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. 11–13). 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ozelius, L. et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nature Genet. 17, 40–48 (1997).
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).
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).
Gasser, T. Inherited myoclonus-dystonia syndrome. Adv. Neurol. 78, 325–334 (1998).
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).
Kurlan, R., Behr, J., Medved, L. & Shoulson, I. Myoclonus and dystonia: a family study. Adv. Neurol. 50, 385–389 (1988).
Gasser, T. et al. Linkage studies in alcohol-responsive myoclonic dystonia. Mov. Disord. 12, 363–370 (1996).
Kyllerman, M. et al. Alcohol-responsive myoclonic dystonia in a large family: dominant inheritance and phenotypic variation. Mov. Disord. 5, 270–279 (1990).
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).
Doheny, D. et al. Phenotypic features of myoclonic dystonia in two kindreds. Mov. Disord. 15, S162 (2000).
Nygaard, T.G. et al. Localization of a gene for myoclonus-dystonia to chromosome 7q21-q31. Ann. Neurol. 46, 794–798 (1999).
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).
Asmus, F. et al. Inherited myoclonus-dystonia syndrome: narrowing the 7q21-q31 locus in German families. Ann. Neurol. 49, 121–124 (2001).
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).
Lundemo, G. & Persson, H.E. Hereditary essential myoclonus. Acta Neurol. Scand. 72, 176–179 (1985).
Kurlan, R., Behr, J. & Shoulson, I. Hereditary myoclonus and chorea: the spectrum of hereditary nonprogressive hyperkinetic movement disorders. Mov. Disord. 2, 301–306 (1987).
Fahn, S. & Sjaastad, O. Hereditary essential myoclonus in a large Norwegian family. Mov. Disord. 6, 237–247 (1991).
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).
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).
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).
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).
Durr, A. et al. D2 dopamine receptor gene in myoclonic dystonia and essential myoclonus. Ann. Neurol. 48, 127–128 (2000).
Grimes, D.A., Bulman, D., George-Hyslop, P. & Lang, A.E. Inherited myoclonus-dystonia: evidence supporting genetic heterogeneity. Mov. Disord. 16, 106–110 (2001).
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).
Lim, L.E. & Campbell, K.P. The sarcoglycan complex in limb-girdle muscular dystrophy. Curr. Opin. Neurol. 11, 443–452 (1998).
Selemon, L.D. & Goldman-Rakic, P.S. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol. Psychiatry 45, 17–25 (1999).
Scheidtmann, K., Muller, F., Hartmann, E. & Koenig, E. Familial myoclonus-dystonia syndrome associated with panic attacks. Nervenarzt 71, 839–842 (2000).
Acknowledgements
We thank G. Denuschl for referral of the index patient in family MD2.
Author information
Authors and Affiliations
Corresponding author
Supplementary Information
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng709