Title

Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes

Document Type

Article

Abstract

Potassium channel mutations have been described in episodic neurological diseases. We report that K+ channel mutations cause disease phenotypes with neurodevelopmental and neurodegenerative features. In a Filipino adult-onset ataxia pedigree, the causative gene maps to 19q13, overlapping the SCA13 disease locus described in a French pedigree with childhood-onset ataxia and cognitive delay. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3(R420H), located in the voltage-sensing domain, had no channel activity when expressed alone and had a dominant-negative effect when co-expressed with the wild-type channel. KCNC3(F448L) shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3(R420H) and KCNC3(F448L) are expected to change the output characteristics of fast-spiking cerebellar neurons, in which KCNC channels confer capacity for high-frequency firing. Our results establish a role for KCNC3 in phenotypes ranging from developmental disorders to adult-onset neurodegeneration and suggest voltage-gated K+ channels as candidates for additional neurodegenerative diseases.

Medical Subject Headings

Amino Acid Sequence; Animals; Cerebellar Ataxia (genetics); Humans; Ion Channel Gating; Molecular Sequence Data; Mutation; Mutation, Missense; Phenotype; Shaw Potassium Channels (chemistry, genetics); Xenopus laevis

Publication Date

4-1-2006

Publication Title

Nature genetics

ISSN

1061-4036

Volume

38

Issue

4

First Page

447

Last Page

51

PubMed ID

16501573

Digital Object Identifier (DOI)

10.1038/ng1758

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