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Gene Review

FSHMD1A  -  facioscapulohumeral muscular dystrophy 1A

Homo sapiens

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Disease relevance of FSHMD1A


Psychiatry related information on FSHMD1A

  • Facioscapulohumeral muscular dystrophy (FSHD), a pathology primarily characterized by involvement of the muscles in the face, shoulder and upper arm, can be associated to several CNS disorders, including sensorineural hearing deficits, schizophrenia, epilepsy and mental retardation [6].
  • Among persons with arthritis, those with FMD as compared with those without FMD were more likely to be underweight and obese than normal weight; they also were more likely to be insufficiently active or inactive than following recommended physical activity guidelines [7].
  • Multiple regression analysis showed alcohol consumption to be one of the factors favorably influencing FMD [8].
  • Adult male patients affected with Becker (BMD, N = 22), limb girdle (LGMD, N = 22) and facioscapulohumeral (FSHMD, N = 18) muscular dystrophy were interviewed to assess for the first time how the disease's severity and recurrence risk (RR) magnitude alter their social adjustment [9].
  • In both studies, the FSHD patients showed significantly larger values for all parameters except the flexion of shoulder joint and reaction time, compared with controls before the ML task [10].

High impact information on FSHMD1A

  • Facioscapulohumeral muscular dystrophy (FSHD), a common myopathy, is an autosomal dominant disease of unknown molecular mechanism [11].
  • Almost all FSHD patients carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35 [11].
  • Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle [11].
  • By using as a probe a clone isolated from a cosmid containing sequences related to a homeobox domain, de novo DNA rearrangements were reported in sporadic and familial cases of FSHD [12].
  • Both observations indicate that FSHD is caused by independent de novo DNA rearrangements in the EcoRI fragment detected by p13E-11 [13].

Chemical compound and disease context of FSHMD1A


Biological context of FSHMD1A

  • The apparent low level of expressed sequences from within this region, the integral deletions of D4Z4 repeats observed in FSHD patients and the close proximity of these repeats to the 4q telomere, all suggest that the disease may be the result of position effect variegation [1].
  • 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 [18].
  • Additional mis-expressed genes confirm a diminished capacity to buffer oxidative stress, as demonstrated in FSHD myoblasts [19].
  • Disruptions in FSHD myogenesis and oxidative capacity may therefore not arise from a position effect mechanism as has been previously suggested, but rather from a global effect on gene regulation [19].
  • This finding was corroborated by expression analysis of FSHD muscle using a custom cDNA microarray containing 51 genes and ESTs from the 4q35 region [19].

Anatomical context of FSHMD1A

  • Investigation of heterozygous FSHD myoblasts demonstrated no significant displacement of the mutant allele from the nuclear periphery [2].
  • Localization of 4q35.2 to the nuclear periphery: is FSHD a nuclear envelope disease [20]?
  • Contrary to the loss-of-PEV model and a recent report, there was no position-dependent increase in transcript levels from these genes in FSHD skeletal muscle samples compared with controls [21].
  • Contrary to the above model, H4 acetylation levels of a non-repeated region adjacent to the 4q35 and 10q26 D4Z4 arrays in normal and FSHD lymphoid cells were like those in unexpressed euchromatin and not constitutive heterochromatin [21].
  • Facioscapulohumeral disease (FSHD), an inherited neuromuscular disorder, is characterized by progressive wasting of specific muscle groups, particularly the proximal musculature of the upper limbs; the primary defect in this disorder is unknown [22].

Associations of FSHMD1A with chemical compounds

  • At the end of the 12-month period, a worsening was observed in NID (P = 0.02) and a marginal worsening was seen in systolic blood pressure (P = 0.04) and FMD (P = 0.04) in the vitamin E compared with the placebo group [23].
  • In the simvastatin FH group, FMD increased to a level similar to the non-FH controls (15.6% +/- 6.8% vs. 15.5% +/- 5.4%, p = 0.958) [24].
  • RESULTS: FMD was significantly reduced in women with previous Gh compared with controls (P < 0.0001), whereas nitroglycerin-induced dilatation was comparable in both groups [25].
  • FMD improved in the atorvastatin-treated, at-risk subjects [median (25-75 percentile), 7.2% (2.9-9.6%) at exit visit vs. 6.6% (2.9-9.5%) at baseline; P < 0.05] [26].
  • The effects of albuterol in FSHD are currently being evaluated in a larger, randomized, double-blind, placebo-controlled trial lasting 1 year [27].

