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• W2011042013 abstract "Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4 to a size of 1–10 units. The residual number of D4Z4 units inversely correlates with clinical severity, but significant clinical variability exists. Each unit contains a copy of the DUX4 retrogene. Repeat contractions are associated with changes in D4Z4 chromatin structure that increase the likelihood of DUX4 expression in skeletal muscle, but only when the repeat resides in a genetic background that contains a DUX4 polyadenylation signal. Mutations in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier of D4Z4, also result in the increased likelihood of DUX4 expression in individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may act as a genetic modifier in FSHD1. We describe three unrelated individuals with FSHD1 presenting an unusual high clinical severity based on their upper-sized FSHD1 repeat array of nine units. Each of these individuals also carries a mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4 expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which the FSHD2 gene can act as modifier for disease severity in families affected by FSHD1. Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4 to a size of 1–10 units. The residual number of D4Z4 units inversely correlates with clinical severity, but significant clinical variability exists. Each unit contains a copy of the DUX4 retrogene. Repeat contractions are associated with changes in D4Z4 chromatin structure that increase the likelihood of DUX4 expression in skeletal muscle, but only when the repeat resides in a genetic background that contains a DUX4 polyadenylation signal. Mutations in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier of D4Z4, also result in the increased likelihood of DUX4 expression in individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may act as a genetic modifier in FSHD1. We describe three unrelated individuals with FSHD1 presenting an unusual high clinical severity based on their upper-sized FSHD1 repeat array of nine units. Each of these individuals also carries a mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4 expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which the FSHD2 gene can act as modifier for disease severity in families affected by FSHD1. Facioscapulohumeral muscular dystrophy (FSHD [MIM 158900]) is one of the three most common muscular dystrophies in adults with an estimated prevalence of 1:20,000.1Padberg, G.W. (1982). Facioscapulohumeral disease. PhD thesis, Leiden University, Leiden.Google Scholar Individuals with FSHD have facial, shoulder girdle, and upper extremity weakness that can spread with progression of the disease to abdominal, humeral, anterior lower leg muscles, and (in more severely affected individuals) to pelvic girdle muscles. The peculiar involvement of specific muscles is such a striking feature that it often distinguishes FSHD from other forms of muscular dystrophy.2Padberg G.W. Lunt P.W. Koch M. Fardeau M. Diagnostic criteria for facioscapulohumeral muscular dystrophy.Neuromuscul. Disord. 1991; 1: 231-234Abstract Full Text PDF PubMed Scopus (188) Google Scholar The disease usually becomes manifest in the second decade, but the progression and severity are highly variable with one-fifth of affected individuals becoming wheelchair dependent while an equal proportion of gene carriers remain asymptomatic throughout their lives.3Pandya S. King W.M. Tawil R. Facioscapulohumeral dystrophy.Phys. Ther. 2008; 88: 105-113Crossref PubMed Scopus (54) Google Scholar Autosomal-dominant FSHD1 represents the most common form, accounting for at least 95% of cases.4Upadhyaya M. Maynard J. Rogers M.T. Lunt P.W. Jardine P. Ravine D. Harper P.S. Improved molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD): validation of the differential double digestion for FSHD.J. Med. Genet. 