Most cases of<unk>  are a result of CAG repeat expansion beyond the normal range, i.e., more than 19 repeats, in the Cav2.1 calcium channel encoding gene CACNA1A. This gene has two splice forms, "Q-type" and "P-type", and the polyglutamine coding CAG expansion occurs in the P-type splice form. This form is expressed heavily in the cerebellum where it is localized in Purkinje cells. In Purkinje cells from<unk>  patients, mutant Cav2.1 proteins form ovular intracellular inclusions, or aggregations, similar in many ways to those seen in other polyglutamine expansion disorders such as Huntington's disease. In cell culture models of the disease, this leads to early apoptotic cell death. Mutant channels that are able to traffic properly to the membrane have a negatively shifted voltage-dependence of inactivation. The result of this is that the channels are active for a shorter amount of time and, consequently, cell excitability is decreased. There are also a number of point mutations resulting in patients with phenotypes reminiscent of episodic ataxia and<unk>  (C271Y, G293R and R1664Q) or familial hemiplegic migraine and<unk>  (R583Q and I1710T). C287Y and G293R are both located in the pore region of domain 1 and are present in a single family each. Expression of these mutant channels results in cells with drastically decreased current density compared to wild-type expressing cells. In cell-based assays, it was found that these mutant channels aggregate in the endoplasmic reticulum, not dissimilar from that seen in the CAG expansion mutants above. R1664Q is in the 4th transmembrane spanning segment of domain 4 and, presumably, affects the channel's voltage dependence of activation. Little is known about the point mutations resulting in overlapping phenotypes of familial hemiplegic migraine and episodic ataxia. R583Q is present in the 4th transmembrane spanning region of domain 2 while the I1710T mutation is segment 5 of domain 4.
Spinocerebellar ataxia type 6
Spinocerebellar ataxia type 1
Spinocerebellar ataxia type-13
Autosomal recessive cerebellar ataxia type 1
Metachromatic leukodystrophy
Stratton Parker syndrome
Friedreich's ataxia
Autosomal recessive spastic ataxia of Charlevoix-Saguenay