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A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia
Author(s) -
Helbig Katherine L.,
Hedrich Ulrike B.S.,
Shinde Deepali N.,
Krey Ilona,
Teichmann AnneChristin,
Hentschel Julia,
Schubert Julian,
Chamberlin Adam C.,
Huether Robert,
Lu HsiaoMei,
Alcaraz Wendy A.,
Tang Sha,
Jungbluth Chelsy,
Dugan Sarah L.,
Vainionpää Leena,
Karle Kathrin N.,
Synofzik Matthis,
Schöls Ludger,
Schüle Rebecca,
Lehesjoki AnnaElina,
Helbig Ingo,
Lerche Holger,
Lemke Johannes R.
Publication year - 2016
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24762
Subject(s) - hereditary spastic paraplegia , ataxia , paraplegia , mutation , spastic , medicine , genetics , physical medicine and rehabilitation , biology , phenotype , psychiatry , cerebral palsy , spinal cord , gene
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 K V 1.2 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. Ann Neurol 2016