, fatal
neurodegenerative disease. Several genes are associated with ALS. Copper-zinc
superoxide dismutase 1 (SOD1) is one of the most commonly mutated genes in ALS,
and more than 160 mutations in SOD1 have been reported. We reported a novel
heterozygous insertion mutation that led to a frameshift and a premature
termination at position 136 in exon 5 of the SOD1 gene (c.392_393insGCAAAGGTGG;
p.N132Qfs*5) in a Chinese familial ALS pedigree. This mutation in the pedigree
demonstrated an autosomal dominant pattern of inheritance and a phenotype
characterized by an early onset (approximately 34 years old) with a relatively
rapid course (approximately 2 years) and limb onset with respiratory
involvement. The clinical feature of the p.N132Qfs*5 mutation was nearly
identical to a previously reported mutation (Gly127insTGGG). Experiments in
G127X mice demonstrated that the G127X mutation was pathogenic. SOD1 activity in
the p.N132Qfs*5 mutation carriers in the family decreased significantly compared
with normal family members. In conclusion, we identified a novel SOD1 mutation
in an ALS family, which is an important addition to the catalog of SOD1
mutations in ALS.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neurobiolaging.2016.04.021
PMID: 27297615 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7951249 | 1. Hum Mol Genet. 1994 Jun;3(6):981-7. doi: 10.1093/hmg/3.6.981.
A frequent ala 4 to val superoxide dismutase-1 mutation is associated with a
rapidly progressive familial amyotrophic lateral sclerosis.
Rosen DR(1), Bowling AC, Patterson D, Usdin TB, Sapp P, Mezey E, McKenna-Yasek
D, O'Regan J, Rahmani Z, Ferrante RJ, et al.
Author information:
(1)Day Neuromuscular Research Laboratory, Massachusetts General Hospital,
Charlestown 02129-2060.
Familial amyotrophic lateral sclerosis (FALS), a degenerative disorder of motor
neurons, is associated with mutations in the Cu/Zn superoxide dismutase gene
SOD1 in some affected families. We confirm a recently reported ala4-->val
mutation in exon 1 of the SOD1 gene and report that this mutation is both the
most commonly detected of all SOD1 mutations and among the most clinically
severe. By comparison with our other FALS families, the exon 1 mutation is
associated with reduced survival time after onset: 1.2 years, as compared to 2.5
years for all other FALS patients. We also demonstrate that SOD1 is prominently
expressed in normal motor neurons and that neural expression of SOD1 is not
prevented by this exon 1 mutation. Assays of SOD1 enzymatic activity in extracts
from red blood cells, lymphoblastoid cells, and brain tissues revealed an
approximately 50% reduction in activity of cytosolic SOD1 in patients with this
mutation compared to normal individuals. By contrast, patients with sporadic ALS
had normal levels of SOD1 enzymatic activity. Why this SOD1 mutation causes
motor neuron death in FALS remains to be established. While it may be that FALS
is a consequence of loss of SOD1 function, it is also possible that motor neuron
death in this dominantly inherited disease occurs because the mutations confer
an additional, cytotoxic function on the SOD1 protein.
DOI: 10.1093/hmg/3.6.981
PMID: 7951249 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7820674 | 1. Brain Res. 1994 Oct 3;659(1-2):272-6. doi: 10.1016/0006-8993(94)90892-3.
Copper/zinc superoxide dismutase mRNA levels are increased in sporadic
amyotrophic lateral sclerosis motorneurons.
Bergeron C(1), Muntasser S, Somerville MJ, Weyer L, Percy ME.
Author information:
(1)Centre for Research in Neurodegenerative Diseases, University of Toronto,
Ont., Canada.
Mutations of the Cu/Zn superoxide dismutase (SOD-1) gene were recently
implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS).
We measured SOD-1 mRNA levels in motorneurons of the more common sporadic form
of the disease and found a 42% increase in ALS motorneurons (P = 0.058) as
compared with controls. These results suggest that oxidative stress may also
play a role in the pathogenesis of sporadic ALS.
DOI: 10.1016/0006-8993(94)90892-3
PMID: 7820674 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9065559 | 1. Neurology. 1997 Mar;48(3):746-51. doi: 10.1212/wnl.48.3.746.
Clinical and functional investigation of 10 missense mutations and a novel
frameshift insertion mutation of the gene for copper-zinc superoxide dismutase
in UK families with amyotrophic lateral sclerosis.
Orrell RW(1), Habgood JJ, Gardiner I, King AW, Bowe FA, Hallewell RA, Marklund
SL, Greenwood J, Lane RJ, deBelleroche J.
Author information:
(1)Department of Biochemistry, Charing Cross and Westminster Medical School,
London, England.
Mutations of the gene SOD-1, which encodes the enzyme copper-zinc superoxide
dismutase, occur in patients with a familial form of amyotrophic lateral
sclerosis (ALS). We investigated 71 families with more than one individual
affected by ALS for clinical features and SOD-1 mutations. Mutations were
identified in 14 families, indicating the presence of SOD-1 mutations in around
20% of this population. There were 10 different heterozygote missense point
mutations in eight different codons, and a novel two-base frameshift insertion
(132insTT), which leads to substitution of aspartic acid for glutamic acid at
codon 132, and a premature stop codon at 133, with predicted truncation of the
protein. SOD enzyme activity was reduced to around 50% of normal in individuals
with SOD-1 mutations, and may be a useful predictor for the presence of these
mutations. A predilection for disease onset in the lower limbs appears to be a
distinguishing feature of familial ALS with SOD-1 mutations, and accords with
findings in transgenic mouse models. In general, the finding of an SOD-1
mutation does not accurately predict a prognosis or disease severity.
DOI: 10.1212/wnl.48.3.746
PMID: 9065559 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9506558 | 1. Ann Neurol. 1998 Mar;43(3):390-4. doi: 10.1002/ana.410430319.
Mutations in all five exons of SOD-1 may cause ALS.
Shaw CE(1), Enayat ZE, Chioza BA, Al-Chalabi A, Radunovic A, Powell JF, Leigh
PN.
Author information:
(1)Department of Clinical Neurosciences, Institute of Psychiatry and King's
College School of Medicine and Dentistry, London, United Kingdom.
Eight of 38 patients (21%) with familial and 5 of 175 patients (3%) with
sporadic amyotrophic lateral sclerosis (ALS) had missense mutations in the SOD-1
gene. Two novel mutations were identified. One in exon 4 substituting leucine
with phenylalanine (L84F) in a familial patient and the second in exon 3 at
substituting glycine with serine (G72S) in an "apparently" sporadic patient.
Over 60 point mutations have now been described in all five exons of SOD-1,
involving 43 of the 153 residues. Hypotheses about the toxic role of mutant
SOD-1 in the pathogenesis of ALS must account for this molecular diversity.
DOI: 10.1002/ana.410430319
PMID: 9506558 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7917302 | 1. Neuron. 1994 Sep;13(3):727-36. doi: 10.1016/0896-6273(94)90039-6.
Analysis of the functional effects of a mutation in SOD1 associated with
familial amyotrophic lateral sclerosis.
Tsuda T(1), Munthasser S, Fraser PE, Percy ME, Rainero I, Vaula G, Pinessi L,
Bergamini L, Vignocchi G, McLachlan DR, et al.
Author information:
(1)Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Mutations in the Cu, Zn superoxide dismutase (SOD1) gene have been reported in
some pedigrees with Familial Amyotrophic Lateral Sclerosis (FALS). We have
investigated the functional and structural effects of a Gly-->Ser mutation at
codon 41 of SOD1 in a pedigree with FALS and the topography of SOD1 expression
in the mammalian CNS. These analyses show that the 41Gly-->Ser mutation causes a
27% reduction in Cu, Zn SOD activity. SOD1 is transcribed at high levels in rat
motoneurons and four other types of neurons homologous to upper motoneurons that
degenerate in human ALS. However, SOD1 is transcribed at lower levels in other
types of neurons, such as cerebellar Purkinje cells, which are not usually
involved significantly in human ALS. On the other hand, immunocytochemical
studies indicate that most types of rat neurons contain similar levels of Cu, Zn
SOD immunoreactive protein. Nevertheless, these results suggest that the
essential feature causing this subtype of ALS is either a reduction in Cu, Zn
SOD activity in cell types that presumably critically require Cu, Zn SOD for
protection against oxidative damage or the fact that the mutation in SOD1
associated with FALS results in a novel gain of function that is particularly
deleterious to those cell types expressing SOD1 at high levels.
DOI: 10.1016/0896-6273(94)90039-6
PMID: 7917302 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11464949 | 1. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Jun;1(3):143-61. doi:
10.1080/14660820050515151.
Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic
lateral sclerosis.
Shibata N(1), Hirano A, Yamamoto T, Kato Y, Kobayashi M.
Author information:
(1)Department of Pathology, Tokyo Women's Medical University, Japan.
shibatan@research.twmu.ac.jp
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder
characterized by motor neuron system involvement, and is epidemiologically
subclassified into sporadic, familial and endemic forms. About 20% of ALS
families are associated with mutations in the gene for superoxide dismutase-1
(SOD1) encoded on chromosome 21q22.1. Several studies have pointed to a variety
of functions of mutant SOD1, which has enhanced catalytic activity of the
peroxynitrite-mediated tyrosine nitration, readily releases the reactive Cu
ions, induces apoptotic cell death, has enhanced peroxidase activity, damages
the mitochondria to release Ca2+, and forms SOD1-containing aggregates in the
cytoplasm. Many of these studies have obtained evidence for increased oxidative
damage in ALS. On the other hand, some reports disagree with oxidative damage
involvement in SOD1 mutant ALS. In considering the findings of increased
oxidative damage in mutant SOD1-expressing transgenic mice, it should be
remembered that overexpression of mutant SOD1 may enhance oxidative stress
generation from this enzyme. In this review, we present the clinicopathological
features of SOD1 mutant familial ALS and its transgenic mouse model, and also
discuss SOD1 mutation-related neurotoxicity, including SOD1 protein aggregation
and post-translational protein modification.
DOI: 10.1080/14660820050515151
PMID: 11464949 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8446170 | 1. Nature. 1993 Mar 4;362(6415):59-62. doi: 10.1038/362059a0.
Mutations in Cu/Zn superoxide dismutase gene are associated with familial
amyotrophic lateral sclerosis.
Rosen DR(1), Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson
D, Goto J, O'Regan JP, Deng HX, et al.
Author information:
(1)Day Neuromuscular Research Laboratory, Massachusetts General Hospital,
Charlestown 02129.
Erratum in
Nature. 1993 Jul 22;364(6435):362. doi: 10.1038/364362c0.
Comment in
Nature. 1993 Mar 4;362(6415):20-1. doi: 10.1038/362020a0.
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons
in the cortex, brainstem and spinal cord. Its cause is unknown and it is
uniformly fatal, typically within five years. About 10% of cases are inherited
as an autosomal dominant trait, with high penetrance after the sixth decade. In
most instances, sporadic and autosomal dominant familial ALS (FALS) are
clinically similar. We have previously shown that in some but not all FALS
pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8,
9). Here we report tight genetic linkage between FALS and a gene that encodes a
cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric
metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.-
to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free
radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a
candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13
different FALS families.
DOI: 10.1038/362059a0
PMID: 8446170 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23954173 | 1. Neurobiol Aging. 2014 Jan;35(1):266.e1-4. doi:
10.1016/j.neurobiolaging.2013.07.012. Epub 2013 Aug 15.
Novel SOD1 mutation p.V31A identified with a slowly progressive form of
amyotrophic lateral sclerosis.
Dangoumau A(1), Verschueren A, Hammouche E, Papon MA, Blasco H, Cherpi-Antar C,
Pouget J, Corcia P, Andres CR, Vourc'h P.
Author information:
(1)UMR INSERM U930, Université François-Rabelais, Tours, PRES Centre - Val de
Loire Université, France.
The SOD1 gene encoding the superoxide dismutase 1 (SOD1) protein is mutated in
approximately 15% of familial amyotrophic lateral sclerosis (ALS) and 3% of
sporadic ALS. We identified a novel mutation in SOD1 in a man who presented at
age 49 with lower limb stiffness, and at age 53, a spastic paraparesia with
distal muscular atrophy in the lower limbs and fasciculations in the quadriceps.
A diagnosis of ALS was established. Eleven years after disease onset his
condition continues gradually and slowly to deteriorate. The heterozygous
mutation observed in exon 2 resulted in a valine to alanine substitution at
position 31 in the β-barrel domain of the SOD1 protein. Functional analysis in
NSC34 cells showed that the overexpression of the mutant form of SOD1(V31A)
induced aggregates and decreased cell viability. This mutation is located
outside of the regions carrying most of the ALS-related mutations (i.e., the
catalytic center, the region of dimerization, and the loops between the
β-strands of the β-barrel). In conclusion, we identified a novel SOD1 mutation
in a patient with slow disease progression and supported the idea that different
SOD1 mutations can lead to distinct ALS phenotypes.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neurobiolaging.2013.07.012
PMID: 23954173 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27556028 | 1. Front Mol Biosci. 2016 Aug 9;3:40. doi: 10.3389/fmolb.2016.00040. eCollection
2016.
Screening of Drugs Inhibiting In vitro Oligomerization of Cu/Zn-Superoxide
Dismutase with a Mutation Causing Amyotrophic Lateral Sclerosis.
Anzai I(1), Toichi K(1), Tokuda E(1), Mukaiyama A(2), Akiyama S(2), Furukawa
Y(1).
Author information:
(1)Laboratory for Mechanistic Chemistry of Biomolecules, Department of
Chemistry, Keio University Yokohama, Japan.
(2)Research Center of Integrative Molecular Systems, Institute for Molecular
ScienceOkazaki, Japan; Department of Functional Molecular Science, SOKENDAI (The
Graduate University for Advanced Studies)Okazaki, Japan.
Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) gene have been shown to
cause a familial form of amyotrophic lateral sclerosis (SOD1-ALS). A major
pathological hallmark of this disease is abnormal accumulation of mutant SOD1
oligomers in the affected spinal motor neurons. While no effective therapeutics
for SOD1-ALS is currently available, SOD1 oligomerization will be a good target
for developing cures of this disease. Recently, we have reproduced the formation
of SOD1 oligomers abnormally cross-linked via disulfide bonds in a test tube.
