Predisposing chromosome for spinocerebellar ataxia type 6 (SCA6) in Japanese.

The autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders which can be classified into three major categories on the basis of their clinical features and mode of inheritance.1 ADCA type III is a pure cerebellar syndrome that is genetically heterogeneous and includes spinocerebellar ataxia type 5 (SCA5),2 SCA6,3SCA10,4 5 and SCA11.6 The gene responsible for SCA6 has been identified as coding for the α1Asubunit of the P/Q type voltage dependent calcium channel ( CACNA1A ). Moderate CAG expansion in the coding region causes the disorder, with the number of CAG repeats being originally reported as 21-27 in mutant alleles (n=8) and 4-16 in control alleles (n=950).3 Subsequent studies have indicated that the range of pathological expansion in SCA6 alleles varies from 207 to 33.8 The CACNA1A gene was first identified during the search for specific mutations causing familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2).9 The gene product has four transmembrane domains and glutamine repeats are located at the C-terminal side of the intracellular segment. Missense mutations of these transmembrane domains and deletions or splice mutations leading to a truncated protein are responsible for FHM and EA2, respectively. The CACNA1A gene is predominantly expressed in Purkinje cells and granule cells of the cerebellum and is essential for the survival and maintenance of normal function by these neurones.10 11 Biochemical mechanisms leading to the development of SCA6 are not fully understood. However, the fact that slowly progressive ataxia is often observed in EA2 indicates that a small glutamine expansion in the SCA6 gene also disturbs the function of P/Q-type calcium channels, leading to selective neuronal degeneration in the cerebellum. The pathogenic expansion in SCA6 is relatively small compared with those in other SCAs caused by …