title: Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.
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. KCNC3(R420H), 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. 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.
authors.affiliation: 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.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Waters
authors.forename: Natali A
authors.initials: NA
authors.lastname: Minassian
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Karla P
authors.initials: KP
authors.lastname: Figueroa
authors.forename: John P A
authors.initials: JP
authors.lastname: Bannister
authors.forename: Dagmar
authors.initials: D
authors.lastname: Nolte
authors.forename: Allan F
authors.initials: AF
authors.lastname: Mock
authors.forename: Virgilio Gerald H
authors.initials: VG
authors.lastname: Evidente
authors.forename: Dominic B
authors.initials: DB
authors.lastname: Fee
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dürr
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Diane M
authors.initials: DM
authors.lastname: Papazian
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pulst
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002524:Cerebellar Ataxia / Q000235:genetics*; D006801:Humans; D015640:Ion Channel Gating; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D051670:Shaw Potassium Channels / Q000737:chemistry / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: C489594:KCNC3 protein, human; D051670:Shaw Potassium Channels