Using our in vitro model of SOD1 oligomerization, therefore, we screened 640
FDA-approved drugs for inhibiting the oligomerization of SOD1 proteins, and
three effective classes of chemical compounds were identified. Those hit
compounds will provide valuable information on the chemical structures for
developing a novel drug candidate suppressing the abnormal oligomerization of
mutant SOD1 and possibly curing the disease.
DOI: 10.3389/fmolb.2016.00040
PMCID: PMC4977284
PMID: 27556028 |
http://www.ncbi.nlm.nih.gov/pubmed/15679043 | 1. Folia Neuropathol. 2004;42(4):239-48.
Transgenic models of amyotrophic lateral sclerosis.
Grieb P(1).
Author information:
(1)Department of Experimental Pharmacology, Mossakowski Medical Research Centre,
Polish Academy of Sciences, Warszawa, Poland. pgrieb@cmdik.pan.pl
Amyotrophic lateral sclerosis (ALS), the most frequent paralytic disease of
adults, is untreatable and invariably fatal. Up to 20% of ALS cases are
inherited (familial, fALS) and associated with mutations, usually of the
superoxide dismutase type 1 (SOD-1) gene. This paper shortly reviews the
background for and the use of rodent transgenic models of ALS. Silencing the
SOD-1 gene does not produce paralytic phenotype, but transgenic rodents
expressing human mutated (hm) SOD-1 atop their own enzyme develop relatively
selective and fatal degeneration of motoneurons. Many essential
neuropathological and biochemical features of the paralytic disease in hmSOD-1
transgenic mice and rats are similar to human fALS, and these animals are
currently considered a model of the human disease. Two types of hypotheses put
forward to explain pathomechanism of motoneuron degeneration in hmSOD-1
transgenics (hence also in human ALS) are the "gain of function" hypotheses
which assume that the mutated enzyme displays new toxic catalytic properties,
and the "gain of interaction" hypotheses which assume that the mutated protein
molecules are toxic because they became misfolded and undergo oligomerization.
Transgenic animal models of ALS are used for preclinical assessments of new
therapeutic approaches ranging from mono- and polipharmacotherapy to gene
therapy and stem cell therapy.
PMID: 15679043 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15079798 | 1. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2004 Apr;21(2):149-52.
[Identification of the mutation of SOD1 gene in a familial amyotrophic lateral
sclerosis].
[Article in Chinese]
Shi SG(1), Li LS, Chen KN, Liu X.
Author information:
(1)Department of Neurology, Southwest Hospital, Third Military Medical
University, Chongqing, 400038 PR China. shishg@mail.tmmu.com.cn
OBJECTIVE: To identify the mutation of Cu/Zn superoxide dismutase(SOD1) gene in
an amyotrophic lateral sclerosis (ALS) family with unique phenotype.
METHODS: Five exons of SOD1 gene were amplified by PCR. The differences of these
products were analyzed by PCR-single strand conformation polymorphism and
visualized by silver staining.
RESULTS: Abnormal bands were found in exons 2 and 5 of SOD1 gene in several
familial members. DNA sequence analysis verified that a base pair insertion
occurred in the codon area of exon 2 and in the intron area of exon 5. And the
insertion mutation of exon 2 led to a frameshift mutation and premature stop. It
is a new type of SOD1 mutation which may be associated with familial amyotrophic
lateral sclerosis.
CONCLUSION: Insertion mutation of exon 2 may be responsible for the disease of
an ALS family in Chongqing.
PMID: 15079798 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31928838 | 1. Bioorg Med Chem Lett. 2020 Feb 15;30(4):126950. doi:
10.1016/j.bmcl.2020.126950. Epub 2020 Jan 7.
Development of novel small molecules for the treatment of ALS.
Mathew B(1), Ruiz P(1), Pathak V(1), Suto MJ(2).
Author information:
(1)Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue
South, Birmingham, AL 35205, USA.
(2)Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue
South, Birmingham, AL 35205, USA. Electronic address:
msuto@southernresearch.org.
Amyotrophic lateral sclerosis (ALS) is a rare and progressive neurodegenerative
disease with unknown etiology. It is caused by the degeneration of motor neurons
responsible for controlling voluntary muscles. It has been reported that
mutations in the superoxide dismutase (SOD) 1 gene can lead to ALS. SOD1
abnormalities have been identified in both familial, as well as sporadic ALS
cases. SOD2 is a highly inducible SOD that works in conjunction with SOD1. SOD2
can be induced through activation of NF-κBs. We previously reported that the
novel small molecule, SRI-22818, increases NF-κB expression and activation and
SOD2 levels in vitro and has activity in vivo in the SOD1-G93A reference model
of ALS. We report herein the synthesis and biological evaluation of SRI-22818
analogs.
Copyright © 2020 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.bmcl.2020.126950
PMID: 31928838 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10869061 | 1. Brain. 2000 Jul;123 ( Pt 7):1505-15. doi: 10.1093/brain/123.7.1505.
Preserved slow conducting corticomotoneuronal projections in amyotrophic lateral
sclerosis with autosomal recessive D90A CuZn-superoxide dismutase mutation.
Weber M(1), Eisen A, Stewart HG, Andersen PM.
Author information:
(1)The Neuromuscular Diseases Unit, Vancouver Hospital and the University of
British Columbia, Vancouver, Canada.
Recently, a subgroup of the amyotrophic lateral sclerosis (ALS) syndrome
associated with mutations in the gene encoding the free radical scavenging
enzyme CuZn-superoxide dismutase (CuZn-SOD, SOD1) has been identified. Some 67
different mutations have been reported worldwide to date, comprising about
one-fifth of familial ALS cases in the populations studied. The autosomal
recessively inherited D90A CuZn-SOD mutation has been associated with a very
slowly progressive, clinically distinct phenotype, and is neurophysiologically
characterized by very slow central motor conduction. It is not known which
physiological and/or biochemical mechanisms are responsible for the different
clinical course. To delineate ALS associated with this particular CuZn-SOD
mutation from ALS without mutations, we performed a detailed neurophysiological
study of the corticomotoneuronal function using peristimulus time histograms
(PSTHs) in eight ALS patients homozygous for the D90A CuZn-SOD mutation. The
results were compared with those obtained in 12 non-hereditary ALS patients and
11 healthy subjects. PSTHs were constructed from three to seven different,
voluntarily recruited motor units of the extensor digitorum communis muscle
(EDC) in each patient. The onset latency, number of excess bins, duration and
synchrony of the primary peak were analysed. All measurements differed
significantly between healthy controls and the D90A patients (P < 0.0007). The
mean onset latency of the primary peak in D90A patients was 35.3 ms, compared
with 24.2 ms for non-hereditary ALS patients and 19.3 ms for normal subjects (P
< 0.0000). Delayed primary peaks in the D90A patients were desynchronized and
characteristically preceded by a marked suppression phase. This suppression
phase was not seen in non-hereditary ALS patients. We conclude that the mainly
slow conducting and/or polysynaptic corticomotoneuronal connections are
preserved in the D90A homozygous cases, and that the cortical and possibly
spinal inhibitory circuitry is preserved. These events may partially protect the
motor neurons, slowing down the degenerative process.
DOI: 10.1093/brain/123.7.1505
PMID: 10869061 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8981308 | 1. J Neurol Sci. 1996 Nov;143(1-2):118-20. doi: 10.1016/s0022-510x(96)00190-6.
Serum Cu/Zn superoxide dismutase activity is reduced in sporadic amyotrophic
lateral sclerosis patients.
Cohen O(1), Kohen R, Lavon E, Abramsky O, Steiner I.
Author information:
(1)Department of Neurology, Hadassah University Hospital, Hebrew University
Hadassah Medical School, Jerusalem, Israel.
Comment in
J Neurol Sci. 1997 Nov 25;152(2):226, 229.
Accumulated evidence implies that mutations in the gene coding for Cu/Zn
superoxide dismutase (SOD) are associated with the pathogenesis of the familial
form of amyotrophic lateral sclerosis (ALS). The clinical and pathological
similarities of the familial and the sporadic forms of the disease may suggest
that abnormal SOD activity takes also part in the pathogenesis of sporadic ALS.
We therefore measured serum SOD activity in fifteen sporadic ALS patients. Mean
serum SOD activity was 1.15 +/- 0.40 u/ml in ALS patients, 1.50 +/- 0.45 u/ml.
in patients with other neurological disorders and 1.45 +/- 0.45 u/ml in.healthy
controls (p < 0.021 and p < 0.031 respectively). If this sporadic ALS-related
reduction in serum SOD activity will be confirmed in the diseased nervous system
tissue, it may suggest that abnormal SOD activity is also associated with the
motor neuron damage in the sporadic form of ALS.
DOI: 10.1016/s0022-510x(96)00190-6
PMID: 8981308 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24611504 | 1. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Jun;15(3-4):312-4. doi:
10.3109/21678421.2013.873051. Epub 2014 Mar 10.
Multiple system involvement in a Japanese patient with a V31A mutation in the
SOD1 gene.
Sakamoto H(1), Akamatsu M, Hirano M, Saigoh K, Ueno S, Isono C, Kusunoki S,
Nakamura Y.
Author information:
(1)Department of Neurology, Sakai Hospital Kinki University Faculty of Medicine
, Osaka , Japan.
The superoxide dismutase-1 (SOD1) gene is the first gene for familial
amyotrophic lateral sclerosis (ALS) with autosomal dominant inheritance. We
describe a Japanese patient who had slowly progressive motor neuron disease with
autonomic and sensory disturbances, urine incontinence and sensory neuropathy.
This patient was found to have V31A mutation in the SOD1 gene. Although slow
progression has been previously observed in patients with ALS caused by several
mutations in the SOD1 gene, symptoms unrelated with motor systems are very rare.
In addition, MRI showed cerebellar and brainstem atrophy, a finding previously
unreported in SOD1-related ALS. The COQ2 gene, a gene very recently reported to
be associated with multiple system atrophy, as well as genes for spinocerebellar
ataxias was analyzed, the result of which showed no mutation in this patient.
The V31A mutation is thus likely to be associated with atypical ALS affecting
multiple systems.
DOI: 10.3109/21678421.2013.873051
PMID: 24611504 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35170113 | 1. Cell Prolif. 2022 Apr;55(4):e13202. doi: 10.1111/cpr.13202. Epub 2022 Feb 16.
Enhancer RNA: What we know and what we can achieve.
Han Z(1), Li W(1).
Author information:
(1)Stem Cell and Cancer Center, The First Hospital of Jilin University,
Changchun, China.
Enhancers are important cis-acting elements that can regulate gene transcription
and cell fate alongside promoters. In fact, many human cancers and diseases are
associated with the malfunction of enhancers. Recent studies have shown that
enhancers can produce enhancer RNAs (eRNAs) by RNA polymerase II. In this
review, we discuss eRNA production, characteristics, functions and mechanics.
eRNAs can determine chromatin accessibility, histone modification and gene
expression by constructing a 'chromatin loop', thereby bringing enhancers to
their target gene. eRNA can also be involved in the phase separation with
enhancers and other proteins. eRNAs are abundant, and importantly,
tissue-specific in tumours, various diseases and stem cells; thus, eRNAs can be
a potential target for disease diagnosis and treatment. As eRNA is produced from
the active transcription of enhancers and is involved in the regulation of cell
fate, its manipulation will influence cell function, and therefore, it can be a
new target for biological therapy.
© 2022 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.
DOI: 10.1111/cpr.13202
PMCID: PMC9055912
PMID: 35170113 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/31944157 | 1. Transcription. 2020 Feb;11(1):26-36. doi: 10.1080/21541264.2020.1713682. Epub
2020 Jan 16.
Epigenetic plasticity of enhancers in cancer.
Yao J(1), Chen J(1), Li LY(1), Wu M(1).
Author information:
(1)College of Life Sciences, Frontier Science Center for Immunology and
Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of
Developmentally Originated Disease, Hubei Key Laboratory of Enteropathy, Wuhan
University, Wuhan, Hubei, China.
Enhancers are cis-acting elements with many sites bound by transcription factors
and activate transcription over long distance. Histone modifications are
critical for enhancer activity and utilized as hallmarks for the identification
of putative enhancers. Monomethylation of histone H3 lysine 4 (H3K4me1) is the
mark for enhancer priming; acetylation of histone H3 lysine 27 (H3K27ac) for
active enhancers and trimethylation of histone H3 lysine 27 (H3K27me3) for
silent enhancers. Recent studies from multiple groups have provided evidence
that enhancer reprogramming, especially gain of enhancer activity, is closely
related to tumorigenesis and cancer development. In this review, we will
summarize the recent discoveries about enhancer regulation and the mechanisms of
enhancer reprogramming in tumorigenesis, and discuss the potential application
of enhancer manipulation in precision medicine.
DOI: 10.1080/21541264.2020.1713682
PMCID: PMC7053964
PMID: 31944157 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31993419 | 1. Front Cell Dev Biol. 2020 Jan 14;7:377. doi: 10.3389/fcell.2019.00377.
eCollection 2019.
Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression
and Cell Fate.
Arnold PR(1)(2), Wells AD(3), Li XC(2).
Author information:
(1)Texas A&M Health Science Center, College of Medicine, Bryan, TX, United
States.
(2)Immunobiology and Transplant Sciences, Department of Surgery, Houston
Methodist Hospital, Houston, TX, United States.
(3)Department of Pathology and Laboratory Medicine, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, United States.
Enhancers are cis-regulatory elements in the genome that cooperate with
promoters to control target gene transcription. Unlike promoters, enhancers are
not necessarily adjacent to target genes and can exert their functions
regardless of enhancer orientations, positions and spatial segregations from
target genes. Thus, for a long time, the question as to how enhancers act in a
temporal and spatial manner attracted considerable attention. The recent
discovery that enhancers are also abundantly transcribed raises interesting
questions about the exact roles of enhancer RNA (eRNA) in gene regulation. In
this review, we highlight the process of enhancer transcription and the diverse
features of eRNA. We review eRNA functions, which include enhancer-promoter
looping, chromatin modifying, and transcription regulating. As eRNA are
transcribed from active enhancers, they exhibit tissue and lineage specificity,
and serve as markers of cell state and function. Finally, we discuss the unique
relationship between eRNA and super enhancers in phase separation wherein eRNA
may contribute significantly to cell fate decisions.
Copyright © 2020 Arnold, Wells and Li.