Other interactions of FSHMD1A

  • The identification of the FSHD gene and characterization of the gene product will not only potentiate accurate diagnosis but may also unravel the complexities of the 4q35 FSHD region [1].
  • The global gene expression profiling of mature muscle tissue presented here provides the first insight into an FSHD-specific defect in myogenic differentiation [19].
  • FSHD expression profiles generated by oligonucleotide microarrays were compared with those from normal muscle as well as other types of muscular dystrophies (DMD, aSGD) in order to determine FSHD-specific changes [19].
  • Two-point linkage analysis between FSHD and D4S139 in nine informative families showed a maximum combined lod score (Zmax) of 17.28 at a recombination fraction theta of 0.027 [28].

Analytical, diagnostic and therapeutic context of FSHMD1A


  1. Molecular genetics of facioscapulohumeral muscular dystrophy (FSHD). Fisher, J., Upadhyaya, M. Neuromuscul. Disord. (1997) [Pubmed]
  2. The 4q subtelomere harboring the FSHD locus is specifically anchored with peripheral heterochromatin unlike most human telomeres. Tam, R., Smith, K.P., Lawrence, J.B. J. Cell Biol. (2004) [Pubmed]
  3. The evolutionary distribution and structural organization of the homeobox-containing repeat D4Z4 indicates a functional role for the ancestral copy in the FSHD region. Winokur, S.T., Bengtsson, U., Vargas, J.C., Wasmuth, J.J., Altherr, M.R., Weiffenbach, B., Jacobsen, S.J. Hum. Mol. Genet. (1996) [Pubmed]
  4. Facioscapulohumeral dystrophy: a distinct regional myopathy with a novel molecular pathogenesis. FSH Consortium. Tawil, R., Figlewicz, D.A., Griggs, R.C., Weiffenbach, B. Ann. Neurol. (1998) [Pubmed]
  5. Preterm birth, vascular function, and risk factors for atherosclerosis. Singhal, A., Kattenhorn, M., Cole, T.J., Deanfield, J., Lucas, A. Lancet (2001) [Pubmed]
  6. Modifications of brain tissue volumes in facioscapulohumeral dystrophy. Quarantelli, M., Lanzillo, R., Del Vecchio, W., Mollica, C., Prinster, A., Iadicicco, L., Iodice, V., Santoro, L., Salvatore, M. Neuroimage (2006) [Pubmed]
  7. Frequent mental distress status among adults with arthritis age 45 years and older, 2001. Strine, T.W., Hootman, J.M., Okoro, C.A., Balluz, L., Moriarty, D.G., Owens, M., Mokdad, A. Arthritis Rheum. (2004) [Pubmed]
  8. Effect of alcohol consumption on endothelial function in men with coronary artery disease. Teragawa, H., Fukuda, Y., Matsuda, K., Higashi, Y., Yamagata, T., Matsuura, H., Chayama, K. Atherosclerosis (2002) [Pubmed]
  9. Social adjustment in adult males affected with progressive muscular dystrophy. Eggers, S., Zatz, M. Am. J. Med. Genet. (1998) [Pubmed]
  10. The effect of motor learning in facioscapulohumeral muscular dystrophy patients. Bakhtiary, A.H., Phoenix, J., Edwards, R.H., Frostick, S.P. European journal of applied physiology. (2000) [Pubmed]
  11. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Gabellini, D., Green, M.R., Tupler, R. Cell (2002) [Pubmed]
  12. Mapping the facioscapulohumeral muscular dystrophy gene is complicated by chromsome 4q35 recombination events. Weiffenbach, B., Dubois, J., Storvick, D., Tawil, R., Jacobsen, S.J., Gilbert, J., Wijmenga, C., Mendell, J.R., Winokur, S., Altherr, M.R. Nat. Genet. (1993) [Pubmed]
  13. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Wijmenga, 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. Nat. Genet. (1992) [Pubmed]
  14. Androgenic anabolic steroids and arterial structure and function in male bodybuilders. Sader, M.A., Griffiths, K.A., McCredie, R.J., Handelsman, D.J., Celermajer, D.S. J. Am. Coll. Cardiol. (2001) [Pubmed]
  15. A folate- and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats. Ghoshal, K., Li, X., Datta, J., Bai, S., Pogribny, I., Pogribny, M., Huang, Y., Young, D., Jacob, S.T. J. Nutr. (2006) [Pubmed]