1997; 34: 476-479Crossref PubMed Scopus (70) Google Scholar It is caused by a contraction of the D4Z4 macrosatellite repeat array located in the subtelomeric region of chromosome 4q. The D4Z4 repeat is highly polymorphic in size, varying between 11 and 150 units in the general population, each unit being 3.3 kb in size.5Hewitt J.E. Lyle R. Clark L.N. Valleley E.M. Wright T.J. Wijmenga C. van Deutekom J.C. Francis F. Sharpe P.T. Hofker M. et al.Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.Hum. Mol. Genet. 1994; 3: 1287-1295Crossref PubMed Scopus (258) Google Scholar, 6van Deutekom J.C. Wijmenga C. van Tienhoven E.A. Gruter A.M. Hewitt J.E. Padberg G.W. van Ommen G.J. Hofker M.H. Frants R.R. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit.Hum. Mol. Genet. 1993; 2: 2037-2042Crossref PubMed Scopus (444) Google Scholar, 7van Deutekom J.C. Bakker E. Lemmers R.J. van der Wielen M.J. Bik E. Hofker M.H. Padberg G.W. Frants R.R. Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1.Hum. Mol. Genet. 1996; 5: 1997-2003Crossref PubMed Scopus (132) Google Scholar Individuals with FSHD1 have at least one allele of 1–10 units on chromosome 4.7van Deutekom J.C. Bakker E. Lemmers R.J. van der Wielen M.J. Bik E. Hofker M.H. Padberg G.W. Frants R.R. Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1.Hum. Mol. Genet. 1996; 5: 1997-2003Crossref PubMed Scopus (132) Google Scholar, 8Wijmenga C. Hewitt J.E. Sandkuijl L.A. Clark L.N. Wright T.J. Dauwerse H.G. Gruter A.M. Hofker M.H. Moerer P. Williamson R. et al.Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.Nat. Genet. 1992; 2: 26-30Crossref PubMed Scopus (547) Google Scholar Despite the extensive interfamilial and intrafamilial variability in clinical severity and disease progression in FSHD1 families, there is a rough and inverse correlation between the residual size of the D4Z4 repeat, the age at onset, and the severity of muscular involvement. Indeed, small repeat arrays of 1–3 units tend to be associated with earlier onset and more rapid disease progression.9Goto K. Lee J.H. Matsuda C. Hirabayashi K. Kojo T. Nakamura A. Mitsunaga Y. Furukawa T. Sahashi K. Arahata K. DNA rearrangements in Japanese facioscapulohumeral muscular dystrophy patients: clinical correlations.Neuromuscul. Disord. 1995; 5: 201-208Abstract Full Text PDF PubMed Scopus (38) Google Scholar, 10Lunt P.W. Jardine P.E. Koch M. Maynard J. Osborn M. Williams M. Harper P.S. Upadhyaya M. Phenotypic-genotypic correlation will assist genetic counseling in 4q35- facioscapulohumeral muscular dystrophy.Muscle Nerve. 1995; 2: 103-109Crossref Scopus (47) Google Scholar, 11Ricci E. Galluzzi G. Deidda G. Cacurri S. Colantoni L. Merico B. Piazzo N. Servidei S. Vigneti E. Pasceri V. et al.Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype.Ann. Neurol. 1999; 45: 751-757Crossref PubMed Scopus (231) Google Scholar, 12Tawil R. Forrester J. Griggs R.C. Mendell J. Kissel J. McDermott M. King W. Weiffenbach B. Figlewicz D. The FSH-DY GroupEvidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy.Ann. Neurol. 1996; 39: 744-748Crossref PubMed Scopus (167) Google Scholar Gender differences may also account for variability in clinical severity with males being more severely affected then females.1Padberg, G.W. (1982). Facioscapulohumeral disease. PhD thesis, Leiden University, Leiden.Google Scholar, 13Zatz M. Marie S.K. Cerqueira A. Vainzof M. Pavanello R.C. Passos-Bueno M.R. The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females.Am. J. Med. Genet. 