DOI: 10.3389/fcell.2019.00377
PMCID: PMC6971116
PMID: 31993419 |
http://www.ncbi.nlm.nih.gov/pubmed/30026829 | 1. J Cancer. 2018 Jun 6;9(13):2334-2340. doi: 10.7150/jca.25829. eCollection
2018.
Enhancer RNAs (eRNAs): New Insights into Gene Transcription and Disease
Treatment.
Ding M(1)(2), Liu Y(1)(3), Liao X(3), Zhan H(1)(3), Liu Y(3), Huang W(3).
Author information:
(1)Department of Urology, Shenzhen Second People's Hospital, the First
Affiliated Hospital of Shenzhen University, Clinical Medicine College of Anhui
Medical University, Shenzhen 518000, Guangdong, China.
(2)Anhui Medical University, Hefei 230032, Anhui Province, China.
(3)Department of Urology, Shenzhen Second People's Hospital, the First
Affiliated Hospital of Shenzhen University, Shenzhen 518000, China.
Enhancers are cis-acting elements that have the ability to increase the
expression of target genes. Recent studies have shown that enhancers can act as
transcriptional units for the production of enhancer RNAs (eRNAs), which are
hallmarks of activity enhancers and are involved in the regulation of gene
transcription. The in-depth study of eRNAs is of great significance for us to
better understand enhancer function and transcriptional regulation in various
diseases. Therefore, eRNAs may be a potential therapeutic target for diseases.
Here, we review the current knowledge of the characteristics of eRNAs, the
molecular mechanisms of eRNAs action, as well as diseases related to
dysregulation of eRNAs.
DOI: 10.7150/jca.25829
PMCID: PMC6036709
PMID: 30026829
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interest exists. |
http://www.ncbi.nlm.nih.gov/pubmed/29284524 | 1. Genome Biol. 2017 Dec 28;18(1):242. doi: 10.1186/s13059-017-1379-8.
Bidirectional transcription initiation marks accessible chromatin and is not
specific to enhancers.
Young RS(1), Kumar Y(2), Bickmore WA(2), Taylor MS(3).
Author information:
(1)MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine,
University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
robert.young@igmm.ed.ac.uk.
(2)MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine,
University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
(3)MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine,
University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
martin.taylor@igmm.ed.ac.uk.
BACKGROUND: Enhancers are modular regulatory elements that are central to the
spatial and temporal regulation of gene expression. Bidirectional transcription
initiating at enhancers has been proposed to mark active enhancers and as such
has been utilized to experimentally identify active enhancers de novo.
RESULTS: Here, we show that bidirectional transcription initiation is a
pervasive feature of accessible chromatin, including at enhancers, promoters,
and other DNase hypersensitive regions not marked with canonical histone
modification profiles. Transcription is less predictive for enhancer activity
than epigenetic modifications such as H3K4me1 or the accessibility of DNA when
measured both in enhancer assays and at endogenous loci. The stability of
enhancer initiated transcripts does not influence measures of enhancer activity
and we cannot detect evidence of purifying selection on the resulting enhancer
RNAs within the human population.
CONCLUSIONS: Our results indicate that bidirectional transcription initiation
from accessible chromatin is not sufficient for, nor specific to, enhancer
activity. Transcription initiating at enhancers may be a frequent by-product of
promiscuous RNA polymerase initiation at accessible chromatin and is unlikely to
generally play a functional role in enhancer activity.
DOI: 10.1186/s13059-017-1379-8
PMCID: PMC5747114
PMID: 29284524 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The
authors declare that they have no competing interests. PUBLISHER’S NOTE:
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/28239713 | 1. Mol Biosyst. 2017 Mar 28;13(4):767-774. doi: 10.1039/c7mb00054e.
EnhancerPred2.0: predicting enhancers and their strength based on
position-specific trinucleotide propensity and electron-ion interaction
potential feature selection.
He W(1), Jia C(1).
Author information:
(1)Department of Mathematics, Dalian Maritime University, No. 1 Linghai Road,
Dalian 116026, China. cangzhijia@dlmu.edu.cn.
Enhancers are cis-acting elements that play major roles in upregulating
eukaryotic gene expression by providing binding sites for transcription factors
and their complexes. Because enhancers are highly cell/tissue specific, lack
common motifs, and are far from the target gene, the systematic and precise
identification of enhancer regions in DNA sequences is a big challenge. In this
study, we developed an enhancer prediction method called EnhancerPred2.0 by
combining position-specific trinucleotide propensity (PSTNP) information with
the electron-ion interaction potential (EIIP) values for trinucleotides, to
predict enhancers and their subgroups. To obtain the optimal combination of
features, F-score values were used in a two-step wrapper-based feature selection
method, which was applied in a high dimensional feature vector from PSTNP and
EIIP. Finally, 126 optimized features from PSTNP combined with 32 optimized
features from EIIP yielded the best performance for identifying enhancers and
non-enhancers, with an overall accuracy (Acc) of 88.27% and a Matthews
correlation coefficient (MCC) of 0.77. Additionally, 198 features from PSTNP
combined with 37 features from EIIP yielded the best performance for identifying
strong and weak enhancers, with an overall Acc of 98.05% and a MCC of 0.96.
Rigorous jackknife tests indicated that EnhancerPred2.0 was significantly better
than the existing enhancer prediction methods in both overall accuracy and
stability.
DOI: 10.1039/c7mb00054e
PMID: 28239713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30139328 | 1. BMC Genomics. 2018 Aug 23;19(1):633. doi: 10.1186/s12864-018-5016-z.
Nascent RNA sequencing analysis provides insights into enhancer-mediated gene
regulation.
Wang J(1)(2), Zhao Y(3), Zhou X(4), Hiebert SW(3)(5), Liu Q(6)(7), Shyr Y(8)(9).
Author information:
(1)Center for Quantitative Sciences, Vanderbilt University Medical Center,
Nashville, TN, USA.
(2)Department of Biostatistics, Vanderbilt University Medical Center, Nashville,
TN, USA.
(3)Department of Biochemistry, Vanderbilt University School of Medicine,
Nashville, TN, USA.
(4)Department of Biological Science, Vanderbilt University, Nashville, TN, USA.
(5)Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN, USA.
(6)Center for Quantitative Sciences, Vanderbilt University Medical Center,
Nashville, TN, USA. qi.liu@vanderbilt.edu.
(7)Department of Biostatistics, Vanderbilt University Medical Center, Nashville,
TN, USA. qi.liu@vanderbilt.edu.
(8)Center for Quantitative Sciences, Vanderbilt University Medical Center,
Nashville, TN, USA. yu.shyr@vanderbilt.edu.
(9)Department of Biostatistics, Vanderbilt University Medical Center, Nashville,
TN, USA. yu.shyr@vanderbilt.edu.
BACKGROUND: Enhancers are distal cis-regulatory elements that control gene
expression. Despite an increasing appreciation of the importance of enhancers in
cellular function and disease, our knowledge of enhancer-regulated transcription
is very limited. Nascent RNA sequencing technologies, such as global nuclear
run-on sequencing (GRO-seq) and precision run-on sequencing (PRO-seq), not only
provide a direct and reliable measurement of enhancer activity, but also allow
for quantifying transcription of enhancers and target genes simultaneously,
making these technologies extremely useful for exploring enhancer-mediated
regulation.
RESULTS: Nascent RNA sequencing analysis (NRSA) provides a comprehensive view of
enhancer-mediated gene regulation. NRSA not only outperforms existing methods
for enhancer identification, but also enables annotation and quantification of
active enhancers, and prediction of their target genes. Furthermore, NRSA
identifies functionally important enhancers by integrating 1) nascent
transcriptional changes in enhancers and their target genes and 2) binding
profiles from regulator(s) of interest. Applied to wildtype and histone
deacetylase 3 (Hdac3) knockout mouse livers, NRSA showed that HDAC3 regulates
RNA polymerase recruitment through both proximal (promoter) and distal
(enhancer) regulatory elements. Integrating ChIP-seq with PRO-seq data, NRSA
prioritized enhancers based on their potential contribution to mediating HDAC3
regulation.
CONCLUSIONS: NRSA will greatly facilitate the usage of nascent RNA sequencing
techniques and accelerate the study of enhancer-mediated regulation.
DOI: 10.1186/s12864-018-5016-z
PMCID: PMC6107967
PMID: 30139328 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The
genetically engineered mice were created, bred and housed under specific
pathogen-free conditions at and in accordance with guidelines set forth by
Vanderbilt University Medical Center. Animal ethics was approved by the
Vanderbilt University Institutional Animal Care and Use Committee (IACUC),
protocol number M/12/021. CONSENT FOR PUBLICATION: Not applicable. COMPETING
INTERESTS: The authors declare that they have no competing interests.
PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/28334114 | 1. Bioinformatics. 2017 Jul 1;33(13):1930-1936. doi:
10.1093/bioinformatics/btx105.
BiRen: predicting enhancers with a deep-learning-based model using the DNA
sequence alone.
Yang B(1), Liu F(1)(2), Ren C(1), Ouyang Z(1), Xie Z(3), Bo X(1), Shu W(1).
Author information:
(1)Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing
100850.
(2)Department of Information, The 188th Hospital of Chaozhou, Chaozhou 521000.
(3)Department of Biomedical Engineering, College of Life Science and Technology,
Huazhong University of Science and Technology, Wuhan 430074, China.
MOTIVATION: Enhancer elements are noncoding stretches of DNA that play key roles
in controlling gene expression programmes. Despite major efforts to develop
accurate enhancer prediction methods, identifying enhancer sequences continues
to be a challenge in the annotation of mammalian genomes. One of the major
issues is the lack of large, sufficiently comprehensive and experimentally
validated enhancers for humans or other species. Thus, the development of
computational methods based on limited experimentally validated enhancers and
deciphering the transcriptional regulatory code encoded in the enhancer
sequences is urgent.
RESULTS: We present a deep-learning-based hybrid architecture, BiRen, which
predicts enhancers using the DNA sequence alone. Our results demonstrate that
BiRen can learn common enhancer patterns directly from the DNA sequence and
exhibits superior accuracy, robustness and generalizability in enhancer
prediction relative to other state-of-the-art enhancer predictors based on
sequence characteristics. Our BiRen will enable researchers to acquire a deeper
understanding of the regulatory code of enhancer sequences.
AVAILABILITY AND IMPLEMENTATION: Our BiRen method can be freely accessed at
https://github.com/wenjiegroup/BiRen .
CONTACT: shuwj@bmi.ac.cn or boxc@bmi.ac.cn.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
© The Author 2017. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
DOI: 10.1093/bioinformatics/btx105
PMID: 28334114 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28716036 | 1. BMC Genomics. 2017 Jul 17;18(1):536. doi: 10.1186/s12864-017-3934-9.
Short DNA sequence patterns accurately identify broadly active human enhancers.
Colbran LL(1), Chen L(2), Capra JA(3)(4)(5).
Author information:
(1)Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, 37235,
USA.
(2)Department of Biological Sciences, Vanderbilt University, Nashville, TN,
37235, USA.
(3)Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, 37235,
USA. tony.capra@vanderbilt.edu.
(4)Department of Biological Sciences, Vanderbilt University, Nashville, TN,
37235, USA. tony.capra@vanderbilt.edu.
(5)Center for Structural Biology, Departments of Biomedical Informatics and
Computer Science, Vanderbilt University, Nashville, TN, 37235, USA.
tony.capra@vanderbilt.edu.
BACKGROUND: Enhancers are DNA regulatory elements that influence gene
expression. There is substantial diversity in enhancers' activity patterns: some
enhancers drive expression in a single cellular context, while others are active
across many. Sequence characteristics, such as transcription factor (TF) binding
motifs, influence the activity patterns of regulatory sequences; however, the
regulatory logic through which specific sequences drive enhancer activity
patterns is poorly understood. Recent analysis of Drosophila enhancers suggested
that short dinucleotide repeat motifs (DRMs) are general enhancer sequence
features that drive broad regulatory activity. However, it is not known whether
the regulatory role of DRMs is conserved across species.
RESULTS: We performed a comprehensive analysis of the relationship between short
DNA sequence patterns, including DRMs, and human enhancer activity in 38,538
enhancers across 411 different contexts. In a machine-learning framework, the
occurrence patterns of short sequence motifs accurately predicted broadly active
human enhancers. However, DRMs alone were weakly predictive of broad enhancer
activity in humans and showed different enrichment patterns than in Drosophila.
In general, GC-rich sequence motifs were significantly associated with broad
enhancer activity, and consistent with this enrichment, broadly active human TFs
recognize GC-rich motifs.
CONCLUSIONS: Our results reveal the importance of specific sequence motifs in
broadly active human enhancers, demonstrate the lack of evolutionary
conservation of the role of DRMs, and provide a computational framework for
investigating the logic of enhancer sequences.
DOI: 10.1186/s12864-017-3934-9
PMCID: PMC5512948
PMID: 28716036 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The
authors declare they have no competing interests. PUBLISHER’S NOTE: Springer
Nature remains neutral with regard to jurisdictional claims in published maps
and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/33320871 | 1. PLoS One. 2020 Dec 15;15(12):e0243791. doi: 10.1371/journal.pone.0243791.
eCollection 2020.
PEREGRINE: A genome-wide prediction of enhancer to gene relationships supported
by experimental evidence.
Mills C(1), Muruganujan A(2), Ebert D(2), Marconett CN(3)(4)(5), Lewinger JP(1),
Thomas PD(2), Mi H(2).
Author information:
(1)Division of Biostatistics, Department of Preventive Medicine, Keck School of
Medicine, University of Southern California, Los Angeles, CA, United States of
America.
(2)Division of Bioinformatics, Department of Preventive Medicine, Keck School of
Medicine, University of Southern California, Los Angeles, CA, United States of
America.
(3)Department of Surgery, Keck School of Medicine, University of Southern
California, Los Angeles, CA, United States of America.
(4)Department of Biochemistry and Molecular Medicine, Keck School of Medicine
USC, Los Angeles, CA, United States of America.
(5)Norris Cancer Center, Keck School of Medicine USC, Los Angeles, CA, United
States of America.
