Skip to main content
SpringerLink
Log in

Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping

  • Article
  • Published:

From Nature Genetics

View current issue Submit your manuscript

Abstract

Friedreich ataxia and ataxia with selective vitamin E deficiency (AVED) share very similar clinical phenotypes. We have mapped the AVED locus to proximal 8q with only three large consanguinous Tunisian families, representing to our knowledge the first use of homozygosity mapping for primary linkage analysis. Subsequently, three additional families showed linkage with the same markers. A maximum lod score of 17.9 was obtained at θ = 0 for the haplotype D8S260–D8S510, consisting of the two closest markers. With only 6 families, the AVED locus is therefore mapped precisely as illustrated by the lod–1 confidence interval of 2.4 cM on either side of D8S260–D8S510. Isolation of a yeast artificial chromosome contig >800 kilobases (kb) showed that D8S260 and D8S510 are less than 400 kb apart.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Muller, D.P., Lloyd, J.K. & Wolff, O.H. Vitamin E and neurological function. Lancet 1, 225–228 (1983).

    Article  CAS  Google Scholar 

  2. Burck, U., Goebel, H.H., Kuhlendahl, H.D., Meier, C. & Goebel, K.M. Neuromyopathy and vitamin E deficiency in man. Neuropediatrics 12, 267–278 (1981).

    Article  CAS  Google Scholar 

  3. Harding, A.E. et al. Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. New Engl. J. Med. 313, 32–35 (1985).

    Article  CAS  Google Scholar 

  4. Krendel, D.A., Gilchrist, J.M., Johnson, A.O. & Bossen, E.H. Isolated deficiency of vitamin E with progressive neurologic deterioration. Neurology 37, 538–540 (1987).

    Article  CAS  Google Scholar 

  5. Yokota, T. et al. Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann. Neurol. 22, 84–87 (1987).

    Article  CAS  Google Scholar 

  6. Stumpf, D.A. et al. Friedreich's disease: V. Variant form with vitamin E deficiency and normal fat absorption. Neurology 37, 68–74 (1987).

    Article  CAS  Google Scholar 

  7. Ben Hamida, M. et al. Friedreich's ataxiaphenotype not linked to chromosome 9 and associated to selective autosomal recessive vitamin E deficiency in two inbred Tunisian families. Neurology (in the press).

  8. Lander, E.S. & Botstein, D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 236, 1567–1570 (1987).

    Article  CAS  Google Scholar 

  9. Hazan, J., Dubay, C., Pankowiak, M.-P., Becuwe, N. & Weissenbach, J. A genetic linkage map of human chromosome 20 composed entirely of microsatellite markers. Genomics 12, 183–189 (1992).

    Article  CAS  Google Scholar 

  10. Wilkie, P.J., Krizman, D.B. & Weber, J.L. Linkage map of human chromosome 9 microsatellite polymorphisms. Genomics 12, 607–609 (1992).

    Article  CAS  Google Scholar 

  11. Weissenbach, J. et al. A second-generation linkage map of the human genome. Nature 359, 794–801 (1992).

    Article  CAS  Google Scholar 

  12. Tomfohrde, J. et al. Human chromosome 8 linkage map based on short tandem repeat polymorphisms: effect of genotyping errors. Genomics 14, 144–152 (1992).

    Article  CAS  Google Scholar 

  13. Fujita, R., Hanauer, A., Sirugo, G., Heilig, R. & Mandel, J.L. Additional polymorphisms at marker loci D9S5 and D9S15 generate extended haplotypes in linkage disequilibrium with Friedreich ataxia. Proc. natn. Acad. Sci. U.S.A. 87, 1796–1800 (1990).

    Article  CAS  Google Scholar 

  14. Albertsen, H.M., Abderrahim, H., Cann, H.M., Dausset, J., Le Paslier, D. & Cohen, D. Construction and characterization of a yeast artificial chromosome library containing seven haploid human genome equivalents. Proc. natn. Acad. Sci. U.S.A. 87, 4256–4260 (1990).

    Article  CAS  Google Scholar 

  15. Bellanne-Chantelot, C. et al. Mapping the whole human genome by fingerprinting yeast artificial chromosomes. Cell 70, 1059–1068 (1992).

    Article  CAS  Google Scholar 

  16. Kere, J. et al. Mapping human chromosomes by walking with sequence-tagged sites from end fragments of yeast artificial chromosome inserts. Genomics 14, 241–248 (1992).

    Article  CAS  Google Scholar 

  17. Schellenberg, G.D. et al. Homozygosity mapping and Werner's syndrome. Lancet 339, 1002 (1992).

    Article  CAS  Google Scholar 

  18. Ben Othmane, K. et al. Linkage of Tunisian autosomal recessive Duchenne-like muscular dystrophy to the pericentromeric region of chromosome 13q. Nature Genet. 2, 315–317 (1993).

