Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Groen, Justus L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Andrade, Arturo UNSPECIFIED UNSPECIFIED UNSPECIFIED Ritz, Katja UNSPECIFIED UNSPECIFIED UNSPECIFIED Jalalzadeh, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED Haagmans, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Bradley, Ted E. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jongejan, Aldo UNSPECIFIED UNSPECIFIED UNSPECIFIED Verbeek, Dineke S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Denome, Sylvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Hennekam, Raoul C. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lipscombe, Diane UNSPECIFIED UNSPECIFIED UNSPECIFIED Baas, Frank UNSPECIFIED orcid.org/0000-0003-3912-5428 UNSPECIFIED Tijssen, Marina A. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language FAMILIAL HEMIPLEGIC MIGRAINE; CALCIUM-CHANNELS; SYNAPTIC-TRANSMISSION; POTASSIUM CHANNEL; PERMEANT IONS; CA2+ CHANNEL; PROTEIN; SELECTIVITY; DEPENDENCE; PROTONS Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40754