1998; 77: 155-161Crossref PubMed Scopus (98) Google Scholar The marked intrafamilial clinical variability further suggests the involvement of other genetic or environmental factors that modify the disease severity of a commonly inherited contraction size. A minimum of one D4Z4 repeat is required to develop FSHD, suggesting that the repeat itself plays a critical role in the development of the disease.14Tupler R. Berardinelli A. Barbierato L. Frants R. Hewitt J.E. Lanzi G. Maraschio P. Tiepolo L. Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy.J. Med. Genet. 1996; 33: 366-370Crossref PubMed Scopus (103) Google Scholar Indeed, each unit contains a copy of the DUX4 retrogene (MIM 606009) that becomes inappropriately derepressed in skeletal muscle of individuals with FSHD.15Dixit M. Ansseau E. Tassin A. Winokur S. Shi R. Qian H. Sauvage S. Mattéotti C. van Acker A.M. Leo O. et al.DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.Proc. Natl. Acad. Sci. USA. 2007; 104: 18157-18162Crossref PubMed Scopus (269) Google Scholar, 16Geng L.N. Yao Z. Snider L. Fong A.P. Cech J.N. Young J.M. van der Maarel S.M. Ruzzo W.L. Gentleman R.C. Tawil R. Tapscott S.J. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.Dev. Cell. 2012; 22: 38-51Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 17Jones T.I. Chen J.C. Rahimov F. Homma S. Arashiro P. Beermann M.L. King O.D. Miller J.B. Kunkel L.M. Emerson Jr., C.P. et al.Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis.Hum. Mol. Genet. 2012; 21: 4419-4430Crossref PubMed Scopus (125) Google Scholar, 18Snider L. Geng L.N. Lemmers R.J.L.F. Kyba M. Ware C.B. Nelson A.M. Tawil R. Filippova G.N. van der Maarel S.M. Tapscott S.J. Miller D.G. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.PLoS Genet. 2010; 6: e1001181Crossref PubMed Scopus (314) Google Scholar DUX4 is a germline transcription factor that is normally repressed in somatic cells most probably by a mechanism of repeat-mediated heterochromatin formation. Its expression in skeletal muscle triggers germline and early stem cell programs, eventually causing muscle cell death.16Geng L.N. Yao Z. Snider L. Fong A.P. Cech J.N. Young J.M. van der Maarel S.M. Ruzzo W.L. Gentleman R.C. Tawil R. Tapscott S.J. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.Dev. Cell. 2012; 22: 38-51Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 19Bosnakovski D. Xu Z. Gang E.J. Galindo C.L. Liu M. Simsek T. Garner H.R. Agha-Mohammadi S. Tassin A. Coppée F. et al.An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies.EMBO J. 2008; 27: 2766-2779Crossref PubMed Scopus (220) Google Scholar, 20Mitsuhashi H. Mitsuhashi S. Lynn-Jones T. Kawahara G. Kunkel L.M. Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy.Hum. Mol. Genet. 2013; 22: 568-577Crossref PubMed Scopus (58) Google Scholar, 21Wallace L.M. Liu J. Domire J.S. Garwick-Coppens S.E. Guckes S.M. Mendell J.R. Flanigan K.M. Harper S.Q. RNA interference inhibits DUX4-induced muscle toxicity in vivo: implications for a targeted FSHD therapy.Mol. Ther. 2012; 20: 1417-1423Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Consequent to the contraction, the repressive chromatin structure is compromised as evidenced by a loss of CpG methylation (hypomethylation) and repressive chromatin proteins and modifications22de Greef J.C. Lemmers R.J. Camaño P. Day J.W. Sacconi S. Dunand M. van Engelen B.G. Kiuru-Enari S. Padberg G.W. Rosa A.L. et al.Clinical features of facioscapulohumeral muscular dystrophy 2.Neurology. 2010; 75: 1548-1554Crossref PubMed Scopus (135) Google Scholar, 23van Overveld P.G. Lemmers R.J. Sandkuijl L.A. Enthoven L. Winokur S.T. Bakels F. Padberg G.W. van Ommen G.J. Frants R.R. van der Maarel S.M. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy.Nat. Genet. 