Spinocerebellar ataxia type 6: channelopathy or glutamine repeat disorder?
Spinocerebellar ataxia type 6 (SCA6) is due to small expansions of a CAG repeat at the 3' end of the CACNA1A gene, coding for the alpha(1A) subunit of voltage-gated calcium channels type P/Q, expressed in the cerebellar Purkinje and granule cells. It is one of three allelic disorders, the other two being episodic ataxia type 2 (EA2), due mostly to protein truncating mutations, and familial hemiplegic migraine, associated with missense mutations. The latter disorders, due to point mutations altering the P/Q channel activity, clearly belong to the group of channelopathies. For SCA6, due to CAGn expansions, a toxic gain of function might, instead, be envisaged homologous to that of glutamine repeat disorders. A comparison between SCA6 and EA2 phenotypes performed on available literature data, shows that the clinical features of the two disorders are widely overlapping and that the differences could be accounted for with the older age of patients in the SCA6 group. A similar phenotype in the two disorders could imply the same pathogenic process. Functional analyses on cells expressing the protein with an expanded polyglutamine stretch have shown, in fact, an altered channel activity. In conclusion, available data seem to suggest that SCA6 is more likely belonging to channelopathies than to polyglutamine disorders.
Frontali
M
M
Istituto di Neurobiologia e Medicina Molecolare, Consiglio Nazionale delle Ricerche, Rome, Italy. marina.frontali@ims.rm.cnr.it
D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics*; D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000235:genetics; D005973:Glutamine / Q000235:genetics*; D006801:Humans; D020754:Spinocerebellar Ataxias / Q000209:etiology / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D005973:Glutamine; C105656:CACNA1A protein, human