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.
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References
Friedreich, N. Über ataxie mit besonderer berücksichtigung der hereditären formen. Virchows Arch. Pathol. Anat. 68, 145–245 (1876).
Friedreich, N. Über ataxie mit besonderer berücksichtigung der hereditären formen. Virchows Arch. Pathol. Anat. 70, 140–142 (1877).
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).
Dürr, A. et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N. Engl. J. Med. 335, 1169–1175 (1996).
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).
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).
Cogan, D. A type of congenital ocular motor apraxia presenting jerky head movements. Am. J. Ophthalmol. 36, 433–441 (1953).
Aicardi, J. et al. Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia. Ann. Neurol. 24, 497–502 (1988).
Barbot, C. et al. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch. Neurol. 58, 201–205 (2001).
Koike, R., Tanaka, H. & Tsuji, S. Early onset ataxia associated with hypoalbuminemia. Neurol. Med. 48, 237–242 (1998).
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).
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).
Araie, M., Ozawa, T. & Awaya, Y. A case of congenital ocular motor apraxia with cerebellospinal degeneration. Jpn. J. Opthalmol. 21, 355–365 (1977).
Kurita-Takahashi, S., Sakai, T., Shibasaki, H. & Iwashita, H. Friedrich's ataxia associated with congenital ocular motor apraxia. Neuro-ophthalmol. 12, 41–45
Brenner, C., Bieganowski, P., Pace, H.C. & Huebner, K. The histidine triad superfamily of nucleotide-binding proteins. J. Cell Physiol. 181, 179–187 (1999).
Seraphin, B. The HIT protein family: a new family of proteins present in prokaryotes, yeast and mammals. DNA Seq. 3, 177–179 (1992).
Kubota, H. et al. Familial early onset cerebellar ataxia with hypoalbuminemia. Brain and Nerve 47, 289–294 (1995).
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).
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).
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).
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).
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).
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).
Cottingham, R. W. Jr, Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).
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).
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).
Saitou, N. & Nei, M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4, 406–425 (1987).
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).
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.
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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
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DOI: https://doi.org/10.1038/ng1001-184
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