2003; 35: 315-317Crossref PubMed Scopus (301) Google Scholar, 24Zeng W. de Greef J.C. Chen Y.Y. Chien R. Kong X. Gregson H.C. Winokur S.T. Pyle A. Robertson K.D. Schmiesing J.A. et al.Specific loss of histone H3 lysine 9 trimethylation and HP1gamma/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD).PLoS Genet. 2009; 5: e1000559Crossref PubMed Scopus (200) Google Scholar and the concomitant gain in transcription-activating chromatin marks.25Cabianca D.S. Casa V. Bodega B. Xynos A. Ginelli E. Tanaka Y. Gabellini D. A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy.Cell. 2012; 149: 819-831Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar Together, these changes in D4Z4 chromatin increase the likelihood of DUX4 expression in skeletal muscle, leading to a variegated pattern of DUX4-positive myonuclei.17Jones T.I. Chen J.C. Rahimov F. Homma S. Arashiro P. Beermann M.L. King O.D. Miller J.B. Kunkel L.M. Emerson Jr., C.P. et al.Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis.Hum. Mol. Genet. 2012; 21: 4419-4430Crossref PubMed Scopus (125) Google Scholar, 18Snider L. Geng L.N. Lemmers R.J.L.F. Kyba M. Ware C.B. Nelson A.M. Tawil R. Filippova G.N. van der Maarel S.M. Tapscott S.J. Miller D.G. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.PLoS Genet. 2010; 6: e1001181Crossref PubMed Scopus (314) Google Scholar, 26Tassin A. Laoudj-Chenivesse D. Vanderplanck C. Barro M. Charron S. Ansseau E. Chen Y.W. Mercier J. Coppée F. Belayew A. DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy?.J. Cell. Mol. Med. 2013; 17: 76-89Crossref PubMed Scopus (92) Google Scholar For FSHD to result, D4Z4 contraction needs to occur on FSHD-permissive chromosomal backgrounds.27Lemmers R.J. Wohlgemuth M. van der Gaag K.J. van der Vliet P.J. van Teijlingen C.M. de Knijff P. Padberg G.W. Frants R.R. van der Maarel S.M. Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy.Am. J. Hum. Genet. 2007; 81: 884-894Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 28Lemmers R.J. van der Vliet P.J. van der Gaag K.J. Zuninga S. Frants R.R. de Knijff P. van der Maarel S.M. Worldwide population analysis of the 4q and 10q subtelomeres identifies only four discrete interchromosomal sequence transfers in human evolution.Am. J. Hum. Genet. 2010; 86: 364-377Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Internal copies of the DUX4 retrogene do not have a polyadenylation signal (PAS) but the distal copy of the D4Z4 repeat array can make use of a polymorphic PAS present on approximately one-half of the chromosome 4, commonly referred to as 4qA chromosomes (e.g., 4A161).15Dixit M. Ansseau E. Tassin A. Winokur S. Shi R. Qian H. Sauvage S. Mattéotti C. van Acker A.M. Leo O. et al.DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.Proc. Natl. Acad. Sci. USA. 2007; 104: 18157-18162Crossref PubMed Scopus (269) Google Scholar, 29Lemmers R.J. van der Vliet P.J. Klooster R. Sacconi S. Camaño P. Dauwerse J.G. Snider L. Straasheijm K.R. van Ommen G.J. Padberg G.W. et al.A unifying genetic model for facioscapulohumeral muscular dystrophy.Science. 2010; 329: 1650-1653Crossref PubMed Scopus (521) Google Scholar, 30Snider L. Asawachaicharn A. Tyler A.E. Geng L.N. Petek L.M. Maves L. Miller D.G. Lemmers R.J. Winokur S.T. Tawil R. et al.RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy.Hum. Mol. Genet. 2009; 18: 2414-2430Crossref PubMed Scopus (172) Google Scholar In the absence of this DUX4 PAS, such as on 4qB chromosomes and on chromosome 10 where a highly homologous repeat array resides, transcriptional derepression of the FSHD locus does not normally lead to the production of stable DUX4 transcripts or to the appearance of FSHD clinical phenotype.29Lemmers R.J. van der Vliet P.J. Klooster R. Sacconi S. Camaño P. Dauwerse J.G. Snider L. Straasheijm K.R. van Ommen G.J. Padberg G.W. et al.A unifying genetic model for facioscapulohumeral muscular dystrophy.Science. 