Splice-variant specific effects of a CACNA1H mutation associated with writer’s cramp

Abstract The CACNA1H gene encodes the α1 subunit of the low voltage-activated Ca v 3.2 T-type calcium channel, an important regulator of neuronal excitability. Alternative mRNA splicing can generate multiple channel variants with distinct biophysical properties and expression patterns. Two major splice variants, containing or lacking exon 26 (± 26) have been found in different human tissues. In this study, we report splice variant specific effects of a Ca v 3.2 mutation found in patients with autosomal dominant writer’s cramp, a specific type of focal dystonia. We had previously reported that the R481C missense mutation caused a gain of function effect when expressed in Ca v 3.2 (+ 26) by accelerating its recovery from inactivation. Here, we show that when the mutation is expressed in the short variant of the channel (− 26), we observe a significant increase in current density when compared to wild-type Ca v 3.2 (− 26) but the effect on the recovery from inactivation is lost. Our data add to growing evidence that the functional expression of calcium channel mutations depends on which splice variant is being examined.