    Article  Google Scholar 

  19. Sokol, R.J. et al. Isolated vitamin E deficiency in the absence of fat malabsorption — familial and sporadic cases: characterization and investigation of causes. J. Lab. Clin. Med. 111, 548–559 (1988).

    CAS  PubMed  Google Scholar 

  20. Sirugo, G. et al. Friedreich ataxia locus in Louisiana Acadians: Demonstration of a founder effect by analysis of microsatellite-generated extended haplotypes. Hum. Genet. 50, 559–566 (1992).

    CAS  Google Scholar 

  21. Hästbacka, J. et al. Linkage disequilibrium mapping in isolated founder population: diastrophic dysplasia in Finland. Nature Genet. 2, 204–211 (1993).

    Article  Google Scholar 

  22. Tagle, D.A., Swaroop, M., Lovett, M. & Collins, F.S. Magnetic bead capture of expressed sequences encoded within large genomic segments. Nature 361, 751–753 (1993).

    Article  CAS  Google Scholar 

  23. Buckler, A.J. et al. Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. Proc. natn. Acad. Scit. U.S.A. 88, 4005–4009 (1991).

    Article  CAS  Google Scholar 

  24. Wallace, M.R. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181–186 (1990).

    Article  CAS  Google Scholar 

  25. Elvin, P. et al. Isolation of cDNA clones using yeast artificial chromosome probes. Nucl. Acids Res. 18, 3913–3917 (1990).

    Article  CAS  Google Scholar 

  26. Traber, M.G. et al. Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver. J. clin. Invest. 85, 397–407 (1990).

    Article  CAS  Google Scholar 

  27. Behrens, W.A. & Madere, R. Transfer of a-tocopherol to microsomes mediated by partially purified liver a-tocopherol binding protein. Nutr. Res. 2, 611–618 (1982).

    Article  CAS  Google Scholar 

  28. Rosen, D.R. et al. Mutation in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).

    Article  CAS  Google Scholar 

  29. Di Mascio, P., Murphy, M.E. & Sies, H. Antioxidant defense systems: the role of carotenoids, tocopherols, and thiols. Am. J. clin. Nutr. 53, 194S–200S (1991).

    Article  CAS  Google Scholar 

  30. Harding, A.E. Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnosis criteria and intrafamilial clustering of clinical features. Brain 104, 589–620 (1981).

    Article  CAS  Google Scholar 

  31. Ben Hamida, M., Attia-Romdhane, N., Triki, C.H., Oueslati, S. & Hentati, F. Clinical and genetic analysis of 188 families with spinocerebellar degeneration. Friedreich's disease and P. Marie's hereditary ataxias. Rev. Neurol. (Paris). 147, 798–808 (1991).

    CAS  PubMed  Google Scholar 

  32. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. hum. Genet. 37, 482–498 (1993).

    Google Scholar 

  33. Fujita, R. et al. A 530 kb YAC contig tightly linked to the Friedreich ataxia locus contains five CpG clusters and a new highly polymorphic microsatellite. Hum. Genet. 89, 531–538 (1992).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. C. Linder

    Present address: Renal Cell Biology Section, Bldg 10, Rm 3N110, NIDDK-NIH, 9000 Rockvillepike, Bethesda, Maryland, 20892, USA

Authors and Affiliations

  1. Laboratoire de Neurobiologie Moléculaire et de Neuropathologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia

    C. Ben Hamida, S. Belal, F. Hentati & M. Ben Hamida

  2. Laboratoire de Génétique Moléculaire du CNRS, U.184 de l'INSERM, Faculté de Médecine et Centre Hospitalier Régional et Universitaire, Strasbourg, France

    N. Doerflinger, C. Linder, L. Reutenauer, J.-L. Mandel & M. Kœnig

  3. Généthon, 1 rue de l'Internationale, Evry, France

    C. Dib, G. Gyapay & A. Vignal

  4. Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France

    D. Le Paslier & D. Cohen

  5. Istituto Neurologico “Carlo Besta”, Milan, Italy

    M. Pandolfo

  6. Department of Pediatrics, University of Tirana, Tirana, Albania

    V. Mokini

  7. Chair of Human Genetics, Catholic University of Rome, Rome, Italy

    G. Novelli

Authors
  1. C. Ben Hamida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Doerflinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Belal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Linder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. Reutenauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Dib
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G. Gyapay
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Vignal
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D. Le Paslier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D. Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M. Pandolfo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. V. Mokini
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. G. Novelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. F. Hentati
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M. Ben Hamida
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J.-L. Mandel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. M. Kœnig
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ben Hamida, C., Doerflinger, N., Belal, S. et al. Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat Genet 5, 195–200 (1993). https://doi.org/10.1038/ng1093-195

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1093-195

  • Springer Nature America, Inc.

This article is cited by

Search

Navigation