Abstract found on Wiley Online Library
Objective: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novosequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies.
Methods: Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage-clamp.
Results: We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect pore lining S6 ?-helix of KV1.6. Prominent finding of functional characterisation in Xenopusoocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type KV1.6 or KV1.1 subunits.
Significance: This is the first report of de novo non-synonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.