Enhancers are powerful and versatile agents of cell-type specific gene
regulation, which are thought to play key roles in human disease. Enhancers are
short DNA elements that function primarily as clusters of transcription factor
binding sites that are spatially coordinated to regulate expression of one or
more specific target genes. These regulatory connections between enhancers and
target genes can therefore be characterized as enhancer-gene links that can
affect development, disease, and homeostatic cellular processes. Despite their
implication in disease and the establishment of cell identity during
development, most enhancer-gene links remain unknown. Here we introduce a new,
publicly accessible database of predicted enhancer-gene links, PEREGRINE. The
PEREGRINE human enhancer-gene links interactive web interface incorporates
publicly available experimental data from ChIA-PET, eQTL, and Hi-C assays across
78 cell and tissue types to link 449,627 enhancers to 17,643 protein-coding
genes. These enhancer-gene links are made available through the new Enhancer
module of the PANTHER database and website where the user may easily access the
evidence for each enhancer-gene link, as well as query by target gene and
enhancer location.
DOI: 10.1371/journal.pone.0243791
PMCID: PMC7737992
PMID: 33320871 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/31665430 | 1. Nucleic Acids Res. 2020 Jan 8;48(D1):D51-D57. doi: 10.1093/nar/gkz973.
ENdb: a manually curated database of experimentally supported enhancers for
human and mouse.
Bai X(1), Shi S(1), Ai B(1), Jiang Y(1), Liu Y(1), Han X(1), Xu M(1), Pan Q(1),
Wang F(1), Wang Q(1), Zhang J(1), Li X(1), Feng C(1), Li Y(1), Wang Y(1), Song
Y(1), Feng K(1), Li C(1).
Author information:
(1)School of Medical Informatics, Daqing Campus, Harbin Medical University.
Daqing 163319, China.
Enhancers are a class of cis-regulatory elements that can increase gene
transcription by forming loops in intergenic regions, introns and exons.
Enhancers, as well as their associated target genes, and transcription factors
(TFs) that bind to them, are highly associated with human disease and biological
processes. Although some enhancer databases have been published, most only focus
on enhancers identified by high-throughput experimental techniques. Therefore,
it is highly desirable to construct a comprehensive resource of manually curated
enhancers and their related information based on low-throughput experimental
evidences. Here, we established a comprehensive manually-curated enhancer
database for human and mouse, which provides a resource for experimentally
supported enhancers, and to annotate the detailed information of enhancers. The
current release of ENdb documents 737 experimentally validated enhancers and
their related information, including 384 target genes, 263 TFs, 110 diseases and
153 functions in human and mouse. Moreover, the enhancer-related information was
supported by experimental evidences, such as RNAi, in vitro knockdown, western
blotting, qRT-PCR, luciferase reporter assay, chromatin conformation capture
(3C) and chromosome conformation capture-on-chip (4C) assays. ENdb provides a
user-friendly interface to query, browse and visualize the detailed information
of enhancers. The database is available at http://www.licpathway.net/ENdb.
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkz973
PMCID: PMC7145688
PMID: 31665430 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27662874 | 1. Methods Mol Biol. 2017;1468:121-38. doi: 10.1007/978-1-4939-4035-6_10.
Computational Approaches for Mining GRO-Seq Data to Identify and Characterize
Active Enhancers.
Nagari A(1)(2), Murakami S(1)(2)(3), Malladi VS(1)(2), Kraus WL(4)(5)(6).
Author information:
(1)The Laboratory of Signaling and Gene Expression, Cecil H. and Ida Green
Center for Reproductive Biology Sciences, University of Texas Southwestern
Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8511, USA.
(2)The Division of Basic Research, Department of Obstetrics and Gynecology,
University of Texas Southwestern Medical Center, Dallas, TX, 75390-8511, USA.
(3)Program in Genetics, Development and Disease, Graduate School of Biomedical
Sciences, University of Texas Southwestern Medical Center, Dallas, TX, 75390,
USA.
(4)The Laboratory of Signaling and Gene Expression, Cecil H. and Ida Green
Center for Reproductive Biology Sciences, University of Texas Southwestern
Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8511, USA.
LEE.KRAUS@utsouthwestern.edu.
(5)The Division of Basic Research, Department of Obstetrics and Gynecology,
University of Texas Southwestern Medical Center, Dallas, TX, 75390-8511, USA.
LEE.KRAUS@utsouthwestern.edu.
(6)Program in Genetics, Development and Disease, Graduate School of Biomedical
Sciences, University of Texas Southwestern Medical Center, Dallas, TX, 75390,
USA. LEE.KRAUS@utsouthwestern.edu.
Transcriptional enhancers are DNA regulatory elements that are bound by
transcription factors and act to positively regulate the expression of nearby or
distally located target genes. Enhancers have many features that have been
discovered using genomic analyses. Recent studies have shown that active
enhancers recruit RNA polymerase II (Pol II) and are transcribed, producing
enhancer RNAs (eRNAs). GRO-seq, a method for identifying the location and
orientation of all actively transcribing RNA polymerases across the genome, is a
powerful approach for monitoring nascent enhancer transcription. Furthermore,
the unique pattern of enhancer transcription can be used to identify enhancers
in the absence of any information about the underlying transcription factors.
Here, we describe the computational approaches required to identify and analyze
active enhancers using GRO-seq data, including data pre-processing, alignment,
and transcript calling. In addition, we describe protocols and computational
pipelines for mining GRO-seq data to identify active enhancers, as well as known
transcription factor binding sites that are transcribed. Furthermore, we discuss
approaches for integrating GRO-seq-based enhancer data with other genomic data,
including target gene expression and function. Finally, we describe molecular
biology assays that can be used to confirm and explore further the function of
enhancers that have been identified using genomic assays. Together, these
approaches should allow the user to identify and explore the features and
biological functions of new cell type-specific enhancers.
DOI: 10.1007/978-1-4939-4035-6_10
PMCID: PMC5522910
PMID: 27662874 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29583027 | 1. Epigenomics. 2018 Apr 1;10(4):483-498. doi: 10.2217/epi-2017-0157. Epub 2018
Mar 27.
Enhancer talk.
Snetkova V(1)(2), Skok JA(1).
Author information:
(1)Department of Pathology, New York University School of Medicine, 550 First
Avenue, MSB 599, New York, NY 10016, USA.
(2)MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Enhancers are short noncoding segments of DNA (100-1000 bp) that control the
temporal and spatial activity of genes in an orientation-independent manner.
They can be separated from their target genes by large distances and are thus
known as distal regulatory elements. One consequence of the variability in the
distance separating enhancers and their target promoters is that it is difficult
to determine which elements are involved in the regulation of a particular gene.
Moreover, enhancers can be found in clusters in which multiple regulatory
elements control expression of the same target gene. However, little is known
about how the individual elements contribute to gene expression. Here, we
describe how chromatin conformation promotes and constraints enhancer activity.
Further, we discuss enhancer clusters and what is known about the contribution
of individual elements to the regulation of target genes. Finally, we examine
the reliability of different methods used to identify enhancers.
DOI: 10.2217/epi-2017-0157
PMCID: PMC5925435
PMID: 29583027 [Indexed for MEDLINE]
Conflict of interest statement: Financial & competing interests disclosure JA
Skok is supported by NIH grant R35GM122515, 4P30CA016087-36 Cancer Center
Support Grant NIH/NCI (Neel) and 2R01CA140729-06A1 NIH/NCI (Carroll). The
authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart from those
disclosed. No writing assistance was utilized in the production of this
manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/32197056 | 1. Annu Rev Biochem. 2020 Jun 20;89:213-234. doi:
10.1146/annurev-biochem-011420-095916. Epub 2020 Mar 20.
Evaluating Enhancer Function and Transcription.
Field A(1), Adelman K(1).
Author information:
(1)Department of Biological Chemistry and Molecular Pharmacology, Blavatnik
Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; email:
karen_adelman@hms.harvard.edu.
Cell-type- and condition-specific profiles of gene expression require
coordination between protein-coding gene promoters and cis-regulatory sequences
called enhancers. Enhancers can stimulate gene activity at great genomic
distances from their targets, raising questions about how enhancers communicate
with specific gene promoters and what molecular mechanisms underlie enhancer
function. Characterization of enhancer loci has identified the molecular
features of active enhancers that accompany the binding of transcription factors
and local opening of chromatin. These characteristics include coactivator
recruitment, histone modifications, and noncoding RNA transcription. However, it
remains unclear which of these features functionally contribute to enhancer
activity. Here, we discuss what is known about how enhancers regulate their
target genes and how enhancers and promoters communicate. Further, we describe
recent data demonstrating many similarities between enhancers and the gene
promoters they control, and we highlight unanswered questions in the field, such
as the potential roles of transcription at enhancers.
DOI: 10.1146/annurev-biochem-011420-095916
PMID: 32197056 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33431820 | 1. Nat Commun. 2021 Jan 11;12(1):223. doi: 10.1038/s41467-020-20400-z.
BET inhibition disrupts transcription but retains enhancer-promoter contact.
Crump NT(1), Ballabio E(1), Godfrey L(1), Thorne R(1), Repapi E(2), Kerry J(1),
Tapia M(1)(3)(4), Hua P(5), Lagerholm C(6), Filippakopoulos P(7), Davies JOJ(5),
Milne TA(8).
Author information:
(1)MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular
Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe
Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
(2)MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of
Molecular Medicine, Radcliffe Department of Medicine, University of Oxford,
Oxford, OX3 9DS, UK.
(3)The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University
of Copenhagen, Copenhagen, Denmark.
(4)Biotech Research and Innovation Centre (BRIC), Faculty of Health Sciences,
University of Copenhagen, Copenhagen, Denmark.
(5)MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular
Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3
9DS, UK.
(6)Wolfson Imaging Centre Oxford, MRC Weatherall Institute of Molecular
Medicine, University of Oxford, Oxford, OX3 9DS, UK.
(7)Structural Genomics Consortium, Nuffield Department of Clinical Medicine,
University of Oxford, Oxford, OX3 7DQ, UK.
(8)MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular
Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe
Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
thomas.milne@imm.ox.ac.uk.
Enhancers are DNA sequences that enable complex temporal and tissue-specific
regulation of genes in higher eukaryotes. Although it is not entirely clear how
enhancer-promoter interactions can increase gene expression, this proximity has
been observed in multiple systems at multiple loci and is thought to be
essential for the maintenance of gene expression. Bromodomain and Extra-Terminal
domain (BET) and Mediator proteins have been shown capable of forming phase
condensates and are thought to be essential for super-enhancer function. Here,
we show that targeting of cells with inhibitors of BET proteins or
pharmacological degradation of BET protein Bromodomain-containing protein 4
(BRD4) has a strong impact on transcription but very little impact on
enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and
Mediator binding at enhancers and can also strongly affect gene transcription,
without disrupting enhancer-promoter interactions. These results suggest that
activation of transcription and maintenance of enhancer-promoter interactions
are separable events. Our findings further indicate that enhancer-promoter
interactions are not dependent on high levels of BRD4 and Mediator, and are
likely maintained by a complex set of factors including additional activator
complexes and, at some sites, CTCF and cohesin.
DOI: 10.1038/s41467-020-20400-z
PMCID: PMC7801379
PMID: 33431820 [Indexed for MEDLINE]
Conflict of interest statement: T.A.M. is a founding shareholder of OxStem
Oncology (OSO), a subsidiary company of OxStem Ltd. J.O.J.D. is a co-founder of
Nucleome Therapeutics Ltd. to which he provides consultancy. All other authors
have no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/21737276 | 1. Curr Biol. 2011 Jul 26;21(14):1186-96. doi: 10.1016/j.cub.2011.05.056. Epub
2011 Jul 7.
Rapid evolutionary rewiring of a structurally constrained eye enhancer.
Swanson CI(1), Schwimmer DB, Barolo S.
Author information:
(1)Department of Cell and Developmental Biology, University of Michigan Medical
School, Ann Arbor, MI 48109-2200, USA.
Comment in
Curr Biol. 2011 Jul 26;21(14):R542-3. doi: 10.1016/j.cub.2011.06.026.
BACKGROUND: Enhancers are genomic cis-regulatory sequences that integrate
spatiotemporal signals to control gene expression. Enhancer activity depends on
the combination of bound transcription factors as well as-in some cases-the
arrangement and spacing of binding sites for these factors. Here, we examine
evolutionary changes to the sequence and structure of sparkling, a
Notch/EGFR/Runx-regulated enhancer that activates the dPax2 gene in cone cells
of the developing Drosophila eye.
RESULTS: Despite functional and structural constraints on its sequence,
sparkling has undergone major reorganization in its recent evolutionary history.
Our data suggest that the relative strengths of the various regulatory inputs
into sparkling change rapidly over evolutionary time, such that reduced input
from some factors is compensated by increased input from different regulators.
These gains and losses are at least partly responsible for the changes in
enhancer structure that we observe. Furthermore, stereotypical spatial
relationships between certain binding sites ("grammar elements") can be
identified in all sparkling orthologs-although the sites themselves are often
recently derived. We also find that low binding affinity for the Notch-regulated
transcription factor Su(H), a conserved property of sparkling, is required to
prevent ectopic responses to Notch in noncone cells.
CONCLUSIONS: Rapid DNA sequence turnover does not imply either the absence of
critical cis-regulatory information or the absence of structural rules. Our
findings demonstrate that even a severely constrained cis-regulatory sequence
can be significantly rewired over a short evolutionary timescale.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.cub.2011.05.056
PMCID: PMC3143281
PMID: 21737276 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16002789 | 1. Nucleic Acids Res. 2005 Jul 7;33(12):3743-50. doi: 10.1093/nar/gki689. Print
2005.
DNA looping induced by a transcriptional enhancer in vivo.
Petrascheck M(1), Escher D, Mahmoudi T, Verrijzer CP, Schaffner W, Barberis A.
Author information:
(1)Institute of Molecular Biology, University of Zurich Winterthurerstrasse 190,
CH-8057 Zurich, Switzerland. mpetrasc@fhcrc.org
Enhancers are DNA sequences that can activate gene transcription from remote
positions. In yeast, regulatory sequences that are functionally equivalent to
the metazoan enhancers are called upstream activating sequences (UASs). UASs
show a lower degree of flexibility than their metazoan counterparts, but can
nevertheless activate transcription from a distance of >1000 bp from the
promoter. One of several models for the mechanism of action of transcriptional
enhancers proposes that enhancer-bound activating proteins contact
promoter-bound transcription factors and thereby get in close proximity to the
promoter region with concomitant looping of the intervening DNA. We tested the
mode of enhancer activity in yeast. A polymerase II-transcribed gene was paired
with a remote, inducible enhancer. An independent reporter system was inserted
next to the promoter to monitor the potential modes of enhancer activity. Our
results show that the enhancer activated the reporter system only in the
presence of a functional promoter. We also demonstrate that the heterologous
expression of GAGA, a factor known to facilitate DNA loop formation, allows
enhancer action in yeast over a distance of 3000 bp.
