XB-ART-40754Hum Mutat. February 1, 2010; 31 (2): 191-6.
KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients.
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.
PubMed ID: 19953606
PMC ID: PMC2814913
Article link: Hum Mutat.
Grant support: R01 NS058500-03 NINDS NIH HHS , R01 NS033123-10 NINDS NIH HHS , R01 NS058500-04 NINDS NIH HHS , R01 NS058500 NINDS NIH HHS , R01 NS033123 NINDS NIH HHS , M01 RR000425 NCRR NIH HHS
Genes referenced: kcnc3