title: SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy.
abstract: Essential tremor (ET) is the most prevalent movement disorder, affecting millions of people in the USA. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In an attempt to identify genetic causes for ET, we performed whole-exome sequencing analyses in a large Spanish family with ET, in which two patients also developed epilepsy. To further assess pathogenicity, site-directed mutagenesis, mouse and human brain expression analyses, and patch clamp techniques were performed. A disease-segregating mutation (p.Gly1537Ser) in the SCN4A gene was identified. Posterior functional analyses demonstrated that more rapid kinetics at near-threshold potentials altered ion selectivity and facilitated the conductance of both potassium and ammonium ions, which could contribute to tremor and increase susceptibility to epilepsy, respectively. In this report, for the first time, we associated the genetic variability of SCN4A with the development of essential tremor, which adds ET to the growing list of neurological channelopathies.
authors.affiliation: Movement Disorders Unit, Department of Neurology Hospital Universitario Donostia San Sebastián Guipuzcoa Spain, Biodonostia Research Institute, Area of Neurosciences, Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bergareche
authors.affiliation: Division of Neurophysiology, Ulm University, Albert-Einstein-Allee 11, 89070 Ulm, Germany.
authors.forename: Marcin
authors.initials: M
authors.lastname: Bednarz
authors.affiliation: Department of Neurology.
authors.forename: Elena
authors.initials: E
authors.lastname: Sánchez
authors.affiliation: Department of Neurology.
authors.forename: Catharine E
authors.initials: CE
authors.lastname: Krebs
authors.affiliation: Movement Disorders Unit, Department of Neurology Hospital Universitario Donostia San Sebastián Guipuzcoa Spain, Biodonostia Research Institute, Area of Neurosciences, Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Ruiz-Martinez
authors.affiliation: Movement Disorders Unit, Department of Neurology Hospital Universitario Donostia San Sebastián Guipuzcoa Spain, Biodonostia Research Institute, Area of Neurosciences, Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: De La Riva
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.affiliation: Movement Disorders Unit, Department of Neurology Hospital Universitario Donostia San Sebastián Guipuzcoa Spain, Biodonostia Research Institute, Area of Neurosciences, Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gorostidi
authors.affiliation: Division of Neurophysiology, Ulm University, Albert-Einstein-Allee 11, 89070 Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Jurkat-Rott
authors.affiliation: Movement Disorders Unit, Department of Neurology Hospital Universitario Donostia San Sebastián Guipuzcoa Spain, Biodonostia Research Institute, Area of Neurosciences, Department of Neurosciences University of the Basque Country, EHU-UPV San Sebastián Gipuzkoa Spain, Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Madrid, Spain.
authors.forename: Jose Felix
authors.initials: JF
authors.lastname: Marti-Masso
authors.affiliation: Department of Neurology, Department of Psychiatry, Department of Genetics and Genomic Sciences, Friedman Brain Institute, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA and coro.paisan-ruiz@mssm.edu.
authors.forename: Coro
authors.initials: C
authors.lastname: Paisán-Ruiz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004827:Epilepsy / Q000235:genetics*; D020329:Essential Tremor / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; C491391:Scn4a protein, mouse