Journal article

Publication year: 2006

Pages: 447-451

Journal: Nature Genetics

Volume number: 38

Issue number: 4

ISSN: 1061-4036

eISSN: 1546-1718

DOI Link: https://doi.org/10.1038/ng1758

Publisher: Nature Research

Abstract: 
Potassium channel mutations have been described in episodic neurological diseases(1). 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(2). This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression(3). Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3(R420H), located in the voltage-sensing domain(4), 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.

Harvard Citation style: Waters, M., Minassian, N., Stevanin, G., Figueroa, K., Bannister, J., Nolte, D., et al. (2006) Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes, Nature Genetics, 38(4), pp. 447-451. https://doi.org/10.1038/ng1758

APA Citation style: Waters, M., Minassian, N., Stevanin, G., Figueroa, K., Bannister, J., Nolte, D., Mock, A., Evidente, V., Fee, D., Müller, U., Dürr, A., Brice, A., Papazian, D., & Pulst, S. (2006). Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nature Genetics. 38(4), 447-451. https://doi.org/10.1038/ng1758