Nature Genetics 38, 447 - 451 (2006)
Published online: 26 February 2006; | doi:10.1038/ng1758
Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypesMichael F Waters1, 2, Natali A Minassian3, Giovanni Stevanin4, Karla P Figueroa1, John P A Bannister3, Dagmar Nolte5, Allan F Mock3, Virgilio Gerald H Evidente6, Dominic B Fee7, Ulrich Müller5, Alexandra Dürr4, Alexis Brice4, Diane M Papazian3
& Stefan M Pulst1, 2, 81
Division of Neurology and Rose Moss Laboratory for Parkinson's and Neurodegenerative Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, 90048 USA. 2
Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, California, 90024 USA. 3
Department of Physiology, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, California, 90024 USA. 4
INSERM U679 and Department of Genetics, Cytogenetics, and Embryology of Assistance Publique - Hopitaux de Paris, Hôpital de la Salpêtrière, 75013 Paris, France. 5
Institut für Humangenetik, Justus-Liebig-Universität, 35392 Giessen, Germany. 6
Department of Neurology, Mayo Clinic, Scottsdale, Arizona 85259 USA. 7
Department of Neurology, University of Kentucky College of Medicine, Lexington, Kentucky 40536 USA. 8
Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 USA.
Correspondence should be addressed to Stefan M Pulst stefan.pulst@cshs.org Potassium channel mutations have been described in episodic neurological diseases1. 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 delay2. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression3. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3
R420H, located in the voltage-sensing domain4, 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.
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