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J Med Genet. 2004 Nov; 41(11): 826–836.
PMCID: PMC1735617

FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients


Background: Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with partial deletion of the subtelomeric D4Z4 repeat array on chromosome 4qter. This chromosomal rearrangement may result in regional chromatin relaxation and transcriptional deregulation of genes nearby.

Methods and results: Here we describe the isolation and characterisation of FRG2, a member of a chromosomally dispersed gene family, mapping only 37 kb proximal to the D4Z4 repeat array. Homology and motif searches yielded no clues to the function of the predicted protein. FRG2 expression is undetectable in all tissues tested except for differentiating myoblasts of FSHD patients, which display low, yet distinct levels of FRG2 expression, partly from chromosome 4 but predominantly originating from its homologue on chromosome 10. However, in non-FSHD myopathy patients only distantly related FRG2 homologues are transcribed, while differentiating myoblasts from healthy controls fail to express any member of this gene family. Moreover, fibroblasts of FSHD patients and control individuals undergoing forced Ad5-MyoD mediated myogenesis show expression of FRG2 mainly originating from chromosome 10. Luciferase reporter assays show that the FRG2 promoter region can direct high levels of expression but is inhibited by increasing numbers of D4Z4 repeat units. Transient transfection experiments with FRG2 fusion-protein constructs reveal nuclear localisation and apparently FRG2 overexpression causes a wide range of morphological changes.

Conclusion: The localisation of FRG2 genes close to the D4Z4 repeats on chromosome 4 and 10, their transcriptional upregulation specifically in FSHD myoblast cultures, potential involvement in myogenesis, and promoter properties qualify FRG2 as an attractive candidate for FSHD pathogenesis.