DOI: 10.1093/nar/gki689
PMCID: PMC1174898
PMID: 16002789 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30758829 | 1. Methods Mol Biol. 2019;1935:203-221. doi: 10.1007/978-1-4939-9057-3_14.
Experimental and Computational Approaches for Single-Cell Enhancer Perturbation
Assay.
Xie S(1), Hon GC(2).
Author information:
(1)Department of Obstetrics and Gynecology, Cecil H. and Ida Green Center for
Reproductive Biology Sciences, University of Texas Southwestern Medical Center,
Dallas, TX, USA.
(2)Department of Obstetrics and Gynecology, Cecil H. and Ida Green Center for
Reproductive Biology Sciences, University of Texas Southwestern Medical Center,
Dallas, TX, USA. Gary.Hon@UTSouthwestern.edu.
Transcriptional enhancers drive cell-type-specific gene expression patterns, and
thus play key roles in development and disease. Large-scale consortia have
extensively cataloged >one million putative enhancers encoded in the human
genome. But few enhancers have been endogenously tested for function. For almost
all enhancers, it remains unknown what genes they target and how much they
contribute to target gene expression. We have previously developed a method
called Mosaic-seq, which enables the high-throughput interrogation of enhancer
activity by performing pooled CRISPRi-based epigenetic suppression of enhancers
with a single-cell transcriptomic readout. Here, we describe an optimized
version of this method, Mosaic-seq2. We have made several key improvements that
have significantly simplified the library preparation process and increased the
overall sensitivity and throughput of the method.
DOI: 10.1007/978-1-4939-9057-3_14
PMID: 30758829 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32664620 | 1. Cells. 2020 Jul 12;9(7):1675. doi: 10.3390/cells9071675.
Evolution of Regulated Transcription.
Bylino OV(1), Ibragimov AN(1)(2), Shidlovskii YV(1)(3).
Author information:
(1)Laboratory of Gene Expression Regulation in Development, Institute of Gene
Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia.
(2)Center for Precision Genome Editing and Genetic Technologies for Biomedicine,
Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334
Moscow, Russia.
(3)I.M. Sechenov First Moscow State Medical University, 8, bldg. 2 Trubetskaya
St., 119048 Moscow, Russia.
The genomes of all organisms abound with various cis-regulatory elements, which
control gene activity. Transcriptional enhancers are a key group of such
elements in eukaryotes and are DNA regions that form physical contacts with gene
promoters and precisely orchestrate gene expression programs. Here, we follow
gradual evolution of this regulatory system and discuss its features in
different organisms. In eubacteria, an enhancer-like element is often a single
regulatory element, is usually proximal to the core promoter, and is occupied by
one or a few activators. Activation of gene expression in archaea is accompanied
by the recruitment of an activator to several enhancer-like sites in the
upstream promoter region. In eukaryotes, activation of expression is accompanied
by the recruitment of activators to multiple enhancers, which may be distant
from the core promoter, and the activators act through coactivators. The role of
the general DNA architecture in transcription control increases in evolution. As
a whole, it can be seen that enhancers of multicellular eukaryotes evolved from
the corresponding prototypic enhancer-like regulatory elements with the
gradually increasing genome size of organisms.
DOI: 10.3390/cells9071675
PMCID: PMC7408454
PMID: 32664620 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23124110 | 1. Biochim Biophys Acta. 2012 Nov-Dec;1819(11-12):1217-27. doi:
10.1016/j.bbagrm.2012.10.008. Epub 2012 Nov 1.
Long distance relationships: enhancer-promoter communication and dynamic gene
transcription.
Marsman J(1), Horsfield JA.
Author information:
(1)Department of Pathology, The University of Otago, Dunedin, New Zealand.
The three-dimensional regulation of gene transcription involves loop formation
between enhancer and promoter elements, controlling spatiotemporal gene
expression in multicellular organisms. Enhancers are usually located in
non-coding DNA and can activate gene transcription by recruiting transcription
factors, chromatin remodeling factors and RNA Polymerase II. Research over the
last few years has revealed that enhancers have tell-tale characteristics that
facilitate their detection by several approaches, although the hallmarks of
enhancers are not always uniform. Enhancers likely play an important role in the
activation of genes by functioning as a primary point of contact for
transcriptional activators, and by making physical contact with gene promoters
often by means of a chromatin loop. Although numerous transcriptional regulators
participate in the formation of chromatin loops that bring enhancers into
proximity with promoters, the mechanism(s) of enhancer-promoter connectivity
remain enigmatic. Here we discuss enhancer function, review some of the many
proteins shown to be involved in establishing enhancer-promoter loops, and
describe the dynamics of enhancer-promoter contacts during development,
differentiation and in specific cell types.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbagrm.2012.10.008
PMID: 23124110 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27325706 | 1. Cold Spring Harb Symp Quant Biol. 2015;80:27-32. doi:
10.1101/sqb.2015.80.027227.
Regulatory Principles Governing Tissue Specificity of Developmental Enhancers.
Farley EK(1), Olson KM(1), Levine MS(1).
Author information:
(1)Lewis-Sigler Institute for Integrative Genomics, Princeton University,
Princeton, New Jersey 08544.
Transcriptional enhancers are short segments of genomic DNA (50 bp to 1 kb in
length) that can work over long distances (≥1 Mb) to regulate gene expression in
specific cells and tissues. Genomic assays have identified on the order of
400,000 to one million putative enhancers in the human genome (e.g., ENCODE
Consortium). This suggests that a typical gene is regulated by tens of
enhancers, ensuring stringent regulation of gene expression in response to a
variety of intrinsic and external signals. Despite the discovery of the first
transcriptional enhancer more than 30 years ago, we know surprisingly little
about how enhancers regulate gene expression. In particular, the relationship
between primary DNA sequence and enhancer specificity remains obscure. Here we
summarize recent high-throughput studies in whole embryos aimed at the
systematic identification of the sequence and organizational constraints
underlying enhancer function and specificity.
Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
DOI: 10.1101/sqb.2015.80.027227
PMCID: PMC4970742
PMID: 27325706 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28760812 | 1. Development. 2017 Sep 1;144(17):3095-3101. doi: 10.1242/dev.149427. Epub 2017
Jul 31.
Functional regulatory evolution outside of the minimal even-skipped stripe 2
enhancer.
Crocker J(1), Stern DL(2).
Author information:
(1)Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive,
Ashburn, VA 20147, USA justin.crocker@embl.de.
(2)Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive,
Ashburn, VA 20147, USA.
Transcriptional enhancers are regions of DNA that drive precise patterns of gene
expression. Although many studies have elucidated how individual enhancers can
evolve, most of this work has focused on what are called 'minimal' enhancers,
the smallest DNA regions that drive expression that approximates an aspect of
native gene expression. Here, we explore how the Drosophila erecta even-skipped
(eve) locus has evolved by testing its activity in the divergent D. melanogaster
genome. We found, as has been reported previously, that the D. erecta eve stripe
2 enhancer (eveS2) fails to drive appreciable expression in D. melanogaster
However, we found that a large transgene carrying the entire D. erecta eve locus
drives normal eve expression, including in stripe 2. We performed a functional
dissection of the region upstream of the D. erecta eveS2 region and found
multiple Zelda motifs that are required for normal expression. Our results
illustrate how sequences outside of minimal enhancer regions can evolve
functionally through mechanisms other than changes in transcription
factor-binding sites that drive patterning.
© 2017. Published by The Company of Biologists Ltd.
DOI: 10.1242/dev.149427
PMID: 28760812 [Indexed for MEDLINE]
Conflict of interest statement: Competing interestsThe authors declare no
competing or financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/25715743 | 1. Cell Mol Life Sci. 2015 Jun;72(12):2361-75. doi: 10.1007/s00018-015-1871-9.
Epub 2015 Feb 26.
Eukaryotic enhancers: common features, regulation, and participation in
diseases.
Erokhin M(1), Vassetzky Y, Georgiev P, Chetverina D.
Author information:
(1)Department of the Control of Genetic Processes, Institute of Gene Biology,
Russian Academy of Sciences, 34/5 Vavilov St., Moscow, 119334, Russia.
Enhancers are positive DNA regulatory sequences controlling temporal and
tissue-specific gene expression. These elements act independently of their
orientation and distance relative to the promoters of target genes. Enhancers
act through a variety of transcription factors that ensure their correct match
with target promoters and consequent gene activation. There is a growing body of
evidence on association of enhancers with transcription factors, co-activators,
histone chromatin marks, and lncRNAs. Alterations in enhancers lead to
misregulation of gene expression, causing a number of human diseases. In this
review, we focus on the common characteristics of enhancers required for
transcription stimulation.
DOI: 10.1007/s00018-015-1871-9
PMCID: PMC11114076
PMID: 25715743 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32737473 | 1. Nat Methods. 2020 Aug;17(8):807-814. doi: 10.1038/s41592-020-0907-8. Epub 2020
Jul 29.
Supervised enhancer prediction with epigenetic pattern recognition and targeted
validation.
Sethi A(#)(1), Gu M(#)(2)(3), Gumusgoz E(4), Chan L(5), Yan KK(1), Rozowsky
J(1), Barozzi I(6), Afzal V(6), Akiyama JA(6), Plajzer-Frick I(6), Yan C(1),
Novak CS(6), Kato M(6), Garvin TH(6), Pham Q(6), Harrington A(6), Mannion BJ(6),
Lee EA(6), Fukuda-Yuzawa Y(6), Visel A(6), Dickel DE(6), Yip KY(7), Sutton R(4),
Pennacchio LA(6), Gerstein M(8)(9)(10).
Author information:
(1)Department of Molecular Biophysics and Biochemistry, Yale University, New
Haven, CT, USA.
(2)Program in Computational Biology and Bioinformatics, Yale University, New
Haven, CT, USA.
(3)Department of Computer Science, Yale University, New Haven, CT, USA.
(4)Department of Internal Medicine, Section of Infectious Diseases, Yale
University School of Medicine, New Haven, CT, USA.
(5)School of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
(6)Functional Genomics Department, Lawrence Berkeley National Laboratory,
Berkeley, CA, USA.
(7)Department of Computer Science, The Chinese University of Hong Kong, Hong
Kong, China.
(8)Department of Molecular Biophysics and Biochemistry, Yale University, New
Haven, CT, USA. mark@gersteinlab.org.
(9)Program in Computational Biology and Bioinformatics, Yale University, New
Haven, CT, USA. mark@gersteinlab.org.
(10)Department of Computer Science, Yale University, New Haven, CT, USA.
mark@gersteinlab.org.
(#)Contributed equally
Enhancers are important non-coding elements, but they have traditionally been
hard to characterize experimentally. The development of massively parallel
assays allows the characterization of large numbers of enhancers for the first
time. Here, we developed a framework using Drosophila STARR-seq to create
shape-matching filters based on meta-profiles of epigenetic features. We
integrated these features with supervised machine-learning algorithms to predict
enhancers. We further demonstrated that our model could be transferred to
predict enhancers in mammals. We comprehensively validated the predictions using
a combination of in vivo and in vitro approaches, involving transgenic assays in
mice and transduction-based reporter assays in human cell lines (153 enhancers
in total). The results confirmed that our model can accurately predict enhancers
in different species without re-parameterization. Finally, we examined the
transcription factor binding patterns at predicted enhancers versus promoters.
We demonstrated that these patterns enable the construction of a secondary model
that effectively distinguishes enhancers and promoters.
DOI: 10.1038/s41592-020-0907-8
PMCID: PMC8073243
PMID: 32737473 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34879086 | 1. PLoS One. 2021 Dec 8;16(12):e0260432. doi: 10.1371/journal.pone.0260432.
eCollection 2021.
A network-based method for predicting disease-associated enhancers.
Le DH(1).
Author information:
(1)School of Computer Science and Engineering, Thuyloi University, Hanoi,
Vietnam.
BACKGROUND: Enhancers regulate transcription of target genes, causing a change
in expression level. Thus, the aberrant activity of enhancers can lead to
diseases. To date, a large number of enhancers have been identified, yet a small
portion of them have been found to be associated with diseases. This raises a
pressing need to develop computational methods to predict associations between
diseases and enhancers.
RESULTS: In this study, we assumed that enhancers sharing target genes could be
associated with similar diseases to predict the association. Thus, we built an
enhancer functional interaction network by connecting enhancers significantly
sharing target genes, then developed a network diffusion method RWDisEnh, based
on a random walk with restart algorithm, on networks of diseases and enhancers
to globally measure the degree of the association between diseases and
enhancers. RWDisEnh performed best when the disease similarities are integrated
with the enhancer functional interaction network by known disease-enhancer
associations in the form of a heterogeneous network of diseases and enhancers.
It was also superior to another network diffusion method, i.e., PageRank with
Priors, and a neighborhood-based one, i.e., MaxLink, which simply chooses the
closest neighbors of known disease-associated enhancers. Finally, we showed that
RWDisEnh could predict novel enhancers, which are either directly or indirectly
associated with diseases.
CONCLUSIONS: Taken together, RWDisEnh could be a potential method for predicting
disease-enhancer associations.
DOI: 10.1371/journal.pone.0260432
PMCID: PMC8654176
PMID: 34879086 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/27895109 | 1. Genome Res. 2017 Feb;27(2):246-258. doi: 10.1101/gr.210930.116. Epub 2016 Nov
28.
Enhancers and super-enhancers have an equivalent regulatory role in embryonic
stem cells through regulation of single or multiple genes.
Moorthy SD(1), Davidson S(1), Shchuka VM(1), Singh G(1), Malek-Gilani N(1),
Langroudi L(1), Martchenko A(1), So V(1), Macpherson NN(1), Mitchell JA(1)(2).
Author information:
(1)Department of Cell and Systems Biology, University of Toronto, Toronto,
Ontario M5S 3G5, Canada.
(2)Centre for the Analysis of Genome Evolution and Function, University of
Toronto, Toronto, Ontario M5S 3G5, Canada.
