CACNA1B mutation is linked to unique myoclonus-dystonia syndrome

• Published in: Human molecular genetics Vol. 24; no. 4; pp. 987 - 993
• Main Authors: Groen, Justus L, Andrade, Arturo, Ritz, Katja, Jalalzadeh, Hamid, Haagmans, Martin, Bradley, Ted E J, Jongejan, Aldo, Verbeek, Dineke S, Nürnberg, Peter, Denome, Sylvia, Hennekam, Raoul C M, Lipscombe, Diane, Baas, Frank, Tijssen, Marina A J
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15-02-2015
• Subjects: Action Potentials; Calcium Channels, N-Type - genetics; Calcium Channels, N-Type - metabolism; Calcium Signaling; Dystonic Disorders - diagnosis; Dystonic Disorders - genetics; Exome; Female; Genetic Association Studies; Genetic Linkage; High-Throughput Nucleotide Sequencing; Humans; Male; Mutation; Patch-Clamp Techniques; Pedigree; Phenotype
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddu513

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.