Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8474409 | Journal of Molecular and Cellular Cardiology | 2015 | 9 Pages |
Abstract
Gain-of-function mutations in CACNA1C, encoding the L-type Ca2Â + 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.
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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,