A Recurrent Mutation in KCNA2 as a Novel Cause of Hereditary Spastic Paraplegia and Ataxia

Abstract

The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation inKCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K+-channel, KV1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings ofXenopus laevis oocytes expressing mutant KV1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrentKCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. 

Ann Neurol 2016