Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population

Abstract

We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (>90%) of early–onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Goodman, R.M., Disorders among the Jewish People. (Johns Hopkins University Press, Baltimore, 1978).

  2. Motulsky, A.G. Possible selective effects of urbanization on Ashkenazi Jews. In Genetic Diseases among Ashkenazi Jews, eds Goodman, R. A. & Motulsky, A. G. 301–314 (Raven Press, New York, 1979).

    Google Scholar 

  3. Chakravarti, A. & Charaborty, R. Elevated frequency of Tay-Sachs disease among Ashkenazi Jews unlikely by genetic drift alone. Am. J. hum. Genet. 30, 256–261 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Yokoyama, S. Role of genetic drift in the high frequency of Tay-Sachs disease among Ashkenazi Jews. Ann. hum. Genet. 43, 133–136 (1979).

    Article  CAS  PubMed  Google Scholar 

  5. Rotter, J.I. & Diamond, J.M. What maintains the frequencies of human genetic diseases? Nature 329, 289–290 (1987).

    Article  CAS  PubMed  Google Scholar 

  6. Jorde, L. Genetic diseases in the Ashkenazi population: Evolutionary considerations. In Genetic Diversity Among Jews: Diseases and Markers at the DNA Level, eds Bonne-Tamir, B. & Adam, A., 305–318 (Oxford University Press, New York, 1992).

    Google Scholar 

  7. Diamond, J.M. Jewish lysosomes. Nature 368, 291–292 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Fraikor, A.L. Tay-Sachs disease: genetic drift among the Ashkenazim Jews. Soc Bio 24, 117–134 (1977).

    Article  CAS  Google Scholar 

  9. Wagener, D., Cavali-Sforza L.L. & Barakat, R . Ethnic variation of genetic disease: roles of drift for recessive lethal genes. An. J. hum. Genet. 30, 262–270 (1978).

    CAS  Google Scholar 

  10. Chase, G.A. & McKusick, V.A. Controversy in human genetics: founder effect in Tay-Sachs disease. Am. J. hum. Genet. 24, 339–340 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Fahn, S. Generalized dystonia: concept and treatment. Clin. Neuropharmacol. 9, 537–548 (1986).

    Article  Google Scholar 

  12. Zeman, W. & Dyken, P. Dystonia musculorum deformans: clinical, genetic and pathoanatomical studies. Psychiatr. Neurol. Neurochir. 70, 77–121 (1967).

    CAS  PubMed  Google Scholar 

  13. Korczyn, D. et al. Torsion dystonia in lsrael. Ann. Neurol. 8, 387–391 (1980).

    Article  CAS  PubMed  Google Scholar 

  14. Bressman, S.B. et al. Idiopathic dystonia among Ashkenazi Jews: evidence for autosomal dominant inheritance. Ann. Neurol. 26, 612–620 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Eldridge, R. The torsion dystonias: literature review: genetic and clinical studies. Neurology 20, 1–78 (1970).

    Article  CAS  PubMed  Google Scholar 

  16. Eldridge, R. & Gottlieb, R. The primary hereditary dystonias: genetic classification of 768 families and revised estimate of gene frequency, autosomal recessive form, and selected bibliography. Adv. Neurol. 14, 457–474 (1976).

    CAS  PubMed  Google Scholar 

  17. Zilber, N. et al. Inheritance of idiopathic torsion dystonia among Jews. J. Med. Genet. 218, 13–20 (1984).

    Article  Google Scholar 

  18. Risch, N. et al. Segregation analysis of Idiopathic torsion dystonia in Ashkenazi Jews suggests autosomal dominant inheritance. Am. J. Hum. Genet. 46, 533–538 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ozelius, L. et al. Human gene for torsion dystonia located on chromosome 9q32-34. Neuron 2, 1427–1434 (1989).

    Article  CAS  PubMed  Google Scholar 

  20. Kramer, P.L. et al. Dystonia gene in Ashkenazi Jewish population is located on chromosome 9q32-34. Ann. Neurol. 27, 114–120 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Ozelius, L. et al. Strong allelic association between the torsion dystonia gene (DYT1) and loci on chromosome 9q34 in Ashkenazi Jews. Am. J. Hum. Genet. 50, 619–628 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kwaitkowski D. et al. Construction of a GT polymorphism map of human 9q. Genomics 12, 229–240 (1992).

    Article  Google Scholar 

  23. Bressman, S.B. et al. Idiopathic torsion dystonia in Ashkenazi Jews: clinical characterization of a founder mutation. Ann. Neurol. 36, 771–777 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Serre, J.L. et al. Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in population genetics. Hum. Genet 84, 449–454 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. Cox, T.K. et al. Mapping of the cystic fibrosis gene using putative ancestral recombinants. Am. J. Hum. Genet. 45, A136 (1989).

    Google Scholar 

  26. Hastbacka, J. et al. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nature Genet. 2, 204–211 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Schwalbe, W. Eine eigentumliche tonische Krampffoum mit hysterischen Symptonen. Medicin und chirurgie [Dissertation]. (Unlversitats-Buchdrukerei von Gustav Schade, Berline, 1908).

  28. American Jewish Yearbook (The Jewish Publication Society of America, Philadelphia, 1992).

  29. Fletcher, N.A., Harding, A.E. & Marsden, C.D. A genetic study of idiopathic torsion dystonia in the United Kingdom. Brain 113, 379–395 (1990).

    Article  PubMed  Google Scholar 

  30. U.S. Bureau of the Census. Statistical Abstract of theUnited States: 1993 (113th edition). (Washington, D. C., 1993).

  31. Weinryb, B.D. The Jews of Poland. A social and Economic History of the Jewish Community of Poland from 1100 to 1800. (The Jewish Publication Society of America, Philadelphia, 1972).

    Google Scholar 

  32. Blumenfeld, A. et al. Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis. Nature Genet. 4, 160–164 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Ellis, A. et al. Linkage disequillbrium between the FES, D15S727, and BLM Loci in Ashkenazi Jews with Bloom Syndrome. Am. J. hum. Genet. 55, 453–460 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Haines, J.L. et al. A genetic linkage map of chromosome 17. Genomics 8, 1–6 (1990).

    Article  CAS  PubMed  Google Scholar 

  35. Anderson, M. & Gusella, J. Use of cyclosporin A establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro 29, 856–858 (1984).

    Article  Google Scholar 

  36. Breakefield, X. et al. Linkage analysis in a family with domlnantly-inherited torsion dystonia: exclusion of the pro-opiomelanocortln and glutamlc acid decarboxyiase genes and other chromosomal regions using DNA polymorphisms. J. Neurogenetics. 3, 159–175 (1986).

    Article  CAS  Google Scholar 

  37. Henske, E. et al. A high-resolution linkage map of human 9q34. J. Genomics 17, 587–591 (1993).

    Article  CAS  Google Scholar 

  38. Ott, J. A computer program for linkage analysis of general human pedigrees. Am. J. Hum. Genet. 28, 528–529 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bengtsson, B.O. & Thomson, G. Measuring the strength of associations between HLA antigens and diseases. Tissue Antigens 18, 356–363 (1981).

    Article  CAS  PubMed  Google Scholar 

  40. Thomson, G. A review of theoretical aspects of HLA and disease associations. Theor. Pop. Biol. 20, 168–208 (1981).

    Article  CAS  Google Scholar 

  41. Ott, J. Analysis of Human Genetic Linkage. (The Johns Hopkins University Press, Baltimore. 1985).

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Risch, N., Leon, D., Ozelius, L. et al. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet 9, 152–159 (1995). https://doi.org/10.1038/ng0295-152

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0295-152

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing