CACNA1B mutation is linked to unique myoclonus-dystonia syndrome

Justus L. Groen, Arturo Andrade, Katja Ritz, Hamid Jalalzadeh, Martin Haagmans, Ted E. J. Bradley, Aldo Jongejan, Dineke S. Verbeek, Peter Nuernberg, Sylvia Denome, Raoul C. M. Hennekam, Diane Lipscombe, Frank Baas, Marina A. J. Tijssen*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

51 Citaten (Scopus)


Using exome sequencing and linkage analysis in a three-generation family with a unique dominant myoclonusdystonia-like syndrome with cardiac arrhythmias, we identified a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels Ca(V)2.2. 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 Ca(V)2.2 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. Ca(V)2.2 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.

Originele taal-2English
Pagina's (van-tot)987-993
Aantal pagina's7
TijdschriftHuman Molecular Genetics
Nummer van het tijdschrift4
StatusPublished - 15-feb-2015

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