Transcriptional enhancers are critical for maintaining cell-type-specific gene
expression and driving cell fate changes during development. Highly transcribed
genes are often associated with a cluster of individual enhancers such as those
found in locus control regions. Recently, these have been termed stretch
enhancers or super-enhancers, which have been predicted to regulate critical
cell identity genes. We employed a CRISPR/Cas9-mediated deletion approach to
study the function of several enhancer clusters (ECs) and isolated enhancers in
mouse embryonic stem (ES) cells. Our results reveal that the effect of deleting
ECs, also classified as ES cell super-enhancers, is highly variable, resulting
in target gene expression reductions ranging from 12% to as much as 92%. Partial
deletions of these ECs which removed only one enhancer or a subcluster of
enhancers revealed partially redundant control of the regulated gene by multiple
enhancers within the larger cluster. Many highly transcribed genes in ES cells
are not associated with a super-enhancer; furthermore, super-enhancer
predictions ignore 81% of the potentially active regulatory elements predicted
by cobinding of five or more pluripotency-associated transcription factors.
Deletion of these additional enhancer regions revealed their robust regulatory
role in gene transcription. In addition, select super-enhancers and enhancers
were identified that regulated clusters of paralogous genes. We conclude that,
whereas robust transcriptional output can be achieved by an isolated enhancer,
clusters of enhancers acting on a common target gene act in a partially
redundant manner to fine tune transcriptional output of their target genes.
© 2017 Moorthy et al.; Published by Cold Spring Harbor Laboratory Press.
DOI: 10.1101/gr.210930.116
PMCID: PMC5287230
PMID: 27895109 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35552697 | 1. Genome Biol Evol. 2022 May 31;14(6):evac071. doi: 10.1093/gbe/evac071.
Pleiotropic Enhancers are Ubiquitous Regulatory Elements in the Human Genome.
Laiker I(1), Frankel N(1)(2).
Author information:
(1)Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE),
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) y
Universidad de Buenos Aires (UBA), Buenos Aires 1428, Argentina.
(2)Departamento de Ecología, Genética y Evolución, Facultad de Ciencias Exactas
y Naturales (FCEN), Universidad de Buenos Aires (UBA), Buenos Aires 1428,
Argentina.
Enhancers are regulatory elements of genomes that determine spatio-temporal
patterns of gene expression. The human genome contains a vast number of
enhancers, which largely outnumber protein-coding genes. Historically, enhancers
have been regarded as highly tissue-specific. However, recent evidence has
demonstrated that many enhancers are pleiotropic, with activity in multiple
developmental contexts. Yet, the extent and impact of pleiotropy remain largely
unexplored. In this study we analyzed active enhancers across human organs based
on the analysis of both eRNA transcription (FANTOM5 consortium data sets) and
chromatin architecture (ENCODE consortium data sets). We show that pleiotropic
enhancers are pervasive in the human genome and that most enhancers active in a
particular organ are also active in other organs. In addition, our analysis
suggests that the proportion of context-specific enhancers of a given organ is
explained, at least in part, by the proportion of context-specific genes in that
same organ. The notion that such a high proportion of human enhancers can be
pleiotropic suggests that small regions of regulatory DNA contain abundant
regulatory information and that these regions evolve under important
evolutionary constraints.
© The Author(s) 2022. Published by Oxford University Press on behalf of Society
for Molecular Biology and Evolution.
DOI: 10.1093/gbe/evac071
PMCID: PMC9156028
PMID: 35552697 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24920384 | 1. Evol Dev. 2014 Jul-Aug;16(4):207-23. doi: 10.1111/ede.12084. Epub 2014 Jun 11.
Functional analysis of limb transcriptional enhancers in the mouse.
Nolte MJ(1), Wang Y, Deng JM, Swinton PG, Wei C, Guindani M, Schwartz RJ,
Behringer RR.
Author information:
(1)Graduate Program in Genes and Development, University of Texas Graduate
School of Biomedical Sciences at Houston, Houston, TX, USA; Department of
Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Erratum in
Evol Dev. 2014 Nov;16(6):397.
Transcriptional enhancers are genomic sequences bound by transcription factors
that act together with basal transcriptional machinery to regulate gene
transcription. Several high-throughput methods have generated large datasets of
tissue-specific enhancer sequences with putative roles in developmental
processes. However, few enhancers have been deleted from the genome to determine
their roles in development. To understand the roles of two enhancers active in
the mouse embryonic limb bud we deleted them from the genome. Although the genes
regulated by these enhancers are unknown, they were selected because they were
identified in a screen for putative limb bud-specific enhancers associated with
p300, an acetyltransferase that participates in protein complexes that promote
active transcription, and because the orthologous human enhancers (H1442 and
H280) drive distinct lacZ expression patterns in limb buds of embryonic day (E)
11.5 transgenic mice. We show that the orthologous mouse sequences, M1442 and
M280, regulate dynamic expression in the developing limb. Although significant
transcriptional differences in enhancer-proximal genes in embryonic limb buds
accompany the deletion of M1442 and M280 no gross limb malformations during
embryonic development were observed, demonstrating that M1442 and M280 are not
required for mouse limb development. However, M280 is required for the
development and/or maintenance of body size; M280 mice are significantly smaller
than controls. M280 also harbors an "ultraconserved" sequence that is identical
between human, rat, and mouse. This is the first report of a phenotype resulting
from the deletion of an ultraconserved element. These studies highlight the
importance of determining enhancer regulatory function by experiments that
manipulate them in situ and suggest that some of an enhancer's regulatory
capacities may be developmentally tolerated rather than developmentally
required.
© 2014 Wiley Periodicals, Inc.
DOI: 10.1111/ede.12084
PMCID: PMC4130292
PMID: 24920384 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23651551 | 1. FEBS Lett. 2013 Jun 27;587(13):1840-7. doi: 10.1016/j.febslet.2013.04.027.
Epub 2013 May 4.
Communication of genome regulatory elements in a folded chromosome.
Razin SV(1), Gavrilov AA, Ioudinkova ES, Iarovaia OV.
Author information:
(1)Institute of Gene Biology of the Russian Academy of Sciences, 119334 Moscow,
Russia. sergey.v.razin@inbox.ru
The most popular model of gene activation by remote enhancers postulates that
the enhancers interact directly with target promoters via the looping of
intervening DNA fragments. This interaction is thought to be necessary for the
stabilization of the Pol II pre-initiation complex and/or for the transfer of
transcription factors and Pol II, which are initially accumulated at the
enhancer, to the promoter. The direct interaction of enhancer(s) and promoter(s)
is only possible when these elements are located in close proximity within the
nuclear space. Here, we discuss the molecular mechanisms for maintaining the
close proximity of the remote regulatory elements of the eukaryotic genome. The
models of an active chromatin hub (ACH) and an active nuclear compartment are
considered, focusing on the role of chromatin folding in juxtaposing remote DNA
sequences. The interconnection between the functionally dependent architecture
of the interphase chromosome and nuclear compartmentalization is also discussed.
Copyright © 2013 Federation of European Biochemical Societies. Published by
Elsevier B.V. All rights reserved.
DOI: 10.1016/j.febslet.2013.04.027
PMID: 23651551 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32952117 | 1. Yi Chuan. 2020 Sep 20;42(9):817-831. doi: 10.16288/j.yczz.20-097.
The identification of enhancers and its application in cancer studies.
Liu Q(1), Li CY(1)(2).
Author information:
(1)Beijing Advanced Innovation Center for Big Data-Based Precision Medicine &
School of Medical Sciences and Engineering, Beihang University, Beijing 100191,
China.
(2)Key Laboratory of Big Data-Based Precision Medicine (Beihang University),
Ministry of Industry and Information Technology, Beijing 100191, China.
Enhancers are a type of cis-acting DNA elements that enhance transcriptional
activity of target genes. However, the uncertainty in the orientation and
distance between enhancers and target genes could post significant difficulties
in identifying the target genes and the regulatory mechanisms of the enhancers.
Numerous studies have shown that the mutations and/or abnormalities in the
functions of enhancers are associated with development of diseases. A few
studies have reported that enhancers could activate cancer development or drug
resistance by promoting the expression of target genes. At present, enhancers
involved in carcinogenesis and drug resistance have not been fully identified,
and the underlying mechanism are still largely unknown. This paper summarizes
the main methods used in identifying and characterizing enhancers and analyzing
the regulatory mechanism at the genome-wide level. It further reviews the recent
research progress of enhancers in cancer diagnosis, treatment, and the
underlying mechanism during carcinogenesis, thereby providing a reference for
the screening of these enhancers involved in carcinogenesis and drug resistance
and exploring their regulatory mechanisms of target genes. It also provides a
new perspective for improving the diagnosis of cancer and insights for
formulating cancer therapeutic strategies.
Publisher:
增强子是一类增强靶基因转录活性的DNA顺式作用元件。但是增强子与靶基因的方向和距离不确定,大大增加了研究增强子调控的靶基因及其作用机制的困难。已有大量研究显示,增强子的突变或功能异常与疾病发生发展相关;仅有少量研究报道增强子通过促进靶基因的表达,引发癌症或产生抗药性。目前与癌症发生发展和在癌症治疗过程中抗药性产生相关的增强子尚未得到充分鉴定,这些增强子的调控机制也未得到充分解析。本文对目前可在全基因组水平上预测和鉴定增强子以及解析增强子调控机制的方法进行总结和对比,并对近几年增强子在肿瘤诊断、治疗和发生发展机制中的研究进展进行综述。期望本文为筛选与癌症发生发展相关的增强子和解析这些增强子的调控机制提供参考,为提高癌症的诊断和制定癌症的治疗策略提供新的视角。.
DOI: 10.16288/j.yczz.20-097
PMID: 32952117 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34968246 | 1. Epigenomes. 2021 Oct 4;5(4):21. doi: 10.3390/epigenomes5040021.
Role of Enhancers in Development and Diseases.
Maurya SS(1).
Author information:
(1)Department of Pediatrics, Division of Pediatric Hematology and Oncology,
Department of Developmental Biology, School of Medicine, Washington University
in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Enhancers are cis-regulatory elements containing short DNA sequences that serve
as binding sites for pioneer/regulatory transcription factors, thus
orchestrating the regulation of genes critical for lineage determination. The
activity of enhancer elements is believed to be determined by transcription
factor binding, thus determining the cell state identity during development.
Precise spatio-temporal control of the transcriptome during lineage
specification requires the coordinated binding of lineage-specific transcription
factors to enhancers. Thus, enhancers are the primary determinants of cell
identity. Numerous studies have explored the role and mechanism of enhancers
during development and disease, and various basic questions related to the
functions and mechanisms of enhancers have not yet been fully answered. In this
review, we discuss the recently published literature regarding the roles of
enhancers, which are critical for various biological processes governing
development. Furthermore, we also highlight that altered enhancer landscapes
provide an essential context to understand the etiologies and mechanisms behind
numerous complex human diseases, providing new avenues for effective
enhancer-based therapeutic interventions.
DOI: 10.3390/epigenomes5040021
PMCID: PMC8715447
PMID: 34968246
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34897508 | 1. Nucleic Acids Res. 2022 Jan 11;50(1):92-107. doi: 10.1093/nar/gkab1177.
Dynamic modulation of enhancer responsiveness by core promoter elements in
living Drosophila embryos.
Yokoshi M(1), Kawasaki K(1), Cambón M(2), Fukaya T(1)(3).
Author information:
(1)Laboratory of Transcription Dynamics, Research Center for Biological
Visualization, Institute for Quantitative Biosciences, The University of Tokyo,
Bunkyo-ku, Tokyo, Japan.
(2)Applied Mathematics Department, University of Granada, Granada, Spain.
(3)Department of Life Sciences, Graduate School of Arts and Sciences, The
University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Regulatory interactions between enhancers and core promoters are fundamental for
the temporal and spatial specificity of gene expression in development. The
central role of core promoters is to initiate productive transcription in
response to enhancer's activation cues. However, it has not been systematically
assessed how individual core promoter elements affect the induction of
transcriptional bursting by enhancers. Here, we provide evidence that each core
promoter element differentially modulates functional parameters of
transcriptional bursting in developing Drosophila embryos. Quantitative live
imaging analysis revealed that the timing and the continuity of burst induction
are common regulatory steps on which core promoter elements impact. We further
show that the upstream TATA also affects the burst amplitude. On the other hand,
Inr, MTE and DPE mainly contribute to the regulation of the burst frequency.
Genome editing analysis of the pair-rule gene fushi tarazu revealed that the
endogenous TATA and DPE are both essential for its correct expression and
function during the establishment of body segments in early embryos. We suggest
that core promoter elements serve as a key regulatory module in converting
enhancer activity into transcription dynamics during animal development.
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkab1177
PMCID: PMC8754644
PMID: 34897508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24599251 | 1. Nat Struct Mol Biol. 2014 Mar;21(3):210-9. doi: 10.1038/nsmb.2784.
Enhancer biology and enhanceropathies.
Smith E(1), Shilatifard A(1).
Author information:
(1)Stowers Institute for Medical Research, Kansas City, Missouri, USA.
Enhancers are cis-regulatory elements that enable precise spatiotemporal
patterns of gene expression during development and are notable for being able to
function at large distances from their target genes. Such regulatory elements
often bypass intervening genes and typically comprise binding sites for multiple
transcription factors that can also be transcribed by RNA polymerase II (Pol II)
to produce noncoding enhancer RNAs (eRNAs). Genome-wide analyses have revealed
chromatin signatures of enhancers, such as the enrichment for monomethylation of
histone H3 lysine 4 (H3K4me1) and the acetylation or methylation of histone H3
lysine 27 (H3K27). Enhancer signatures have been used to describe the
transitions of these regulatory elements from inactive to primed and from
activated to decommissioned states during development. New mutations of enhancer
sequences and of the protein factors regulating enhancer function in human
disease continue to be identified, contributing to a growing class of
'enhanceropathies'.
DOI: 10.1038/nsmb.2784
PMID: 24599251 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32635644 | 1. Cells. 2020 Jul 5;9(7):1620. doi: 10.3390/cells9071620.
Molecular Basis of the Function of Transcriptional Enhancers.
Ibragimov AN(1)(2), Bylino OV(1), Shidlovskii YV(1)(3).
Author information:
(1)Laboratory of Gene Expression Regulation in Development, Institute of Gene
Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia.
(2)Center for Precision Genome Editing and Genetic Technologies for Biomedicine,
Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334
Moscow, Russia.
