Potassium ion channel dysfunction
.
A recurrent mutation in the KCNA2 gene in two unrelated families causes complex HSP, with potassium ion channel dysfunction implicated as the disease-causing mechanism.
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, KV 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 KV 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.
SOURCE: Ann Neurol. 2016 Oct;80(4). doi: 10.1002/ana.24762. Epub 2016 Sep 9. © 2016 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. PMID: 27543892 DOI: 10.1002/ana.24762
A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia.
Helbig KL1, Hedrich UB2, Shinde DN1, Krey I3, Teichmann AC3, Hentschel J3, Schubert J2, Chamberlin AC4, Huether R4, Lu HM4, Alcaraz WA1, Tang S1, Jungbluth C5, Dugan SL5,6, Vainionpää L7, Karle KN8,9,10, Synofzik M8,9, Schöls L8,9, Schüle R8,9, Lehesjoki AE11, Helbig I12,13, Lerche H2, Lemke JR14.
1 Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA.
2 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
3 Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
4 Department of Bioinformatics, Ambry Genetics, Aliso Viejo, CA.
5 Department of Medical Genetics, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN.
6 Division of Medical Genetics, University of Utah, Salt Lake City, UT.
7 Department of Pediatrics and Adolescence, Oulu University Hospital, PEDEGO Research Unit, University of Oulu, Oulu, Finland.
8 Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
9 German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
10 Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
11 Folkhälsan Institute of Genetics, Helsinki, Finland; Research Programs Unit, Molecular Neurology and Neuroscience Center, University of Helsinki, Helsinki, Finland.
12 Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA.
13 Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.
14 Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany. [email protected].