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Mutations in the gene encoding ɛ-sarcoglycan cause myoclonus–dystonia syndrome

Abstract

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A1 and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP–cyclohydrolase I and mutant in dominant dopa-responsive dystonia2, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease3. Myoclonus–dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles4,5. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease6,7. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive–compulsive behavior8,9,10. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 1113). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for ɛ-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse ɛ-sarcoglycan gene14.

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Figure 1: SGCE mutations in MDS families.
Figure 2: Physical map of the SGCE critical region.
Figure 3: Tissue expression pattern of SGCE.

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References

  1. Ozelius, L. et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nature Genet. 17, 40–48 (1997).

    Article  CAS  Google Scholar 

  2. Ichinose, H. et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nature Genet. 8, 236–242 (1994).

    Article  CAS  Google Scholar 

  3. Ludecke, B., Dworniczak, B. & Bartholome, K. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum. Genet. 95, 123–125 (1995).

    CAS  PubMed  Google Scholar 

  4. Gasser, T. Inherited myoclonus-dystonia syndrome. Adv. Neurol. 78, 325–334 (1998).

    CAS  PubMed  Google Scholar 

  5. Quinn, N.P., Rothwell, J.C., Thompson, P.D. & Marsden, C.D. Hereditary myoclonic dystonia, hereditary torsion dystonia and hereditary essential myoclonus: an area of confusion. Adv. Neurol. 50, 391–401 (1988).

    CAS  PubMed  Google Scholar 

  6. Kurlan, R., Behr, J., Medved, L. & Shoulson, I. Myoclonus and dystonia: a family study. Adv. Neurol. 50, 385–389 (1988).

    CAS  PubMed  Google Scholar 

  7. Gasser, T. et al. Linkage studies in alcohol-responsive myoclonic dystonia. Mov. Disord. 12, 363–370 (1996).

    Article  Google Scholar 

  8. Kyllerman, M. et al. Alcohol-responsive myoclonic dystonia in a large family: dominant inheritance and phenotypic variation. Mov. Disord. 5, 270–279 (1990).

    Article  CAS  Google Scholar 

  9. Klein, C. et al. Association of a missense change in the D2 dopamine receptor with myoclonus dystonia. Proc. Natl Acad. Sci. USA 96, 5173–5176 (1999).

    Article  CAS  Google Scholar 

  10. Doheny, D. et al. Phenotypic features of myoclonic dystonia in two kindreds. Mov. Disord. 15, S162 (2000).

    Google Scholar 

  11. Nygaard, T.G. et al. Localization of a gene for myoclonus-dystonia to chromosome 7q21-q31. Ann. Neurol. 46, 794–798 (1999).

    Article  CAS  Google Scholar 

  12. Klein, C. et al. A major locus for myoclonus-dystonia maps to chromosome 7q in eight families. Am. J. Hum. Genet. 67, 1314–1319 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Asmus, F. et al. Inherited myoclonus-dystonia syndrome: narrowing the 7q21-q31 locus in German families. Ann. Neurol. 49, 121–124 (2001).

    Article  CAS  Google Scholar 

  14. Piras, G. et al. Zac1 (Lot1), a potential tumor suppressor gene, and the gene for epsilon-sarcoglycan are maternally imprinted genes: identification by a subtractive screen of novel uniparental fibroblast lines. Mol. Cell Biol. 20, 3308–3315 (2000).

    Article  CAS  Google Scholar 

  15. Lundemo, G. & Persson, H.E. Hereditary essential myoclonus. Acta Neurol. Scand. 72, 176–179 (1985).

    Article  CAS  Google Scholar 

  16. Kurlan, R., Behr, J. & Shoulson, I. Hereditary myoclonus and chorea: the spectrum of hereditary nonprogressive hyperkinetic movement disorders. Mov. Disord. 2, 301–306 (1987).

    Article  CAS  Google Scholar 

  17. Fahn, S. & Sjaastad, O. Hereditary essential myoclonus in a large Norwegian family. Mov. Disord. 6, 237–247 (1991).

    Article  CAS  Google Scholar 

  18. Ettinger, A.J., Feng, G., & Sanes, J.R. ɛ-Sarcoglycan, a broadly expressed homologue of the gene mutated in limb-girdle muscular dystrophy 2D. J. Biol. Chem. 272, 32534–32538 (1997).

    Article  CAS  Google Scholar 

  19. Straub, V. et al. ɛ-Sarcoglycan replaces alpha-sarcoglycan in smooth muscle to form a unique dystrophin-glycoprotein complex. J. Biol. Chem. 274, 27989–27996 (1999).

    Article  CAS  Google Scholar 

  20. Imamura, M., Araishi, K., Noguchi, S. & Ozawa, E. A sarcoglycan-dystroglycan complex anchors Dp116 and utrophin in the peripheral nervous system. Hum. Mol. Genet. 9, 3091–3100 (2000).

    Article  CAS  Google Scholar 

  21. Hewett, J. et al. Mutant torsinA, responsible for early-onset torsion dystonia, forms membrane inclusions in cultured neural cells. Hum. Mol. Genet. 9, 1403–1413 (2000).

    Article  CAS  Google Scholar 

  22. Durr, A. et al. D2 dopamine receptor gene in myoclonic dystonia and essential myoclonus. Ann. Neurol. 48, 127–128 (2000).

    Article  CAS  Google Scholar 

  23. Grimes, D.A., Bulman, D., George-Hyslop, P. & Lang, A.E. Inherited myoclonus-dystonia: evidence supporting genetic heterogeneity. Mov. Disord. 16, 106–110 (2001).

    Article  CAS  Google Scholar 

  24. McNally, E.M., Ly, C.T. & Kunkel, L.M. Human epsilon-sarcoglycan is highly related to alpha-sarcoglycan (adhalin), the limb girdle muscular dystrophy 2D gene. FEBS Lett. 422, 27–32 (1998).

    Article  CAS  Google Scholar 

  25. Lim, L.E. & Campbell, K.P. The sarcoglycan complex in limb-girdle muscular dystrophy. Curr. Opin. Neurol. 11, 443–452 (1998).

    Article  CAS  Google Scholar 

  26. Selemon, L.D. & Goldman-Rakic, P.S. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol. Psychiatry 45, 17–25 (1999).

    Article  CAS  Google Scholar 

  27. Scheidtmann, K., Muller, F., Hartmann, E. & Koenig, E. Familial myoclonus-dystonia syndrome associated with panic attacks. Nervenarzt 71, 839–842 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank G. Denuschl for referral of the index patient in family MD2.

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Correspondence to Thomas Gasser.

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Zimprich, A., Grabowski, M., Asmus, F. et al. Mutations in the gene encoding ɛ-sarcoglycan cause myoclonus–dystonia syndrome. Nat Genet 29, 66–69 (2001). https://doi.org/10.1038/ng709

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