title: KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients.
abstract: We recently identified KCNC3, encoding the Kv3.3 voltage-gated potassium channel, as the gene mutated in SCA13. One g.10684G>A (p.Arg420His) mutation caused late-onset ataxia resulting in a nonfunctional channel subunit with dominant-negative properties. A French early-onset pedigree with mild mental retardation segregated a g.10767T>C (p.Phe448Leu) mutation. This mutation changed the relative stability of the channel's open conformation. Coding exons were amplified and sequenced in 260 autosomal-dominant ataxia index cases of European descent. Functional analyses were performed using expression in Xenopus oocytes. The previously identified p.Arg420His mutation occurred in three families with late-onset ataxia. A novel mutation g.10693G>A (p.Arg423His) was identified in two families with early-onset. In one pedigree, a novel g.10522G>A (p.Arg366His) sequence variant was seen in one index case but did not segregate with affected status in the respective family. In a heterologous expression system, the p.Arg423His mutation exhibited dominant-negative properties. The p.Arg420His mutation, which results in a nonfunctional channel subunit, was recurrent and associated with late-onset progressive ataxia. In two families the p.Arg423His mutation was associated with early-onset slow-progressive ataxia. Despite a phenotype reminiscent of the p.Phe448Leu mutation, segregating in a large early-onset French pedigree, the p.Arg423His mutation resulted in a nonfunctional subunit with a strong dominant-negative effect.
authors: Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
authors: Karla P
authors: KP
authors: Figueroa
authors: Natali A
authors: NA
authors: Minassian
authors: Giovanni
authors: G
authors: Stevanin
authors: Michael
authors: M
authors: Waters
authors: Vartan
authors: V
authors: Garibyan
authors: Sylvie
authors: S
authors: Forlani
authors: Adam
authors: A
authors: Strzelczyk
authors: Katrin
authors: K
authors: Bürk
authors: Alexis
authors: A
authors: Brice
authors: Alexandra
authors: A
authors: Dürr
authors: Diane M
authors: DM
authors: Papazian
authors: Stefan M
authors: SM
authors: Pulst
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D055592:Biophysical Phenomena; D016022:Case-Control Studies; D002675:Child, Preschool; D003710:Demography; D005190:Family; D005621:Friedreich Ataxia / Q000235:genetics* / Q000473:pathology*; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D051670:Shaw Potassium Channels / Q000235:genetics*; D014981:Xenopus
chemical_list: C489594:KCNC3 protein, human; D051670:Shaw Potassium Channels