(3)I.M. Sechenov First Moscow State Medical University, 8, bldg. 2 Trubetskaya
St., 119048 Moscow, Russia.
Transcriptional enhancers are major genomic elements that control gene activity
in eukaryotes. Recent studies provided deeper insight into the temporal and
spatial organization of transcription in the nucleus, the role of non-coding
RNAs in the process, and the epigenetic control of gene expression. Thus,
multiple molecular details of enhancer functioning were revealed. Here, we
describe the recent data and models of molecular organization of enhancer-driven
transcription.
DOI: 10.3390/cells9071620
PMCID: PMC7407508
PMID: 32635644 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/27863239 | 1. Cell. 2016 Nov 17;167(5):1170-1187. doi: 10.1016/j.cell.2016.09.018.
Ever-Changing Landscapes: Transcriptional Enhancers in Development and
Evolution.
Long HK(1), Prescott SL(2), Wysocka J(3).
Author information:
(1)Department of Chemical and Systems Biology, Stanford School of Medicine,
Stanford University, Stanford, CA 94305, USA; Institute of Stem Cell Biology and
Regenerative Medicine, Stanford School of Medicine, Stanford University,
Stanford, CA 94305, USA.
(2)Department of Chemical and Systems Biology, Stanford School of Medicine,
Stanford University, Stanford, CA 94305, USA; Department of Developmental
Biology, Stanford School of Medicine, Stanford University, Stanford, CA 94305,
USA.
(3)Department of Chemical and Systems Biology, Stanford School of Medicine,
Stanford University, Stanford, CA 94305, USA; Institute of Stem Cell Biology and
Regenerative Medicine, Stanford School of Medicine, Stanford University,
Stanford, CA 94305, USA; Department of Developmental Biology, Stanford School of
Medicine, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical
Institute, Stanford School of Medicine, Stanford University, Stanford, CA 94305,
USA. Electronic address: wysocka@stanford.edu.
A class of cis-regulatory elements, called enhancers, play a central role in
orchestrating spatiotemporally precise gene-expression programs during
development. Consequently, divergence in enhancer sequence and activity is
thought to be an important mediator of inter- and intra-species phenotypic
variation. Here, we give an overview of emerging principles of enhancer
function, current models of enhancer architecture, genomic substrates from which
enhancers emerge during evolution, and the influence of three-dimensional genome
organization on long-range gene regulation. We discuss intricate relationships
between distinct elements within complex regulatory landscapes and consider
their potential impact on specificity and robustness of transcriptional
regulation.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2016.09.018
PMCID: PMC5123704
PMID: 27863239 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25719310 | 1. Biol Chem. 2015 Apr;396(4):311-27. doi: 10.1515/hsz-2014-0303.
Enhancers, enhancers - from their discovery to today's universe of transcription
enhancers.
Schaffner W.
Transcriptional enhancers are short (200-1500 base pairs) DNA segments that are
able to dramatically boost transcription from the promoter of a target gene.
Originally discovered in simian virus 40 (SV40), a small DNA virus,
transcription enhancers were soon also found in immunoglobulin genes and other
cellular genes as key determinants of cell-type-specific gene expression.
Enhancers can exert their effect over long distances of thousands, even hundreds
of thousands of base pairs, either from upstream, downstream, or from within a
transcription unit. The number of enhancers in eukaryotic genomes correlates
with the complexity of the organism; a typical mammalian gene is likely
controlled by several enhancers to fine-tune its expression at different
developmental stages, in different cell types and in response to different
signaling cues. Here, I provide a personal account of how enhancers were
discovered more than 30 years ago, and also address the amazing development of
the field since then.
DOI: 10.1515/hsz-2014-0303
PMID: 25719310 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30780195 | 1. Dev Growth Differ. 2019 Jun;61(5):343-352. doi: 10.1111/dgd.12597. Epub 2019
Feb 19.
Dynamics of transcriptional enhancers and chromosome topology in gene
regulation.
Yokoshi M(1), Fukaya T(1)(2).
Author information:
(1)Institute for Quantitative Biosciences, The University of Tokyo, Bunkyo-ku,
Tokyo, Japan.
(2)Department of Life Sciences, Graduate School of Arts and Sciences, The
University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Transcriptional enhancers are regulatory DNAs that instruct when and where genes
should be transcribed in response to a variety of intrinsic and external
signals. They contain a cluster of binding sites for sequence-specific
transcription factors and co-activators to determine the spatiotemporal
specificity of gene activities during development. Enhancers are often
positioned in distal locations from their target promoters. In some cases, they
work over a million base pairs or more. In the traditional view, enhancers have
been thought to stably interact with promoters in a targeted manner. However,
quantitative imaging studies provide a far more dynamic picture of enhancer
action. Moreover, recent Hi-C methods suggest that regulatory interactions are
dynamically regulated by the higher-order chromosome topology. In this review,
we summarize the emerging findings in the field and propose that assembly of
"transcription hubs" in the context of 3D genome structure plays an important
role in transcriptional regulation.
© 2019 The Authors. Development, Growth & Differentiation published by John
Wiley & Sons Australia, Ltd on behalf of Japanese Society of Developmental
Biologists.
DOI: 10.1111/dgd.12597
PMCID: PMC6850047
PMID: 30780195 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35868358 | 1. J Control Release. 2022 Sep;349:1045-1051. doi: 10.1016/j.jconrel.2022.05.061.
Epub 2022 Sep 8.
Suprachoroidal delivery enables targeting, localization and durability of small
molecule suspensions.
Kansara VS(1), Hancock SE(1), Muya LW(1), Ciulla TA(2).
Author information:
(1)Clearside Biomedical Inc., 900 North Point Parkway, Suite 200, Alpharetta, GA
30005, United States of America.
(2)Clearside Biomedical Inc., 900 North Point Parkway, Suite 200, Alpharetta, GA
30005, United States of America. Electronic address:
thomas.ciulla@clearsidebio.com.
Drug delivery to the suprachoroidal space (SCS®) has become a clinical reality
after the 2021 FDA approval of CLS-TA, a triamcinolone acetonide injectable
suspension for suprachoroidal use (XIPERE®), administered via a
microneedle-based device, the SCS Microinjector®. Suprachoroidal (SC) delivery
facilitates targeting, compartmentalization, and durability of small molecule
suspensions, thereby potentially addressing some of the efficacy, safety, and
treatment burden limitations of current retinal therapies. Herein, the design
features of the SCS Microinjector are reviewed, along with the biomechanics of
SC drug delivery. Also presented are preclinical evaluations of SC small
molecule suspensions from 4 different therapeutic classes (plasma kallikrein
inhibitor, receptor tyrosine kinase inhibitor, corticosteroid, complement factor
D inhibitor), highlighting their potential for durability, targeted
compartmentalization, and acceptable safety profiles following
microinjector-based SC delivery. The clinical evaluations of the safety,
tolerability and efficacy of SC delivered triamcinolone further supports
potential of SC small molecule suspensions as a clinically viable strategy for
the treatment of chorioretinal diseases. Also highlighted are current
limitations, key pharmacological considerations, and future opportunities to
optimize the SC microinjector platform for safe, effective, and potentially
long-acting drug delivery for the treatment of chorioretinal disorders.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jconrel.2022.05.061
PMID: 35868358 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35562158 | 1. Indian J Pathol Microbiol. 2022 May;65(Supplement):S259-S270. doi:
10.4103/ijpm.ijpm_1074_21.
Genetics and muscle pathology in the diagnosis of muscular dystrophies: An
update.
Narasimhaiah D(1), Uppin MS(2), Ranganath P(3).
Author information:
(1)Department of Pathology, Sree Chitra Tirunal Institute for Medical Sciences
and Technology, Thiruvananthapuram, Kerala, India.
(2)Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta,
Hyderabad, Telangana, India.
(3)Department of Medical Genetics, Nizam's Institute of Medical Sciences,
Punjagutta, Hyderabad, Telangana, India.
Muscular dystrophies are a clinically and genetically heterogeneous group of
disorders involving the skeletal muscles. They have a progressive clinical
course and are characterized by muscle fiber degeneration. Congenital muscular
dystrophies (CMD) include dystroglycanopathies, merosin-deficient CMD, collagen
VI-deficient CMD, SELENON-related rigid spine muscular dystrophy, and
LMNA-related CMD. Childhood and adult-onset muscular dystrophies include
dystrophinopathies, limb-girdle muscular dystrophies, Emery-Dreifuss muscular
dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy.
Traditionally, muscle biopsy and histopathology along with special pathology
techniques such as immunohistochemistry or immunoblotting were used for the
diagnosis of muscular dystrophies. However, recent advances in molecular genetic
testing, especially the next-generation sequencing technology, have
revolutionized the diagnosis of muscular dystrophies. Identification of the
underlying genetic basis helps in appropriate management and prognostication of
the affected individual and genetic counseling of the family. In addition,
identification of the exact disease-causing mutations is necessary for accurate
prenatal genetic testing and carrier testing, to prevent recurrence in the
family. Mutation identification is also essential for initiating
mutation-specific therapies (which have been developed recently, especially for
Duchenne muscular dystrophy) and for enrolment of patients into ongoing
therapeutic clinical trials. The 'genetic testing first' approach has now become
the norm in most centers. Nonetheless, muscle biopsy-based testing still has an
important role to play, especially for cases where genetic testing is negative
or inconclusive for the etiology.
DOI: 10.4103/ijpm.ijpm_1074_21
PMID: 35562158 [Indexed for MEDLINE]
Conflict of interest statement: None |
http://www.ncbi.nlm.nih.gov/pubmed/27340611 | 1. Expert Opin Orphan Drugs. 2016;4(2):169-183. doi:
10.1517/21678707.2016.1124039. Epub 2015 Dec 17.
Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy.
Yue Y(1), Binalsheikh IM(2), Leach SB(3), Domeier TL(4), Duan D(5).
Author information:
(1)Department of Molecular Microbiology and Immunology, School of Medicine,
University of Missouri.
(2)Department of Child Health, School of Medicine, University of Missouri.
(3)Department of Veterinary Medicine and Surgery, College of Veterinary
Medicine, University of Missouri.
(4)Department of Medical Physiology and Pharmacology, School of Medicine,
University of Missouri.
(5)Department of Molecular Microbiology and Immunology, School of Medicine,
University of Missouri; Department of Neurology, School of Medicine, University
of Missouri.
INTRODUCTION: Cardiac involvement is a common feature in muscular dystrophies.
It presents as heart failure and/or arrhythmia. Traditionally, dystrophic
cardiomyopathy is treated with symptom-relieving medications. Identification of
disease-causing genes and investigation on pathogenic mechanisms have opened new
opportunities to treat dystrophic cardiomyopathy with gene therapy.
Replacing/repairing the mutated gene and/or targeting the pathogenic
process/mechanisms using alternative genes may attenuate heart disease in
muscular dystrophies.
AREAS COVERED: Duchenne muscular dystrophy is the most common muscular
dystrophy. Duchenne cardiomyopathy has been the primary focus of ongoing
dystrophic cardiomyopathy gene therapy studies. Here, we use Duchenne
cardiomyopathy gene therapy to showcase recent developments and to outline the
path forward. We also discuss gene therapy status for cardiomyopathy associated
with limb-girdle and congenital muscular dystrophies, and myotonic dystrophy.
EXPERT OPINION: Gene therapy for dystrophic cardiomyopathy has taken a slow but
steady path forward. Preclinical studies over the last decades have addressed
many fundamental questions. Adeno-associated virus-mediated gene therapy has
significantly improved the outcomes in rodent models of Duchenne and limb girdle
muscular dystrophies. Validation of these encouraging results in large animal
models will pave the way to future human trials.
DOI: 10.1517/21678707.2016.1124039
PMCID: PMC4914135
PMID: 27340611
Conflict of interest statement: Financial and competing interests disclosure The
authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/19555515 | 1. Expert Rev Mol Med. 2009 Jun 25;11:e18. doi: 10.1017/S1462399409001100.
Emerging strategies for cell and gene therapy of the muscular dystrophies.
Muir LA(1), Chamberlain JS.
Author information:
(1)Program in Molecular and Cellular Biology, University of Washington, Seattle,
Washington 98195, USA.
The muscular dystrophies are a heterogeneous group of over 40 disorders that are
characterised by muscle weakness and wasting. The most common are Duchenne
muscular dystrophy and Becker muscular dystrophy, which result from mutations
within the gene encoding dystrophin; myotonic dystrophy type 1, which results
from an expanded trinucleotide repeat in the myotonic dystrophy protein kinase
gene; and facioscapulohumeral dystrophy, which is associated with contractions
in the subtelomeric region of human chromosome 1. Currently the only treatments
involve clinical management of symptoms, although several promising experimental
strategies are emerging. These include gene therapy using adeno-associated
viral, lentiviral and adenoviral vectors and nonviral vectors, such as plasmid
DNA. Exon-skipping and cell-based therapies have also shown promise in the
effective treatment and regeneration of dystrophic muscle. The availability of
numerous animal models for Duchenne muscular dystrophy has enabled extensive
testing of a wide range of therapeutic approaches for this type of disorder.
Consequently, we focus here on the therapeutic developments for Duchenne
muscular dystrophy as a model of the types of approaches being considered for
various types of dystrophy. We discuss the advantages and limitations of each
therapeutic strategy, as well as prospects and recent successes in the context
of future clinical applications.
DOI: 10.1017/S1462399409001100
PMCID: PMC4890545
PMID: 19555515 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24213305 | 1. J Trop Pediatr. 2014 Apr;60(2):112-7. doi: 10.1093/tropej/fmt090. Epub 2013
Nov 7.
Genetic diagnosis of Duchenne and Becker muscular dystrophy using multiplex
ligation-dependent probe amplification in Rwandan patients.
Uwineza A(1), Hitayezu J, Murorunkwere S, Ndinkabandi J, Kalala Malu CK, Caberg
JH, Dideberg V, Bours V, Mutesa L.
Author information:
(1)Center for Medical Genetics, Department of Molecular Biology & Cytogenetics,
Faculty of Medicine, National University of Rwanda, PO Box 30-Butare, Rwanda.
