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.

  • Letter
  • Published:

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene

Abstract

Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs1,2,3,4. We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus5. We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.

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

Figure 1: Seven pedigrees with EAOH linked to the short arm of chromosome 9.
Figure 2: Physical map of the critical region and the genomic organization of APTX.
Figure 3: Analysis of APTX expression in human tissues.
Figure 4: Multiple alignment and the phylogenetic tree of HIT superfamily proteins.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Friedreich, N. Über ataxie mit besonderer berücksichtigung der hereditären formen. Virchows Arch. Pathol. Anat. 68, 145–245 (1876).

    Article  Google Scholar 

  2. Friedreich, N. Über ataxie mit besonderer berücksichtigung der hereditären formen. Virchows Arch. Pathol. Anat. 70, 140–142 (1877).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Dürr, A. et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N. Engl. J. Med. 335, 1169–1175 (1996).

    Article  Google Scholar 

  5. do Céu Moreira, M. et al. Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity. Am. J. Hum. Genet. 68, 501–508 (2001).

    Article  Google Scholar 

  6. Moreira, M.-C. et al. The gene mutated in ataxia-ocular apraxia 1 (AOA1) encodes aprataxin, a new HIT/Zn-finger protein potentially involved in DNA repair. Nature Genet. 29, 189–193 (2001).

    Article  CAS  Google Scholar 

  7. Cogan, D. A type of congenital ocular motor apraxia presenting jerky head movements. Am. J. Ophthalmol. 36, 433–441 (1953).

    Article  CAS  Google Scholar 

  8. Aicardi, J. et al. Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia. Ann. Neurol. 24, 497–502 (1988).

    Article  CAS  Google Scholar 

  9. Barbot, C. et al. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch. Neurol. 58, 201–205 (2001).

    Article  CAS  Google Scholar 

  10. Koike, R., Tanaka, H. & Tsuji, S. Early onset ataxia associated with hypoalbuminemia. Neurol. Med. 48, 237–242 (1998).

    Google Scholar 

  11. Uekawa, K., Yuasa, T., Kawasaki, S., Makibuchi, T. & Ideta, T. A hereditary ataxia associated with hypoalbuminemia and hyperlipidemia—a variant form of Friedreich's disease or a new clinical entity? Clin. Neurol. 32, 1067–1074 (1992).

    CAS  Google Scholar 

  12. Inoue, N., Izumi, K., Mawatari, S., Shida, K. & Kuroiwa, Y. Congenital ocular motor apraxia and cerebellar degeneration–report of two cases. Clin. Neurol. 11, 855–861 (1971).

    Google Scholar 

  13. Araie, M., Ozawa, T. & Awaya, Y. A case of congenital ocular motor apraxia with cerebellospinal degeneration. Jpn. J. Opthalmol. 21, 355–365 (1977).

    Google Scholar 

  14. Kurita-Takahashi, S., Sakai, T., Shibasaki, H. & Iwashita, H. Friedrich's ataxia associated with congenital ocular motor apraxia. Neuro-ophthalmol. 12, 41–45

  15. Brenner, C., Bieganowski, P., Pace, H.C. & Huebner, K. The histidine triad superfamily of nucleotide-binding proteins. J. Cell Physiol. 181, 179–187 (1999).

    Article  CAS  Google Scholar 

  16. Seraphin, B. The HIT protein family: a new family of proteins present in prokaryotes, yeast and mammals. DNA Seq. 3, 177–179 (1992).

    Article  CAS  Google Scholar 

  17. Kubota, H. et al. Familial early onset cerebellar ataxia with hypoalbuminemia. Brain and Nerve 47, 289–294 (1995).

    CAS  Google Scholar 

  18. Sekijima, Y. et al. Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): clinical and neuropathological features of a Japanese family. J. Neurol. Sci. 158, 30–37 (1998).

    Article  CAS  Google Scholar 

  19. Fukuhara, N., Nakajima, T., Sakajiri, K., Matsubara, N. & Fujita, M. Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): a new disease. J. Neurol. Sci. 133, 140–151 (1995).

    Article  CAS  Google Scholar 

  20. Kawasaki, S., Ideta, T., Ueno, H., Hirase, T. & Tokuomi, H. Three cases of autosomal recessively inherited neuropathy with cerebellar ataxia, optic atrophy and hyperlipidemia. Clin. Neurol. 22, 15–23 (1982).

    CAS  Google Scholar 

  21. Sambrook, J. & Russell, D. Preparation and analysis of eukaryotic genomic DNA. in Molecular Cloning: A Laboratory Manual 3rd ed. Vol. 1 6.4–6.12 (Cold Spring Harbor, New York, 2001).

    Google Scholar 

  22. Lathrop, G. M. & Lalouel, J.M. Easy calculations of lod scores and genetic risks on small computers. Am. J. Hum. Genet. 36, 460–465 (1984).

    CAS  PubMed Central  Google Scholar 

  23. 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 (1985).

    CAS  PubMed Central  Google Scholar 

  24. Cottingham, R. W. Jr, Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).

    PubMed Central  Google Scholar 

  25. Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363 (1996).

    CAS  PubMed Central  Google Scholar 

  26. Thompson, J.D., Higgins, D.G. & Gibson, T.J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994).

    Article  CAS  Google Scholar 

  27. Saitou, N. & Nei, M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4, 406–425 (1987).

    CAS  PubMed Central  Google Scholar 

  28. Lima, C.D., Klein, M.G., Weinstein, I.B. & Hendrickson, W.A. Three-dimensional structure of human protein kinase C interacting protein 1, a member of the HIT family of proteins. Proc. Natl Acad. Sci. USA 93, 5357–5362 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (C)—Advanced Brain Science Project from the Ministry of Education, Culture, Sports, and Science and Technology, Japan, a grant for the Research for the Future Program from the Japan Society for the Promotion of Science, a grant from the Research Committee for Ataxic Diseases, the Ministry of Health, Labor and Welfare, Japan, and a grant for Surveys and Research on Specific Diseases, the Ministry of Health, Labor and Welfare, Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shoji Tsuji.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Date, H., Onodera, O., Tanaka, H. et al. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nat Genet 29, 184–188 (2001). https://doi.org/10.1038/ng1001-184

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1001-184

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