2. Academic Validation
  3. CACNA1B mutation is linked to unique myoclonus-dystonia syndrome

CACNA1B mutation is linked to unique myoclonus-dystonia syndrome

  • Hum Mol Genet. 2015 Feb 15;24(4):987-93. doi: 10.1093/hmg/ddu513.
Justus L Groen 1,  Arturo Andrade 2,  Katja Ritz 3,  Hamid Jalalzadeh 4,  Martin Haagmans 3,  Ted E J Bradley 3,  Aldo Jongejan 5,  Dineke S Verbeek 6,  Peter Nürnberg 7,  Sylvia Denome 2,  Raoul C M Hennekam 8,  Diane Lipscombe 2,  Frank Baas 9,  Marina A J Tijssen 10
Affiliations

Affiliations

  • 1 Department of Neurology, Department of Genome Analysis and Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands.
  • 2 Department of Neuroscience, Brown University, Providence RI 02912, USA.
  • 3 Department of Genome Analysis and.
  • 4 Department of Neurology, Department of Genome Analysis and.
  • 5 Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics and.
  • 6 Department of Genetics, University of Groningen and.
  • 7 Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • 8 Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  • 9 Department of Neurology.
  • 10 Department of Neurology, University of Groningen, Groningen, The Netherlands and m.a.j.de.koning-tijssen@umcg.nl.
PMID: 25296916 DOI: 10.1093/hmg/ddu513
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.

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