Duchenne and Becker muscular dystrophies are the most common clinical forms of
muscular dystrophies. They are genetically X-linked diseases caused by a
mutation in the dystrophin (DMD) gene. A genetic diagnosis was carried out in
six Rwandan patients presenting a phenotype of Duchenne and Becker muscular
dystrophies and six asymptomatic female carrier relatives using multiplex
ligation-dependent probe amplification (MLPA). Our results revealed deletion of
the exons 48-51 in one patient, an inherited deletion of the exons 8-21 in two
brothers and a de novo deletion of the exons 46-50 in the fourth patient. No
copy number variation was found in two patients. Only one female carrier
presented exon deletion in the DMD gene. This is the first cohort of genetic
analysis in Rwandan patients affected by Duchenne and Becker muscular
dystrophies. This report confirmed that MLPA assay can be easily implemented in
low-income countries.
DOI: 10.1093/tropej/fmt090
PMID: 24213305 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3728255 | 1. Am Fam Physician. 1986 Jul;34(1):123-8.
The muscular dystrophies.
Seiler J, Bope ET.
Duchenne muscular dystrophy, the most common childhood-onset muscular dystrophy,
is X-linked and is associated with cardiac and mental abnormalities. Becker's
muscular dystrophy is similar to but milder than Duchenne muscular dystrophy.
The rare facioscapulohumeral muscular dystrophy has an autosomal dominant mode
of transmission. Myotonic muscular dystrophy is the most common of the
adult-onset muscular dystrophies. Treatable diseases that must be excluded
include polymyositis, potassium disorders and endocrine abnormalities.
PMID: 3728255 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24305447 | 1. Continuum (Minneap Minn). 2013 Dec;19(6 Muscle Disease):1535-70. doi:
10.1212/01.CON.0000440659.41675.8b.
The muscular dystrophies.
Wicklund MP.
Erratum in
Continuum (Minneap Minn). 2014 Jun;20(3 Neurology of Systemic Disease):520.
PURPOSE OF REVIEW: With transition to the genetic era, the number of muscular
dystrophies has grown significantly, but so too has our understanding of their
pathogenic underpinnings. Clinical features associated with each muscular
dystrophy still guide us to the diagnosis. However, improved diagnostic
abilities refine and expand phenotypic and genotypic correlates. This article
discusses the epidemiology, clinical features, and diagnosis of these disorders.
RECENT FINDINGS: Some important recent advancements include (1) a much greater
understanding of the pathogenetic pathways underlying facioscapulohumeral
muscular dystrophy and myotonic dystrophy type 1; (2) the publication of
diagnostic and treatment guidelines for Duchenne muscular dystrophy; and (3)
further clarification of the many genetic muscle disorders presenting a
limb-girdle pattern of weakness.
SUMMARY: Muscular dystrophies are genetic, progressive, degenerative disorders
with the primary symptom of muscle weakness. Duchenne, Becker,
facioscapulohumeral, and myotonic muscular dystrophies are most prevalent and
tend to have distinctive features helpful in diagnosis. The limb-girdle,
Emery-Dreifuss, and oculopharyngeal muscular dystrophies are less common but
often may also be diagnosed on the basis of phenotype. Researchers hope to help
patients with future discoveries effective in slowing or halting disease
progression, reversing or preventing underlying mechanisms, and repairing
previously damaged muscle.
DOI: 10.1212/01.CON.0000440659.41675.8b
PMCID: PMC10564029
PMID: 24305447 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31794464 | 1. Continuum (Minneap Minn). 2019 Dec;25(6):1640-1661. doi:
10.1212/CON.0000000000000792.
Congenital Muscular Dystrophy and Congenital Myopathy.
Butterfield RJ.
PURPOSE OF REVIEW: Congenital muscular dystrophies and congenital myopathies are
a heterogeneous group of disorders resulting in hypotonia, muscle weakness, and
dystrophic or myopathic features on muscle biopsy. This article summarizes the
clinical and genetic aspects of these disorders.
RECENT FINDINGS: Historically, diagnoses of congenital muscular dystrophy and
congenital myopathy have been made by clinical features and histopathology;
however, recent advances in genetics have changed diagnostic practice by relying
more heavily on genetic findings. This article reviews the clinical and genetic
features of the most common congenital muscular dystrophies including laminin
subunit alpha 2 (LAMA2)-related (merosin deficient), collagen VI-related, and
α-dystroglycan-related congenital muscular dystrophies and reviews the most
common congenital myopathies including nemaline rod, core, and centronuclear
myopathies. With the increasing accessibility of genetic testing, the number of
genes found to be associated with these disorders has increased dramatically. A
wide spectrum of severity and onset (from birth to adulthood) exist across all
subtypes. Progression and other features are variable depending on the subtype
and severity of the specific genetic mutation.
SUMMARY: Congenital muscular dystrophy and congenital myopathy are increasingly
recognized disorders. A growing appreciation for the breadth of phenotypic
variability and overlap between established subtypes has challenged
long-standing phenotypic and histopathologic classifications of these disorders
but has driven a greater understanding of pathogenesis and opened the door to
the development of novel treatments.
DOI: 10.1212/CON.0000000000000792
PMID: 31794464 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30215857 | 1. Compr Physiol. 2018 Sep 14;8(4):1313-1356. doi: 10.1002/cphy.c170052.
Immunobiology of Inherited Muscular Dystrophies.
Tidball JG(1), Welc SS(2), Wehling-Henricks M(3).
Author information:
(1)Molecular, Cellular & Integrative Physiology Program, University of
California, Los Angeles, California, USA.
(2)Department of Integrative Biology and Physiology, University of California,
Los Angeles, California, USA.
(3)Department of Pathology and Laboratory Medicine, David Geffen School of
Medicine at UCLA, University of California, Los Angeles, California, USA.
The immune response to acute muscle damage is important for normal repair.
However, in chronic diseases such as many muscular dystrophies, the immune
response can amplify pathology and play a major role in determining disease
severity. Muscular dystrophies are inheritable diseases that vary tremendously
in severity, but share the progressive loss of muscle mass and function that can
be debilitating and lethal. Mutations in diverse genes cause muscular dystrophy,
including genes that encode proteins that maintain membrane strength,
participate in membrane repair, or are components of the extracellular matrix or
the nuclear envelope. In this article, we explore the hypothesis that an
important feature of many muscular dystrophies is an immune response adapted to
acute, infrequent muscle damage that is misapplied in the context of chronic
injury. We discuss the involvement of the immune system in the most common
muscular dystrophy, Duchenne muscular dystrophy, and show that the immune system
influences muscle death and fibrosis as disease progresses. We then present
information on immune cell function in other muscular dystrophies and show that
for many muscular dystrophies, release of cytosolic proteins into the
extracellular space may provide an initial signal, leading to an immune response
that is typically dominated by macrophages, neutrophils, helper T-lymphocytes,
and cytotoxic T-lymphocytes. Although those features are similar in many
muscular dystrophies, each muscular dystrophy shows distinguishing features in
the magnitude and type of inflammatory response. These differences indicate that
there are disease-specific immunomodulatory molecules that determine response to
muscle cell damage caused by diverse genetic mutations. © 2018 American
Physiological Society. Compr Physiol 8:1313-1356, 2018.
Copyright © 2018 American Physiological Society. All rights reserved.
DOI: 10.1002/cphy.c170052
PMCID: PMC7769418
PMID: 30215857 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27734165 | 1. J Neurol. 2016 Dec;263(12):2528-2537. doi: 10.1007/s00415-016-8300-3. Epub
2016 Oct 12.
Medication adherence in patients with myotonic dystrophy and facioscapulohumeral
muscular dystrophy.
Fitzgerald BP(1), Conn KM(2), Smith J(2), Walker A(2), Parkhill AL(2), Hilbert
JE(3), Luebbe EA(3), Moxley RT III(3).
Author information:
(1)Wegmans School of Pharmacy, St. John Fisher College, 3690 East Avenue,
Rochester, NY, 14618, USA. bpf08248@sjfc.edu.
(2)Wegmans School of Pharmacy, St. John Fisher College, 3690 East Avenue,
Rochester, NY, 14618, USA.
(3)Department of Neurology, University of Rochester Medical Center, Rochester,
NY, USA.
Myotonic dystrophy (DM) and facioscapulohumeral muscular dystrophy (FSHD) are
the two most common adult muscular dystrophies and have progressive and often
disabling manifestations. Higher levels of medication adherence lead to better
health outcomes, especially important to patients with DM and FSHD because of
their multisystem manifestations and complexity of care. However, medication
adherence has not previously been studied in a large cohort of DM type 1 (DM1),
DM type 2 (DM2), and FSHD patients. The purpose of our study was to survey
medication adherence and disease manifestations in patients enrolled in the
NIH-supported National DM and FSHD Registry. The study was completed by 110 DM1,
49 DM2, and 193 FSHD patients. Notable comorbidities were hypertension in FSHD
(44 %) and DM2 (37 %), gastroesophageal reflux disease in DM1 (24 %) and DM2
(31 %) and arrhythmias (29 %) and thyroid disease (20 %) in DM1. Each group
reported high levels of adherence based on regimen complexity, medication costs,
health literacy, side effect profile, and their beliefs about treatment. Only
dysphagia in DM1 was reported to significantly impact medication adherence.
Approximately 35 % of study patients reported polypharmacy (taking 6 or more
medications). Of the patients with polypharmacy, the DM1 cohort was
significantly younger (mean 55.0 years) compared to DM2 (59.0 years) and FSHD
(63.2 years), and had shorter disease duration (mean 26 years) compared to FSHD
(26.8 years) and DM2 (34.8 years). Future research is needed to assess
techniques to ease pill swallowing in DM1 and to monitor polypharmacy and
potential drug interactions in DM and FSHD.
DOI: 10.1007/s00415-016-8300-3
PMCID: PMC5112113
PMID: 27734165 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23733645 | 1. Compr Physiol. 2011 Jul;1(3):1353-63. doi: 10.1002/cphy.c100062.
Exercise and muscular dystrophy: implications and analysis of effects on
musculoskeletal and cardiovascular systems.
Barnabei MS(1), Martindale JM, Townsend D, Metzger JM.
Author information:
(1)Department of Integrative Biology and Physiology, University of Minnesota
Medical School, Minneapolis, Minnesota, USA.
The muscular dystrophies are a heterogeneous collection of progressive,
inherited diseases of muscle weakness and degeneration. Although these diseases
can vary widely in their etiology and presentation, nearly all muscular
dystrophies cause exercise intolerance to some degree. Here, we focus on
Duchenne muscular dystrophy (DMD), the most common form of muscular dystrophy,
as a paradigm for the effects of muscle disease on exercise capacity. First
described in the mid-1800s, DMD is a rapidly progressive and lethal muscular
dystrophy caused by mutations in the dystrophin gene. Dystrophin is a
membrane-associated cytoskeletal protein, the loss of which causes numerous
cellular defects including mechanical instability of the sarcolemma, increased
influx of extracellular calcium, and cell signaling defects. Here, we discuss
the physiological basis for exercise intolerance in DMD, focusing on the
molecular and cellular defects caused by loss of dystrophin and how these
manifest as organ-level dysfunction and reduced exercise capacity. The main
focus of this article is the defects present in dystrophin-deficient striated
muscle. However, discussion regarding the effects of dystrophin loss on other
tissues, including vascular smooth muscle is also included. Collectively, the
goal of this article is to summarize the current state of knowledge regarding
the mechanistic basis for exercise intolerance in DMD, which may serve as an
archetype for other muscular dystrophies and diseases of muscle wasting.
© 2011 American Physiological Society.
DOI: 10.1002/cphy.c100062
PMID: 23733645 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32095889 | 1. Lung. 2020 Apr;198(2):371-375. doi: 10.1007/s00408-020-00340-7. Epub 2020 Feb
24.
Peak Cough Flow in Children with Neuromuscular Disorders.
Kotwal N(1)(2), Shukla PJ(3), Perez GF(4)(5).
Author information:
(1)Division of Pulmonology and Allergy, Department of Pediatrics, University of
Maryland, Maryland, 737 W Lombard St, Ste 314, Baltimore, MD, 21201, USA.
nkotwal@som.umaryland.edu.
(2)Division of Pulmonary and Sleep Medicine, Children's National Hospital, 111
Michigan Ave, NW, Washington, DC, 20010, USA. nkotwal@som.umaryland.edu.
(3)Department of Pediatrics, MedStar Georgetown University Hospital, 3800
Reservoir Rd, NW, Washington, DC, 20007, USA.
(4)Division of Pulmonary and Sleep Medicine, Children's National Hospital, 111
Michigan Ave, NW, Washington, DC, 20010, USA.
(5)Department of Pediatrics, Oishei Children's Hospital, Jacobs School of
Medicine and Biomedical Sciences, University of Buffalo, New York, NY, 14203,
USA.
PURPOSE: Patients with neuromuscular disease (NMD) experience weakened cough due
to progressive respiratory muscle weakness. Peak cough flow (PCF) measurements
derived from adult populations are used to recommend initiation of assisted
cough therapies. The objective of this study was to characterize PCF values
among pediatric patients with NMD.
METHODS: Retrospective chart review was performed for patients seen in the
multidisciplinary pediatric muscular dystrophy clinic from 2010 to 2016.
Clinical and demographic variables included age, gender, ambulation status, and
PCF measurements.
RESULTS: 366 patients with an established diagnosis of NMD (median age
11.8 years) were included in this study. 102 (27.8%) out of the 366 patients
were affected by Duchenne muscular dystrophy (DMD), 42 (11.5%) by congenital
muscular dystrophy (CMD), 42 (11.5%) by Charcot Marie Tooth disease (CMT) and 24
(6.5%) by Becker's muscular dystrophy (BMD). The mean PCF values in DMD
(255.8 L/min) and CMD (249.1 L/min) were lower than CMT (321.5 L/min) with
p-values of 0.007 and 0.02, respectively. The mean PCF of BMD (333.3 L/min) was
higher than that of DMD and CMD but the difference was not statistically
significant. PCFs were not statistically different between ambulatory and
non-ambulatory status (263.0 L/min versus 290.8 L/min, p = 0.12). Children under
10 years of age had lower PCF relative to older subjects (179.5 L/min versus
300.9 L/min, p < 0.0001).
CONCLUSION: Baseline PCF values in young children are below the adult-specific
values suggested for starting assisted cough techniques. Further longitudinal
trials are required to derive pediatric-specific reference values for PCF in
patients with NMD.
DOI: 10.1007/s00408-020-00340-7
PMID: 32095889 [Indexed for MEDLINE] |