title: 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 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. Ann Neurol 2016.
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Helbig
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Ulrike B S
authors.initials: UB
authors.lastname: Hedrich
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA.
authors.forename: Deepali N
authors.initials: DN
authors.lastname: Shinde
authors.affiliation: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Krey
authors.affiliation: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
authors.forename: Anne-Christin
authors.initials: AC
authors.lastname: Teichmann
authors.affiliation: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hentschel
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schubert
authors.affiliation: Department of Bioinformatics, Ambry Genetics, Aliso Viejo, CA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Chamberlin
authors.affiliation: Department of Bioinformatics, Ambry Genetics, Aliso Viejo, CA.
authors.forename: Robert
authors.initials: R
authors.lastname: Huether
authors.affiliation: Department of Bioinformatics, Ambry Genetics, Aliso Viejo, CA.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Lu
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Alcaraz
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA.
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Medical Genetics, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN.
authors.forename: Chelsy
authors.initials: C
authors.lastname: Jungbluth
authors.affiliation: Department of Medical Genetics, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN.|Division of Medical Genetics, University of Utah, Salt Lake City, UT.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Dugan
authors.affiliation: Department of Pediatrics and Adolescence, Oulu University Hospital, PEDEGO Research Unit, University of Oulu, Oulu, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Vainionpää
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.|Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
authors.forename: Kathrin N
authors.initials: KN
authors.lastname: Karle
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Research Programs Unit, Molecular Neurology and Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA.|Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany. johannes.lemke@medizin.uni-leipzig.de.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
mesh_terms: D000328:Adult; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D059472:Exome; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D051663:Kv1.2 Potassium Channel / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000503:physiopathology; D014982:Xenopus laevis; D055815:Young Adult
chemical_list: C496969:KCNA2 protein, human; D051663:Kv1.2 Potassium Channel