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Selected References

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  • Funakoshi M, Goto K, Arahata K. Epilepsy and mental retardation in a subset of early onset 4q35-facioscapulohumeral muscular dystrophy. Neurology. 1998 Jun;50(6):1791–1794. [PubMed]
  • Padberg GW, Frants RR, Brouwer OF, Wijmenga C, Bakker E, Sandkuijl LA. Facioscapulohumeral muscular dystrophy in the Dutch population. Muscle Nerve Suppl. 1995;2:S81–S84. [PubMed]
  • Sarfarazi M, Wijmenga C, Upadhyaya M, Weiffenbach B, Hyser C, Mathews K, Murray J, Gilbert J, Pericak-Vance M, Lunt P, et al. Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: combined analysis of an international consortium. Am J Hum Genet. 1992 Aug;51(2):396–403. [PMC free article] [PubMed]
  • Wijmenga C, Frants RR, Brouwer OF, Moerer P, Weber JL, Padberg GW. Location of facioscapulohumeral muscular dystrophy gene on chromosome 4. Lancet. 1990 Sep 15;336(8716):651–653. [PubMed]
  • Wijmenga C, Hewitt JE, Sandkuijl LA, Clark LN, Wright TJ, Dauwerse HG, Gruter AM, Hofker MH, Moerer P, Williamson R, et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet. 1992 Sep;2(1):26–30. [PubMed]
  • van Deutekom JC, Wijmenga C, van Tienhoven EA, Gruter AM, Hewitt JE, Padberg GW, van Ommen GJ, Hofker MH, Frants RR. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet. 1993 Dec;2(12):2037–2042. [PubMed]
  • Hewitt JE, Lyle R, Clark LN, Valleley EM, Wright TJ, Wijmenga C, van Deutekom JC, Francis F, Sharpe PT, Hofker M, et al. Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum Mol Genet. 1994 Aug;3(8):1287–1295. [PubMed]
  • Lee JH, Goto K, Matsuda C, Arahata K. Characterization of a tandemly repeated 3.3-kb KpnI unit in the facioscapulohumeral muscular dystrophy (FSHD) gene region on chromosome 4q35. Muscle Nerve Suppl. 1995;2:S6–13. [PubMed]
  • Lunt PW, Jardine PE, Koch MC, Maynard J, Osborn M, Williams M, Harper PS, 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 May;4(5):951–958. [PubMed]
  • Tawil R, Forrester J, Griggs RC, Mendell J, Kissel J, McDermott M, King W, Weiffenbach B, Figlewicz D. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann Neurol. 1996 Jun;39(6):744–748. [PubMed]
  • Winokur ST, Bengtsson U, Feddersen J, Mathews KD, Weiffenbach B, Bailey H, Markovich RP, Murray JC, Wasmuth JJ, Altherr MR, et al. The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin-associated repetitive element: implications for a role of chromatin structure in the pathogenesis of the disease. Chromosome Res. 1994 May;2(3):225–234. [PubMed]
  • Jiang Guanchao, Yang Fan, van Overveld Petra G M, Vedanarayanan Vettaikorumakankav, van der Maarel Silvere, Ehrlich Melanie. Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Hum Mol Genet. 2003 Nov 15;12(22):2909–2921. [PubMed]
  • Winokur Sara T, Chen Yi-Wen, Masny Peter S, Martin Jorge H, Ehmsen Jeffrey T, Tapscott Stephen J, van der Maarel Silvere M, Hayashi Yukiko, Flanigan Kevin M. Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. Hum Mol Genet. 2003 Nov 15;12(22):2895–2907. [PubMed]
  • Stout K, van der Maarel S, Frants RR, Padberg GW, Ropers HH, Haaf T. Somatic pairing between subtelomeric chromosome regions: implications for human genetic disease? Chromosome Res. 1999;7(5):323–329. [PubMed]
  • van der Maarel SM, Deidda G, Lemmers RJ, van Overveld PG, van der Wielen M, Hewitt JE, Sandkuijl L, Bakker B, van Ommen GJ, Padberg GW, et al. De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. Am J Hum Genet. 2000 Jan;66(1):26–35. [PMC free article] [PubMed]
  • Lemmers Richard J L F, Van Overveld Petra G M, Sandkuijl Lodewijk A, Vrieling Harry, Padberg George W, Frants Rune R, van der Maarel Silvère M. Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2004 Jul;75(1):44–53. [PMC free article] [PubMed]
  • van Overveld Petra G M, Lemmers Richard J F L, Sandkuijl Lodewijk A, Enthoven Leo, Winokur Sara T, Bakels Floor, Padberg George W, van Ommen Gert-Jan B, Frants Rune R, van der Maarel Silvère M. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet. 2003 Dec;35(4):315–317. [PubMed]
  • Gabellini Davide, Green Michael R, Tupler Rossella. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell. 2002 Aug 9;110(3):339–348. [PubMed]
  • Gabriëls J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, et al. Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene. 1999 Aug 5;236(1):25–32. [PubMed]
  • Yip Darren J, Picketts David J. Increasing D4Z4 repeat copy number compromises C2C12 myoblast differentiation. FEBS Lett. 2003 Feb 27;537(1-3):133–138. [PubMed]
  • Deidda G, Cacurri S, Grisanti P, Vigneti E, Piazzo N, Felicetti L. Physical mapping evidence for a duplicated region on chromosome 10qter showing high homology with the facioscapulohumeral muscular dystrophy locus on chromosome 4qter. Eur J Hum Genet. 1995;3(3):155–167. [PubMed]
  • van Deutekom JC, Bakker E, Lemmers RJ, van der Wielen MJ, Bik E, Hofker MH, Padberg GW, Frants RR. 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 Dec;5(12):1997–2003. [PubMed]
  • van Overveld PG, Lemmers RJ, Deidda G, Sandkuijl L, Padberg GW, Frants RR, van der Maarel SM. Interchromosomal repeat array interactions between chromosomes 4 and 10: a model for subtelomeric plasticity. Hum Mol Genet. 2000 Nov 22;9(19):2879–2884. [PubMed]
  • Lemmers RJL, de Kievit P, van Geel M, van der Wielen MJ, Bakker E, Padberg GW, Frants RR, van der Maarel SM. Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis. Ann Neurol. 2001 Dec;50(6):816–819. [PubMed]