2010; 329: 1650-1653Crossref PubMed Scopus (521) Google Scholar, 31Lemmers R.J. Wohlgemuth M. Frants R.R. Padberg G.W. Morava E. van der Maarel S.M. Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy.Am. J. Hum. Genet. 2004; 75: 1124-1130Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar A small group of individuals with FSHD show D4Z4 chromatin changes and DUX4 derepression in skeletal muscle in the absence of repeat array contraction. These individuals with FSHD2 (MIM 158901) carry at least one FSHD-permissive 4qA allele and are clinically identical to individuals with FSHD1.22de Greef J.C. Lemmers R.J. Camaño P. Day J.W. Sacconi S. Dunand M. van Engelen B.G. Kiuru-Enari S. Padberg G.W. Rosa A.L. et al.Clinical features of facioscapulohumeral muscular dystrophy 2.Neurology. 2010; 75: 1548-1554Crossref PubMed Scopus (135) Google Scholar, 23van Overveld P.G. Lemmers R.J. Sandkuijl L.A. Enthoven L. Winokur S.T. Bakels F. Padberg G.W. van Ommen G.J. Frants R.R. van der Maarel S.M. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy.Nat. Genet. 2003; 35: 315-317Crossref PubMed Scopus (301) Google Scholar, 32de Greef J.C. Lemmers R.J. van Engelen B.G. Sacconi S. Venance S.L. Frants R.R. Tawil R. van der Maarel S.M. Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD.Hum. Mutat. 2009; 30: 1449-1459Crossref PubMed Scopus (142) Google Scholar Unlike families with FSHD1 where the chromatin changes are mostly occurring on the contracted allele, in families with FSHD2, D4Z4 chromatin relaxation occurs on the D4Z4 repeat arrays of both chromosomes 4 and 10. Recently we showed that in the majority of families with FSHD2, the disease is caused by digenic inheritance of a DUX4 PAS-containing chromosome 4 and a mutation in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1 [MIM 614982]) gene on chromosome 18.33Lemmers R.J. Tawil R. Petek L.M. Balog J. Block G.J. Santen G.W. Amell A.M. van der Vliet P.J. Almomani R. Straasheijm K.R. et al.Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.Nat. Genet. 2012; 44: 1370-1374Crossref PubMed Scopus (414) Google Scholar SMCHD1 is a chromatin modifier necessary for the establishment and maintenance of CpG methylation of the inactive X chromosome and specific classes of repeated elements.34Blewitt M.E. Vickaryous N.K. Hemley S.J. Ashe A. Bruxner T.J. Preis J.I. Arkell R. Whitelaw E. An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse.Proc. Natl. Acad. Sci. USA. 2005; 102: 7629-7634Crossref PubMed Scopus (143) Google Scholar, 35Blewitt M.E. Gendrel A.V. Pang Z. Sparrow D.B. Whitelaw N. Craig J.M. Apedaile A. Hilton D.J. Dunwoodie S.L. Brockdorff N. et al.SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.Nat. Genet. 2008; 40: 663-669Crossref PubMed Scopus (252) Google Scholar, 36Gendrel A.V. Apedaile A. Coker H. Termanis A. Zvetkova I. Godwin J. Tang Y.A. Huntley D. Montana G. Taylor S. et al.Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome.Dev. Cell. 2012; 23: 265-279Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar FSHD2 individuals have reduced SMCHD1 binding to the D4Z4 repeats on all four chromosomes, suggesting a haploinsufficiency mechanism. In support, knockdown of SMCHD1 in control myotube cultures with normal-sized D4Z4 repeat arrays on FSHD-permissive DUX4-PAS containing chromosomes leads to the transcriptional activation of DUX4.33Lemmers R.J. Tawil R. Petek L.M. Balog J. Block G.J. Santen G.W. Amell A.M. van der Vliet P.J. Almomani R. Straasheijm K.R. et al.Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.Nat. Genet. 