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J Mol Cell Cardiol. 2015 Mar;80:186-95. doi: 10.1016/j.yjmcc.2015.01.002. Epub 2015 Jan 26.

Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.

Author information

1
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstr. 1-2, 35037 Marburg, Germany.
2
Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Domagkstr. 3, 48149 Münster, Germany.
3
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
4
Department of Biochemistry, University of Cambridge, Hopkins Building, Tennis Court Road, Cambridge CB2 1QW, UK; Papworth Hospital, Cambridge CB23 3RE, UK.
5
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95 South 2000 East, Salt Lake City, UT 84112, USA; Department of Bioengineering, James LeVoy Sorenson Molecular Biotechnology Building, 36 S. Wasatch Drive, Salt Lake City, UT 84112, USA.
6
Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstr. 1-2, 35037 Marburg, Germany. Electronic address: decher@staff.uni-marburg.de.

Abstract

Gain-of-function mutations in CACNA1C, encoding the L-type Ca(2+) channel Cav1.2, cause Timothy syndrome (TS), a multi-systemic disorder with dysmorphic features, long-QT syndrome (LQTS) and autism spectrum disorders. TS patients have heterozygous mutations (G402S and G406R) located in the alternatively spliced exon 8, causing a gain-of-function by reduced voltage-dependence of inactivation. Screening 540 unrelated patients with non-syndromic forms of LQTS, we identified six functional relevant CACNA1C mutations in different regions of the channel. All these mutations caused a gain-of-function combining different mechanisms, including changes in current amplitude, rate of inactivation and voltage-dependence of activation or inactivation, similar as in TS. Computer simulations support the theory that the novel CACNA1C mutations prolong action potential duration. We conclude that genotype-negative LQTS patients should be investigated for mutations in CACNA1C, as a gain-of-function in Cav1.2 is likely to cause LQTS and only specific and rare mutations, i.e. in exon 8, cause the multi-systemic TS.

KEYWORDS:

Arrhythmia; Cav1.2; Gain-of-function; LQT8; Timothy syndrome

PMID:
25633834
DOI:
10.1016/j.yjmcc.2015.01.002
[Indexed for MEDLINE]

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