An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population

Abstract

BackgroundWe have identified the cardiomyopathy‐susceptibility gene vinculin (VCL) mutation M94I may account for a sudden unexplained nocturnal death syndrome (SUNDS) case. We addressed whether VCL common variant D841H is associated with SUNDS.Methods and ResultsIn 8 of 120 SUNDS cases, we detected an East Asian common VCL variant p.Asp841His (D841H). Comparing the H841 allele frequency of the general population in the local database (15 of 1818) with SUNDS victims (10 of 240) gives an odds ratio for SUNDS of 5.226 (95% CI, 2.321, 11.769). The VCL‐D841H variant was engineered and either coexpressed with cardiac sodium channel (SCN5A) in HEK293 cells or overexpressed in human induced pluripotent stem‐cell–derived cardiomyocytes to examine its effects on sodium channel function using the whole‐cell patch‐clamp method. In HEK293 cells, under physiological pH conditions (pH 7.4), D841H caused a 29% decrease in peak IN a amplitude compared to wild type (WT), whereas under acidotic conditions (pH 7.0), D841H decreased further to 43% along with significant negative shift in inactivation compared to WT at pH 7.4. In induced pluripotent stem‐cell‐derived cardiomyocytes, similar effects of D841H on IN a were observed. VCL colocalized with SCN5A at the intercalated disk in human cardiomyocytes. VCL was also confirmed to directly interact with SCN5A, and VCL‐D841H did not disrupt the association of VCL and SCN5A.ConclusionsA VCL common variant was genetically and biophysically associated with Chinese SUNDS. The aggravation of loss of function of SCN5A caused by VCL‐D841H under acidosis supports that nocturnal sleep respiratory disorders with acidosis may play a key role in the pathogenesis of SUNDS.

Sudden Unexplained Nocturnal Death Syndrome: The Hundred Years' Enigma

“…The H841 allele was more frequent in SUNDS and gave an odds ratio of 5.226 compared with controls. Similar to M94I, D841H also reduced peak I Na without changing the interaction or co‐localization …”

“…However, electrical study showed that SCN5A ‐ H558R not only reversed the decrease of peak I Na amplitude caused by VCL‐D841H , but also significantly increased the late I Na for VCL ‐ D841H in HEK293 cells. In addition, SCN5A ‐ H558R and VCL ‐ D841H were detected in 1 SUNDS case . These suggest that compound variants might play a critical role in SUNDS.…”

“…Several mutations in VCL have been identified to be pathogenic for dilated cardiomyopathy or hypertrophic cardiomyopathy . We identified a rare variant M94I in 1/44 SUNDS cases and an East Asian common variant D841H in 8/120 SUNDS cases . Co‐expression of Nav1.5 with M94I‐ VCL showed a reduction in peak I Na and a further reduction in acid conditions.…”

A SNaPshot assay for detection of 45 mutations in the SCN5A gene in the Chinese Han Population

“…There are several techniques for DNA mutation analysis, such as direct Sanger sequencing or next‐generation sequencing . The SNaPshot multiplex technique in our study is a minisequencing method for SNP detection in molecular genetic testing, which can be easily applied in the laboratory workflow.…”

“…The genetic background of SCD has been addressed in recent years. In forensic medicine, SCD‐related mutations are screened using next‐generation sequencing and whole‐exome sequencing techniques . However, these methods are too expensive for most laboratories and it is hard to meet the demand for examinations, given the worldwide SCD epidemic.…”