2012; 44: 1370-1374Crossref PubMed Scopus (414) Google Scholar Because both FSHD1 and FSHD2 result from the somatic derepression of DUX4, we investigated whether SMCHD1 may act as a modifier for disease severity in families with FSHD1 and may have a role in the marked variability of clinical expression that is encountered in some families. Previous studies were only partially successful in explaining the variation in clinical severity in individuals with FSHD1. In addition to the inverse correlation with the residual repeat size,9Goto K. Lee J.H. Matsuda C. Hirabayashi K. Kojo T. Nakamura A. Mitsunaga Y. Furukawa T. Sahashi K. Arahata K. DNA rearrangements in Japanese facioscapulohumeral muscular dystrophy patients: clinical correlations.Neuromuscul. Disord. 1995; 5: 201-208Abstract Full Text PDF PubMed Scopus (38) Google Scholar, 11Ricci E. Galluzzi G. Deidda G. Cacurri S. Colantoni L. Merico B. Piazzo N. Servidei S. Vigneti E. Pasceri V. et al.Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype.Ann. Neurol. 1999; 45: 751-757Crossref PubMed Scopus (231) Google Scholar, 12Tawil R. Forrester J. Griggs R.C. Mendell J. Kissel J. McDermott M. King W. Weiffenbach B. Figlewicz D. The FSH-DY GroupEvidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy.Ann. Neurol. 1996; 39: 744-748Crossref PubMed Scopus (167) Google Scholar, 37Lunt P.W. Jardine P.E. Koch M.C. Maynard J. Osborn M. Williams M. Harper P.S. Upadhyaya M. Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD).Hum. Mol. Genet. 1995; 4: 951-958Crossref PubMed Scopus (170) Google Scholar CpG methylation and histone modification studies of D4Z4 have likewise uncovered only rough correlations between residual methylation levels and clinical severity, with the most severely affected individuals with the smallest repeat sizes showing the largest reduction in repressive chromatin modifications.38Balog J. Thijssen P.E. de Greef J.C. Shah B. van Engelen B.G. Yokomori K. Tapscott S.J. Tawil R. van der Maarel S.M. Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD.Epigenetics. 2012; 7: 579-584Crossref PubMed Scopus (44) Google Scholar, 39van Overveld P.G. Enthoven L. Ricci E. Rossi M. Felicetti L. Jeanpierre M. Winokur S.T. Frants R.R. Padberg G.W. van der Maarel S.M. Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy.Ann. Neurol. 2005; 58: 569-576Crossref PubMed Scopus (99) Google Scholar To identify modifiers of disease severity, of particular interest are those families with FSHD1 carrying upper-sized D4Z4 repeat arrays of 8–10 units, as shown by the fact that carriers of these alleles are more likely to have a partial or less severe form of FSHD or to be asymptomatic.40Butz M. Koch M.C. Müller-Felber W. Lemmers R.J. van der Maarel S.M. Schreiber H. Facioscapulohumeral muscular dystrophy. Phenotype-genotype correlation in patients with borderline D4Z4 repeat numbers.J. Neurol. 2003; 250: 932-937Crossref PubMed Scopus (55) Google Scholar, 41Felice K.J. Whitaker C.H. The clinical features of facioscapulohumeral muscular dystrophy associated with borderline (>/=35 kb) 4q35 EcoRI fragments.J. Clin. Neuromuscul. Dis. 2005; 6: 119-126Crossref PubMed Scopus (6) Google Scholar, 42Scionti I. Fabbri G. Fiorillo C. Ricci G. Greco F. D’Amico R. Termanini A. Vercelli L. Tomelleri G. Cao M. et al.Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling.J. Med. Genet. 2012; 49: 171-178Crossref PubMed Scopus (44) Google Scholar To explore the possibility that mutations in SMCHD1 may modify the disease severity in families affected by FSHD1, we investigated the SMCHD1 locus in six unrelated individuals with FSHD1 from a cohort of 53 independent families with FSHD1 which carried a FSHD allele of 8–10 D4Z4 units. These individuals were selected based on D4Z4 methylation levels <25% indicative for FSHD2.33Lemmers R.J. Tawil R. Petek L.M. Balog J. Block G.J. Santen G.W. Amell A.M. van der Vliet P.J. Almomani R. Straasheijm K.R. et al.Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.Nat. Genet. 