  • Zhang Y, Forner J, Fournet S, Jeanpierre M. Improved characterization of FSHD mutations. Ann Genet. 2001 Apr-Jun;44(2):105–110. [PubMed]
  • van Geel M, van Deutekom JC, van Staalduinen A, Lemmers RJ, Dickson MC, Hofker MH, Padberg GW, Hewitt JE, de Jong PJ, Frants RR. Identification of a novel beta-tubulin subfamily with one member (TUBB4Q) located near the telomere of chromosome region 4q35. Cytogenet Cell Genet. 2000;88(3-4):316–321. [PubMed]
  • Grewal PK, Todd LC, van der Maarel S, Frants RR, Hewitt JE. FRG1, a gene in the FSH muscular dystrophy region on human chromosome 4q35, is highly conserved in vertebrates and invertebrates. Gene. 1998 Aug 17;216(1):13–19. [PubMed]
  • van Deutekom JC, Lemmers RJ, Grewal PK, van Geel M, Romberg S, Dauwerse HG, Wright TJ, Padberg GW, Hofker MH, Hewitt JE, et al. Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35. Hum Mol Genet. 1996 May;5(5):581–590. [PubMed]
  • van Geel M, Heather LJ, Lyle R, Hewitt JE, Frants RR, de Jong PJ. The FSHD region on human chromosome 4q35 contains potential coding regions among pseudogenes and a high density of repeat elements. Genomics. 1999 Oct 1;61(1):55–65. [PubMed]
  • Shoubridge EA, Johns T, Boulet L. Use of myoblast cultures to study mitochondrial myopathies. Methods Enzymol. 1996;264:465–475. [PubMed]
  • Murry CE, Kay MA, Bartosek T, Hauschka SD, Schwartz SM. Muscle differentiation during repair of myocardial necrosis in rats via gene transfer with MyoD. J Clin Invest. 1996 Nov 15;98(10):2209–2217. [PMC free article] [PubMed]
  • Roest PA, Bakker E, Fallaux FJ, Verellen-Dumoulin C, Murry CE, den Dunnen JT. New possibilities for prenatal diagnosis of muscular dystrophies: forced myogenesis with an adenoviral MyoD-vector. Lancet. 1999 Feb 27;353(9154):727–728. [PubMed]
  • Georgiev O, Bourquin JP, Gstaiger M, Knoepfel L, Schaffner W, Hovens C. Two versatile eukaryotic vectors permitting epitope tagging, radiolabelling and nuclear localisation of expressed proteins. Gene. 1996 Feb 12;168(2):165–167. [PubMed]
  • Cuppen E, Gerrits H, Pepers B, Wieringa B, Hendriks W. PDZ motifs in PTP-BL and RIL bind to internal protein segments in the LIM domain protein RIL. Mol Biol Cell. 1998 Mar;9(3):671–683. [PMC free article] [PubMed]
  • Langer PR, Waldrop AA, Ward DC. Enzymatic synthesis of biotin-labeled polynucleotides: novel nucleic acid affinity probes. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6633–6637. [PMC free article] [PubMed]
  • Dauwerse JG, Jumelet EA, Wessels JW, Saris JJ, Hagemeijer A, Beverstock GC, van Ommen GJ, Breuning MH. Extensive cross-homology between the long and the short arm of chromosome 16 may explain leukemic inversions and translocations. Blood. 1992 Mar 1;79(5):1299–1304. [PubMed]
  • Gould SJ, Keller GA, Hosken N, Wilkinson J, Subramani S. A conserved tripeptide sorts proteins to peroxisomes. J Cell Biol. 1989 May;108(5):1657–1664. [PMC free article] [PubMed]
  • Swinkels BW, Gould SJ, Subramani S. Targeting efficiencies of various permutations of the consensus C-terminal tripeptide peroxisomal targeting signal. FEBS Lett. 1992 Jun 29;305(2):133–136. [PubMed]
  • van Geel Michel, Eichler Evan E, Beck Amy F, Shan Zhihong, Haaf Thomas, van der Maarel Silvère M, Frants Rune R, de Jong Pieter J. A cascade of complex subtelomeric duplications during the evolution of the hominoid and Old World monkey genomes. Am J Hum Genet. 2002 Jan;70(1):269–278. [PMC free article] [PubMed]
  • Mefford Heather C, Trask Barbara J. The complex structure and dynamic evolution of human subtelomeres. Nat Rev Genet. 2002 Feb;3(2):91–102. [PubMed]
  • Winokur Sara T, Barrett Kathy, Martin Jorge H, Forrester James R, Simon Mariella, Tawil Rabi, Chung Seung-Ah, Masny Peter S, Figlewicz Denise A. Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress. Neuromuscul Disord. 2003 May;13(4):322–333. [PubMed]
  • Hettema EH, Distel B, Tabak HF. Import of proteins into peroxisomes. Biochim Biophys Acta. 1999 Aug 12;1451(1):17–34. [PubMed]
  • Trask BJ, Friedman C, Martin-Gallardo A, Rowen L, Akinbami C, Blankenship J, Collins C, Giorgi D, Iadonato S, Johnson F, et al. Members of the olfactory receptor gene family are contained in large blocks of DNA duplicated polymorphically near the ends of human chromosomes. Hum Mol Genet. 1998 Jan;7(1):13–26. [PubMed]
  • Weintraub H, Tapscott SJ, Davis RL, Thayer MJ, Adam MA, Lassar AB, Miller AD. Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5434–5438. [PMC free article] [PubMed]
  • Gerber AN, Klesert TR, Bergstrom DA, Tapscott SJ. Two domains of MyoD mediate transcriptional activation of genes in repressive chromatin: a mechanism for lineage determination in myogenesis. Genes Dev. 1997 Feb 15;11(4):436–450. [PubMed]
  • Jiang Guanchao, Yang Fan, van Overveld Petra G M, Vedanarayanan Vettaikorumakankav, van der Maarel Silvere, Ehrlich Melanie. Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Hum Mol Genet. 2003 Nov 15;12(22):2909–2921. [PubMed]
  • van Geel Michel, Dickson Morag C, Beck Amy F, Bolland Daniel J, Frants Rune R, van der Maarel Silvère M, de Jong Pieter J, Hewitt Jane E. Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin. Genomics. 2002 Feb;79(2):210–217. [PubMed]
  • Lemmers RJLF, Osborn M, Haaf T, Rogers M, Frants RR, Padberg GW, Cooper DN, van der Maarel SM, Upadhyaya M. D4F104S1 deletion in facioscapulohumeral muscular dystrophy: phenotype, size, and detection. Neurology. 2003 Jul 22;61(2):178–183. [PubMed]

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