Spinocerebellar ataxia type 10: a disease caused by a large ATTCT repeat expansion.

Abstract

Spinocerebellar ataxia type 10 (SCA 1 0) is an autosomal dominant disease characterized by ataxia and seizures. 1-3 It belongs to a group of diseases known as autosomal dominant cerebellar ataxias (ADCAs). To date, 16 ADCA loci, including SCA1,4SCA2,5-7 SCA3/Machado-Joseph disease (MJD),8 SCA4,9 SCAS, 10 SCA6, II SCA7,12 SCA8,13 SCAlO,2,3 SCAll,14 SCA12,15 SCAI3,16 SCA14,17 SCA16,17a SCA1717b,17c,17d and dentatorubral-pallidoluysian atrophy (DRPLA), 18,19 have been mapped to specific chromosomal regions. While mutations involved in SCA4, SCAS, SCA 11, SCA13, SCA14 and SCA16 have not been identified, six of these 14 ADCAs, including SCA1, SCA2, SCA3IMJD, SCA6, SCA 7, SCA 17 and DRPLA, have shown an expansion of a coding CAG trinucleotide repeat tract as the disease-causing mutation at the respective loci. In each of these diseases, the CAG repeat encodes a polyglutamine tract; therefore, an expansion of the CAG repeat gives rise to an elongation of the polyglutamine tract in the protein product. There is increasing evidence that the elongated polyglutamine tract leads to a gain of novel toxic function that causes the disease. 2o -29 One exception may be SCA6, in which the polyglutamine tract is located in the alpha-l A calcium channel subunit (CA CNA J A) gene, which shows a high level of expression in cerebellum. II The expansion size is 21-33 repeats, which would be within the normal range for other SCAs. Functional alterations of the P/Q type calcium channels in the cerebellum is a likely consequence although a gain of novel toxic function has also been postulated as the pathogenic mechanism of SCA6. In most ADCAs with polyglutarnine expansions, the age of disease onset becomes progressively earlier in successive generations with