Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.
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.
Waters
Michael F
MF
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.
Minassian
Natali A
NA
Stevanin
Giovanni
G
Figueroa
Karla P
KP
Bannister
John P A
JP
Nolte
Dagmar
D
Mock
Allan F
AF
Evidente
Virgilio Gerald H
VG
Fee
Dominic B
DB
Müller
Ulrich
U
Dürr
Alexandra
A
Brice
Alexis
A
Papazian
Diane M
DM
Pulst
Stefan M
SM
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
C489594:KCNC3 protein, human; D051670:Shaw Potassium Channels