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

作者：Helbig Katherine L; Hedrich Ulrike B S; Shinde Deepali N; Krey Ilona; Teichmann Anne Christin; Hentschel Julia; Schubert Julian; Chamberlin Adam C; Huether Robert; Lu Hsiao Mei; Alcaraz Wendy A; Tang Sha; Jungbluth Chelsy; Dugan Sarah L; Vainionpaa Leena; Karle Kathrin N; Synofzik Matthis; Schols Ludger; Schule Rebecca; Lehesjoki Anna Elina; Helbig Ingo; Lerche Holger; Lemke Johannes R^*

来源：Annals of Neurology, 2016, 80(4): 638-642.

DOI：10.1002/ana.24762

The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K+-channel, K(V)1.2, 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 of Xenopus laevis oocytes expressing mutant KV1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism.

• 出版日期2016-10