KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients.
Hum. Mutat.. 2010-02-01; 31(2): 191-196
DOI: 10.1002/humu.21165
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1. Hum Mutat. 2010 Feb;31(2):191-6. doi: 10.1002/humu.21165.
KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia
patients.
Figueroa KP(1), Minassian NA, Stevanin G, Waters M, Garibyan V, Forlani S,
Strzelczyk A, Bürk K, Brice A, Dürr A, Papazian DM, Pulst SM.
Author information:
(1)Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
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.
(c) 2009 Wiley-Liss, Inc.
DOI: 10.1002/humu.21165
PMCID: PMC2814913
PMID: 19953606 [Indexed for MEDLINE]