Referenced in: none

Automatically associated channels: Cav1.2 , Kv7.1

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

Authors: Konstantin Wemhöner, Corinna Friedrich, Birgit Stallmeyer, Alison J Coffey, Andrew Grace, Sven Zumhagen, Guiscard Seebohm, Beatriz Ortiz-Bonnin, Susanne Rinné, Frank B Sachse, Eric Schulze-Bahr, Niels Decher

Journal, date & volume: J. Mol. Cell. Cardiol., 2015 Mar , 80, 186-95

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25633834

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.