Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes

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Abstract
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. KCNC3R420H, 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. 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.