SCA13

Spinocerebellar ataxia 13 (SCA13), initially described in a four-generation French family, has now also been characterized in a large Filipino pedigree. Ongoing investigations continue to identify additional SCA13 families and individuals. Recently, studies have shown that mutations in the voltage-gated potassium channel KCNC3 are causative for SCA13. Sequence analysis of KCNC3 revealed mutations 1554G→A (R420H) in the Filipino and 1639C→A (F448L) in the French pedigrees. Both mutations alter KCNC3 function in a Xenopus laevis oocyte expression system. KCNC3 ^R420H, located in the voltage sensor of the channel, has no detectable channel activity when expressed alone, and strong dominant negative effects when coexpressed with wild-type KCNC3. KCNC3 ^F448L shifts the activation curve in the negative direction and causes an approximately sevenfold slowing of channel closure. These mutations are expected to change the output characteristics of fast-spiking cerebellar neurons, where KCNC channels confer capacity for high-frequency repetitive firing.