Title

KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients.

Document Type

Article

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.

Keywords

Adolescent, Adult, Aged, Animals, Biophysical Phenomena, Case-Control Studies, Child, Preschool, Demography, Family, Friedreich Ataxia, Genes, Dominant, Humans, Infant, Newborn, Magnetic Resonance Imaging, Middle Aged, Mutation, Phenotype, Shaw Potassium Channels, Xenopus

Medical Subject Headings

Adolescent; Adult; Aged; Animals; Biophysical Phenomena; Case-Control Studies; Child, Preschool; Demography; Family; Friedreich Ataxia; Genes, Dominant; Humans; Infant, Newborn; Magnetic Resonance Imaging; Middle Aged; Mutation; Phenotype; Shaw Potassium Channels; Xenopus

Publication Date

2-1-2010

Publication Title

Human mutation

ISSN

1098-1004

Volume

31

Issue

2

First Page

191

Last Page

196

PubMed ID

19953606

Digital Object Identifier (DOI)

10.1002/humu.21165

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