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- Title
Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.
- Authors
Waters, Michael F.; Minassian, Natali A.; Stevanin, Giovanni; Figueroa, Karla P.; Bannister, John P. A.; Nolte, Dagmar; Mock, Allan F.; Evidente, Virgilio Gerald H.; Fee, Dominic B.; Müller, Ulrich; Dürr, Alexandra; Brice, Alexis; Papazian, Diane M.; Pulst, Stefan M.
- 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. KCNC3R420H, 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. KCNC3F448L shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3R420H and KCNC3F448L 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.
- Subjects
POTASSIUM channels; GENETIC mutation; NEURODEGENERATION; ATAXIA; PHENOTYPES; FILIPINOS
- Publication
Nature Genetics, 2006, Vol 38, Issue 4, p447
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng1758