2012; 44: 1370-1374Crossref PubMed Scopus (414) Google Scholar We report that three of them have a mutation in SMCHD1 although in the remaining cases the cause for D4Z4 hypomethylation remains to be identified. These three cases have a repeat array of nine D4Z4 units on a FSHD-permissive DUX4 PAS-containing chromosome and show an unusually severe clinical presentation of the disease based on clinical evaluation that included manual muscle testing of 60 muscles and determination of the clinical severity score.39van Overveld P.G. Enthoven L. Ricci E. Rossi M. Felicetti L. Jeanpierre M. Winokur S.T. Frants R.R. Padberg G.W. van der Maarel S.M. Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy.Ann. Neurol. 2005; 58: 569-576Crossref PubMed Scopus (99) Google Scholar The relevant biometric and genetic observations in these families are summarized in Table 1 and Table S1 available online. Pedigrees and genetic analyses of these three families are presented in Figure 1A. Signed and informed consent was obtained from all participants and family members according to protocols approved by the Institutional Ethics Review Boards of the University Hospital of Nice and collaborating institutes.Table 1Clinical and Biometric Data of the Three FamiliesRfNrSexAAEAge at OnsetCSSMMT ScoreDiagnosisRf1021I-1M71unknownaThese patients do not report any symptoms.3261/300FSHD1I-2F67unknownaThese patients do not report any symptoms.4255/300FSHD2II-1M48121065/300FSHD1+FSHD2II-2F38–0300/300unaffectedIII-1F15–0300/300unaffectedIII-2M656198/300FSHD1+FSHD2Rf1110I-1M5561055/300FSHD1+FSHD2I-2F53–0300/300unaffectedII-1F26245280/300FSHD2II-2M21unknownaThese patients do not report any symptoms.2269/300FSHD1Rf1121II-1M67151075/300FSHD1+FSHD2Abbreviations are as follows: CSS, clinical severity score; AAE, age at the last examination; MMT, manual muscle testing.a These patients do not report any symptoms. Open table in a new tab Abbreviations are as follows: CSS, clinical severity score; AAE, age at the last examination; MMT, manual muscle testing. In the first family (Rf1021), the proband (II-1) has been followed in our Center since the age of 35 when he became wheelchair dependent. He started to experience asymmetric scapular weakness at the age of 18, but he reported inability to blow into a flute at the age of 12. During the last examination, at age 48, he presented with severe and asymmetric facial weakness of orbicularis oculi and oris, marked shoulder girdle weakness associated with bilateral scapular winging, and humeral weakness. He displays marked hyperlordosis resulting from abdominal muscle weakness and weakness and atrophy of lower legs. Distal upper limb muscles are also becoming involved. He has a clinical severity score (CSS) of 10.11Ricci E. Galluzzi G. Deidda G. Cacurri S. Colantoni L. Merico B. Piazzo N. Servidei S. Vigneti E. Pasceri V. et al.Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype.Ann. Neurol. 1999; 45: 751-757Crossref PubMed Scopus (231) Google Scholar Genetic analysis showed that this proband carries a nine D4Z4 unit 4A161 allele, confirming the diagnosis of FSHD1. His 6-year-old son (III-2) was referred to our Center because of difficulties in raising his arms and a history of frequent falls. At examination he presented with weakness of the orbicularis oculi muscles, mild shoulder girdle weakness with scapular winging, Gower’s sign, and asymmetric foot dorsiflexor weakness (CSS 6). We also examined the proband’s daughter (III-1), 15 years old, and concluded that she" @default.
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• W2011042013 title "The FSHD2 Gene SMCHD1 Is a Modifier of Disease Severity in Families Affected by FSHD1" @default.
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