A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family studyReport as inadecuate




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Background

Early repolarization syndrome ERS may be a near-Mendelian or an oligogenic disease; however, no direct evidence has been provided to support this theory.

Methods and results

We described a large Chinese family with nocturnal sudden cardiac death induced by ERS in most of the young male adults. One missense mutation p.Q1916R was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene SCN5A p.R1193Q was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the CACNA1C-Q1916R mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of CACNA1C-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation.

Conclusions

Our results demonstrated that the loss-of-function CACNA1C-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the SCN5A-R1193Q variant and sex. These findings suggest that phenotypes of ERS are modified by multiple genetic factors, which supports the theory that ERS may be an oligogenic disease.



Author: Xin Liu , Yang Shen , Jinyan Xie, Huihui Bao, Qing Cao, Rong Wan, Xiaoming Xu, Hui Zhou, Lin Huang, Zhenyan Xu, Wengen Zhu, Jinzh

Source: http://plos.srce.hr/



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