Potassium channels and neurodegeneration: mutations in KCNC3 cause Spinocerebellar ataxia type 13 (SCA13). M. Waters1,2, N. Minassian2, G. Stevanin3, K. Figueroa1, D. Nolte4, J. Bannister2, A. Mock2, V. Evidente5, D. Fee6, U. Müller4, A. Dürr3, A. Brice3, D. Papazian2, S. Pulst1,2. 1) Cedars-Sinai Medical Center; 2) UCLA; 3) Hôpital de la Salpêtrière; 4) Justus-Liebig-Universität; 5) Mayo Clinic; 6) Univ of Kentucky.

   Potassium channel mutations have been described in episodic neurological diseases, though not late-onset degenerative disorders. We identified a Filipino pedigree with adult onset gait/limb ataxia, dysmetria, hypotonia, dysarthria, and nystagmus. Linkage analysis mapped the causative mutation to a ~4cM region of 19q13. This partially overlapped with the previously mapped 11.4cM SCA13 locus described in a French pedigree with childhood onset mental retardation, and relatively pure cerebellar ataxia. Both pedigrees show marked cerebellar atrophy on MR imaging. Using STR markers we narrowed the candidate region to a ~900kb region which contained the KCNC3 channel. Sequence analysis of KCNC3 revealed two missense mutations in exon 2: 1554GA (R420H) in the Filipino pedigree and 1639CA (F488L) in the French pedigree. No other sequence variants were observed. KCNC3 (Kv3.3) is a fast-rectifying voltage-gated Shaw subtype potassium channel with enriched expression in the cerebellum. The mutations occur in functionally critical regions of the protein and alter highly conserved residues. Screening of two hundred alleles from normal individuals revealed no polymorphisms at either site. We expressed wildtype and the R420H mutant KCNC3 in X. laevis oocytes. Expression of the wildtype channel resulted in currents with fast activation kinetics and a depolarized range of activation, as expected. In contrast, the 1554GA mutant showed no detectable channel activity. Co-expression of wildtype and mutant KCNC3 resulted in decreased current amplitude consistent with a dominant negative effect of the mutant allele. Identification of KCNC3 mutations contributes a new class of genes to causative etiologies of progressive degenerative ataxias. These findings highlight the importance of voltage-gated potassium channels in both neuronal function and cell survival and should lead to their investigation in other neurodegenerative diseases.