Groen, Justus L., Andrade, Arturo, Ritz, Katja, Jalalzadeh, Hamid, Haagmans, Martin, Bradley, Ted E. J., Jongejan, Aldo, Verbeek, Dineke S., Nuernberg, Peter, Denome, Sylvia, Hennekam, Raoul C. M., Lipscombe, Diane, Baas, Frank ORCID: 0000-0003-3912-5428 and Tijssen, Marina A. J. (2015). CACNA1B mutation is linked to unique myoclonus-dystonia syndrome. Hum. Mol. Genet., 24 (4). S. 987 - 994. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Groen, Justus L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrade, ArturoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ritz, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jalalzadeh, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haagmans, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bradley, Ted E. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jongejan, AldoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verbeek, Dineke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denome, SylviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hennekam, Raoul C. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lipscombe, DianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baas, FrankUNSPECIFIEDorcid.org/0000-0003-3912-5428UNSPECIFIED
Tijssen, Marina A. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-407547
DOI: 10.1093/hmg/ddu513
Journal or Publication Title: Hum. Mol. Genet.
Volume: 24
Number: 4
Page Range: S. 987 - 994
Date: 2015
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FAMILIAL HEMIPLEGIC MIGRAINE; CALCIUM-CHANNELS; SYNAPTIC-TRANSMISSION; POTASSIUM CHANNEL; PERMEANT IONS; CA2+ CHANNEL; PROTEIN; SELECTIVITY; DEPENDENCE; PROTONSMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40754

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