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Gene Review

IOSCA  -  infantile onset spinocerebellar ataxia...

Homo sapiens

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Disease relevance of IOSCA

  • This ataxia, identified so far only in the genetically isolated Finnish population, does not share gene locus with any of the previously identified hereditary ataxias, and a random mapping approach was adopted to assign the IOSCA locus [1].
  • Toward cloning of a novel ataxia gene: refined assignment and physical map of the IOSCA locus (SCA8) on 10q24 [2].
  • We speculate that the presence of a large SCA8 CTA/CTG repeat allele influences the function of channels such as alpha(1A)-voltage-dependent calcium channel through changing or aberrant splicing, resulting in the development of cerebellar ataxia, especially in homozygous patients [3].
  • Previously, we have shown that different mutations in this same gene cause autosomal dominant progressive external ophthalmoplegia (adPEO) with multiple mtDNA deletions (MIM 606075), a neuromuscular disorder sharing a spectrum of symptoms with IOSCA [4].
  • Infantile onset spinocerebellar ataxia (IOSCA) (MIM 271245) is a severe autosomal recessively inherited neurodegenerative disorder characterized by progressive atrophy of the cerebellum, brain stem and spinal cord and sensory axonal neuropathy [4].

Psychiatry related information on IOSCA


High impact information on IOSCA

  • The neurological phenotype in SCA8 BAC expansion but not BAC control lines demonstrates the pathogenicity of the (CTG-CAG)n expansion [6].
  • Moreover, the expression of noncoding (CUG)n expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggests SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and RNA levels [6].
  • We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance [6].
  • 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript (ataxin 8, ATXN8) spanning the repeat in the CAG direction [6].
  • The transcript coding for this Z-band alternatively spliced PDZ motif (ZASP) protein maps on chromosome 10q22.3-10q23.2, near the locus for infantile-onset spinocerebellar ataxia [7].

Chemical compound and disease context of IOSCA


Biological context of IOSCA

  • The identification of a shared chromosomal region in these four patients provided the first evidence that the IOSCA gene locus is on chromosome 10q23.3-q24.1, which was confirmed by conventional linkage analysis in the complete family material [1].
  • Strong linkage disequilibrium observed between IOSCA and the linked markers was utilized to define accurately the critical chromosomal region [1].
  • Haplotype analysis combined with genealogical data provided evidence that all the IOSCA cases in Finland originate from a single 30- to 40-generation-old founder mutation [2].
  • By analyzing extended disease haplotypes observed today, the IOSCA locus can now be restricted to a region between two adjacent microsatellites, D10S192 and D10S1265, with no genetic intermarker distance [2].
  • This allele is expressed at a reduced level, causing the preponderance of messenger RNAs encoding Y508C polypeptides and thus leads to the IOSCA disease phenotype [4].

Associations of IOSCA with chemical compounds

  • While understanding of how expanded polyglutamine tracts compromise or alter protein function has advanced rapidly in the last five years, understanding of how trinucleotide repeat expansions alter the function of the non-coding SCA8 RNA and lead to human disease remains quite limited [10].

Other interactions of IOSCA

  • We have also assigned two previously known genes, PAX2 and CYP17, more precisely into this region, but the sequence analysis of coding regions of these two genes has not revealed mutations in an IOSCA patient [2].
  • Age at onset was correlated with SCA8 repeats rather than SCA6 repeats in these five patients [3].
  • The severe neurological phenotype observed in IOSCA, a result of only a single amino acid substitution in Twinkle and Twinky, suggests that these proteins play a crucial role in the maintenance and/or function of specific affected neuronal subpopulations [4].
  • CONCLUSIONS: Lack of SCA3 and excess of SCA8 are characteristic to the Finnish population [11].
  • Three additional genetic mutations were found: SCA1 (42 repeats), SCA3 (66 repeats), and SCA8 (121 repeats) [12].

Analytical, diagnostic and therapeutic context of IOSCA

  • Sequencing of RT and genomic PCR products of the gene revealed no alterations in IOSCA patients when compared to control subjects, and neither could differences be detected in expression levels between patient and control brain RNA samples, thus excluding mutation(s) in this novel gene as causative for IOSCA [13].


  1. Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus. Nikali, K., Suomalainen, A., Terwilliger, J., Koskinen, T., Weissenbach, J., Peltonen, L. Am. J. Hum. Genet. (1995) [Pubmed]
  2. Toward cloning of a novel ataxia gene: refined assignment and physical map of the IOSCA locus (SCA8) on 10q24. Nikali, K., Isosomppi, J., Lönnqvist, T., Mao, J.I., Suomalainen, A., Peltonen, L. Genomics (1997) [Pubmed]
  3. SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6. Izumi, Y., Maruyama, H., Oda, M., Morino, H., Okada, T., Ito, H., Sasaki, I., Tanaka, H., Komure, O., Udaka, F., Nakamura, S., Kawakami, H. Am. J. Hum. Genet. (2003) [Pubmed]
  4. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Nikali, K., Suomalainen, A., Saharinen, J., Kuokkanen, M., Spelbrink, J.N., Lönnqvist, T., Peltonen, L. Hum. Mol. Genet. (2005) [Pubmed]
  5. The complex clinical and genetic classification of inherited ataxias. II. Autosomal recessive ataxias. Di Donato, S., Gellera, C., Mariotti, C. Neurol. Sci. (2001) [Pubmed]
  6. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Moseley, M.L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A.K., Daughters, R.S., Chen, G., Weatherspoon, M.R., Clark, H.B., Ebner, T.J., Day, J.W., Ranum, L.P. Nat. Genet. (2006) [Pubmed]
  7. ZASP: a new Z-band alternatively spliced PDZ-motif protein. Faulkner, G., Pallavicini, A., Formentin, E., Comelli, A., Ievolella, C., Trevisan, S., Bortoletto, G., Scannapieco, P., Salamon, M., Mouly, V., Valle, G., Lanfranchi, G. J. Cell Biol. (1999) [Pubmed]
  8. Genes implicated in the pathogenesis of spinocerebellar ataxias. Wüllner, U. Drugs of today (Barcelona, Spain : 1998) (2003) [Pubmed]
  9. Rare forms of autosomal recessive neurodegenerative ataxia. Koenig, M. Seminars in pediatric neurology. (2003) [Pubmed]
  10. Molecular genetics of spinocerebellar ataxia type 8 (SCA8). Mutsuddi, M., Rebay, I. RNA biology (2005) [Pubmed]
  11. The occurrence of dominant spinocerebellar ataxias among 251 Finnish ataxia patients and the role of predisposing large normal alleles in a genetically isolated population. Juvonen, V., Hietala, M., Kairisto, V., Savontaus, M.L. Acta neurologica Scandinavica. (2005) [Pubmed]
  12. Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations. Kerber, K.A., Jen, J.C., Perlman, S., Baloh, R.W. J. Neurol. Sci. (2005) [Pubmed]
  13. cDNA cloning, expression profile and genomic structure of a novel human transcript on chromosome 10q24, and its analyses as a candidate gene for infantile onset spinocerebellar ataxia. Nikali, K., Saharinen, J., Peltonen, L. Gene (2002) [Pubmed]
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