Direct sequencing of CACNA1A
in a number of patients with clinical EA2 often fails to identify causative point mutations. However, the last year has witnessed a further step forward in understanding the genetic basis of EA2. Veneziano and colleagues [28
] identified new 5′ and 3′ regions in the CACNA1A
gene, including a gene promoter region and a new final exon 48, both of which harboured mutations in patients with EA. Furthermore, the mutation spectrum has expanded with the findings of large deletions and duplications in CACNA1A
in affected individuals. Previously, nonsense and missense mutations accounted for most cases of EA2. Recently, methods such as MLPA (multiplex ligation-dependent probe amplification) and QMPSF (quantitative multiplex polymerase chain reaction of short fluorescent fragments) have demonstrated large-scale CACNA1A
gene rearrangements in patients with EA2 [29
]. This finding is particularly important for those patients with clinical EA2 in whom sequencing of CACNA1A
fails to identify a point mutation.
EA2 is an autosomal dominant disease, and because large deletions in CACNA1A
are not likely to produce functional transcripts, it is likely that reduced channel density in the cerebellar circuit (possibly in Purkinje cells, where these channels have been shown to play a central role) is sufficient to cause episodes of ataxia. Moreover, the recent observation that nonsense mutations located within a well-known alternatively spliced exon (exon 37A) [31
] can cause EA2 hints at a significant role of CaV
2.1 channels containing exon 37A in the cerebellum and underpins the importance of calcium channel splicing in disease causation.
While increasing evidence points to a loss of robust CaV
2.1 expression in the cerebellum and haploinsufficency as the underlying mechanism of EA2, calcium channel dysfunction may not be at the root of SCA6. In support of this view, the expanded CAG repeat in the SCA6 knock-in mouse does not appear to affect CaV
2.1 function [32
], indicating that the polyglutamine repeat itself may have a cytotoxic effect on the cell. It has recently been suggested that cerebellar dysfunction in a related polyglutamine repeat SCA (SCA2) may arise from aberrant activation of type 1 inositol 1,4,5-trisphosphate receptors (ITPRs) in Purkinje cells by the glutamine tracts themselves [33
]. If activation of the ITPRs is the mechanism of polyglutamine repeat SCAs, then SCA6 may be a result of the relative abundance of P/Q channels in Purkinje cells, rather than specific properties of the channels themselves.