  16. Endothelial dysfunction: methods of assessment and application to hypertension. Nadar, S., Blann, A.D., Lip, G.Y. Curr. Pharm. Des. (2004) [Pubmed]
  17. A phase II study to evaluate the combination of fludarabine, mitoxantrone and dexamethasone (FMD) in patients with follicular lymphoma. Crawley, C.R., Foran, J.M., Gupta, R.K., Rohatiner, A.Z., Summers, K., Matthews, J., Micallef, I.N., Radford, J.A., Johnson, S.A., Johnson, P.W., Sweetenham, J.W., Lister, T.A. Ann. Oncol. (2000) [Pubmed]
  18. FSHD-like patients without 4q35 deletion. Yamanaka, G., Goto, K., Ishihara, T., Oya, Y., Miyajima, T., Hoshika, A., Nishino, I., Hayashi, Y.K. J. Neurol. Sci. (2004) [Pubmed]
  19. Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. Winokur, S.T., Chen, Y.W., Masny, P.S., Martin, J.H., Ehmsen, J.T., Tapscott, S.J., van der Maarel, S.M., Hayashi, Y., Flanigan, K.M. Hum. Mol. Genet. (2003) [Pubmed]
  20. Localization of 4q35.2 to the nuclear periphery: is FSHD a nuclear envelope disease? Masny, P.S., Bengtsson, U., Chung, S.A., Martin, J.H., van Engelen, B., van der Maarel, S.M., Winokur, S.T. Hum. Mol. Genet. (2004) [Pubmed]
  21. Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Jiang, G., Yang, F., van Overveld, P.G., Vedanarayanan, V., van der Maarel, S., Ehrlich, M. Hum. Mol. Genet. (2003) [Pubmed]
  22. Deficiency of complex III of the mitochondrial respiratory chain in a patient with facioscapulohumeral disease. Slipetz, D.M., Aprille, J.R., Goodyer, P.R., Rozen, R. Am. J. Hum. Genet. (1991) [Pubmed]
  23. The effect of vitamin E on endothelial function of micro- and macrocirculation and left ventricular function in type 1 and type 2 diabetic patients. Economides, P.A., Khaodhiar, L., Caselli, A., Caballero, A.E., Keenan, H., Bursell, S.E., King, G.L., Johnstone, M.T., Horton, E.S., Veves, A. Diabetes (2005) [Pubmed]
  24. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. de Jongh, S., Lilien, M.R., op't Roodt, J., Stroes, E.S., Bakker, H.D., Kastelein, J.J. J. Am. Coll. Cardiol. (2002) [Pubmed]
  25. Cardiovascular risk factors in healthy women with previous gestational hypertension. Paradisi, G., Biaggi, A., Savone, R., Ianniello, F., Tomei, C., Caforio, L., Caruso, A. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  26. The effects of atorvastatin on endothelial function in diabetic patients and subjects at risk for type 2 diabetes. Economides, P.A., Caselli, A., Tiani, E., Khaodhiar, L., Horton, E.S., Veves, A. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  27. Pilot trial of albuterol in facioscapulohumeral muscular dystrophy. FSH-DY Group. Kissel, J.T., McDermott, M.P., Natarajan, R., Mendell, J.R., Pandya, S., King, W.M., Griggs, R.C., Tawil, R. Neurology (1998) [Pubmed]
  28. Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization. Wijmenga, C., Padberg, G.W., Moerer, P., Wiegant, J., Liem, L., Brouwer, O.F., Milner, E.C., Weber, J.L., van Ommen, G.B., Sandkuyl, L.A. Genomics (1991) [Pubmed]
  29. D4F104S1 deletion in facioscapulohumeral muscular dystrophy: phenotype, size, and detection. Lemmers, R.J., Osborn, M., Haaf, T., Rogers, M., Frants, R.R., Padberg, G.W., Cooper, D.N., van der Maarel, S.M., Upadhyaya, M. Neurology (2003) [Pubmed]
  30. A radiation hybrid map of 15 loci on the distal long arm of chromosome 4, the region containing the gene responsible for facioscapulohumeral muscular dystrophy (FSHD). Winokur, S.T., Schutte, B., Weiffenbach, B., Washington, S.S., McElligott, D., Chakravarti, A., Wasmuth, J.H., Altherr, M.R. Am. J. Hum. Genet. (1993) [Pubmed]
  31. 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). Lunt, P.W., Jardine, P.E., Koch, M.C., Maynard, J., Osborn, M., Williams, M., Harper, P.S., Upadhyaya, M. Hum. Mol. Genet. (1995) [Pubmed]
  32. Somatic mosaicism in FSHD often goes undetected. Lemmers, R.J., van der Wielen, M.J., Bakker, E., Padberg, G.W., Frants, R.R., van der Maarel, S.M. Ann. Neurol. (2004) [Pubmed]
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