title: CACNA1B mutation is linked to unique myoclonus-dystonia syndrome.
abstract: Using exome sequencing and linkage analysis in a three-generation family with a unique dominant myoclonus-dystonia-like syndrome with cardiac arrhythmias, we identified a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels CaV2.2. This mutation (c.4166G>A;p.Arg1389His) is a disruptive missense mutation in the outer region of the ion pore. The functional consequences of the identified mutation were studied using whole-cell and single-channel patch recordings. High-resolution analyses at the single-channel level showed that, when open, R1389H CaV2.2 channels carried less current compared with WT channels. Other biophysical channel properties were unaltered in R1389H channels including ion selectivity, voltage-dependent activation or voltage-dependent inactivation. CaV2.2 channels regulate transmitter release at inhibitory and excitatory synapses. Functional changes could be consistent with a gain-of-function causing the observed hyperexcitability characteristic of this unique myoclonus-dystonia-like syndrome associated with cardiac arrhythmias.
authors.affiliation: Department of Neurology, Department of Genome Analysis and Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Justus L
authors.initials: JL
authors.lastname: Groen
authors.affiliation: Department of Neuroscience, Brown University, Providence RI 02912, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Andrade
authors.affiliation: Department of Genome Analysis and.
authors.forename: Katja
authors.initials: K
authors.lastname: Ritz
authors.affiliation: Department of Neurology, Department of Genome Analysis and.
authors.forename: Hamid
authors.initials: H
authors.lastname: Jalalzadeh
authors.affiliation: Department of Genome Analysis and.
authors.forename: Martin
authors.initials: M
authors.lastname: Haagmans
authors.affiliation: Department of Genome Analysis and.
authors.forename: Ted E J
authors.initials: TE
authors.lastname: Bradley
authors.affiliation: Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics and.
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.affiliation: Department of Genetics, University of Groningen and.
authors.forename: Dineke S
authors.initials: DS
authors.lastname: Verbeek
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Neuroscience, Brown University, Providence RI 02912, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Denome
authors.affiliation: Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.affiliation: Department of Neuroscience, Brown University, Providence RI 02912, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Lipscombe
authors.affiliation: Department of Neurology.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: Department of Neurology, University of Groningen, Groningen, The Netherlands and m.a.j.de.koning-tijssen@umcg.nl.
authors.forename: Marina A J
authors.initials: MA
authors.lastname: Tijssen
mesh_terms: D000200:Action Potentials; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling; D020821:Dystonic Disorders / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype
chemical_list: C500545:CACNA1B protein, human; D020864:Calcium Channels, N-Type