Karla P. Figueroa, Natali A. Minassian, and Giovanni Stevanin contributed equally to this work.
KCNC3: phenotype, mutations, channel biophysics—a study of 260 familial ataxia patients†
Article first published online: 1 DEC 2009
© 2010 Wiley-Liss, Inc.
Volume 31, Issue 2, pages 191–196, February 2010
How to Cite
Figueroa, K. P., Minassian, N. A., Stevanin, G., Waters, M., Garibyan, V., Forlani, S., Strzelczyk, A., Bürk, K., Brice, A., Dürr, A., Papazian, D. M. and Pulst, S. M. (2010), KCNC3: phenotype, mutations, channel biophysics—a study of 260 familial ataxia patients. Hum. Mutat., 31: 191–196. doi: 10.1002/humu.21165
Communicated by Michel Goossens
- Issue published online: 26 JAN 2010
- Article first published online: 1 DEC 2009
- Accepted manuscript online: 1 DEC 2009 12:00AM EST
- Manuscript Accepted: 8 NOV 2009
- Manuscript Received: 17 AUG 2009
- ion channel gene defects;
- spinocerebellar ataxia;
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. Hum Mutat 31:191–196, 2010. © 2009 Wiley-Liss, Inc.