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An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in
Jianding Cheng1, John W Kyle2, Di Lang2
1Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China chengjd@mail.sysu.edu.cn.
Insights
A common vinculin (VCL) variant, D841H, is linked to sudden unexplained nocturnal death syndrome (SUNDS) in East Asians. This variant impairs cardiac sodium channel function, especially during acidosis, suggesting a role in SUNDS pathogenesis.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Sudden Death Syndromes
Background:
- The vinculin (VCL) gene is implicated in cardiomyopathy.
- A specific VCL mutation (M94I) was previously linked to a sudden unexplained nocturnal death syndrome (SUNDS) case.
- The association of a common VCL variant (D841H) with SUNDS requires investigation.
Purpose of the Study:
- To investigate the association between the VCL common variant D841H and SUNDS.
- To determine the functional impact of VCL-D841H on cardiac sodium channel (SCN5A) function.
- To explore the role of acidosis in VCL-D841H-associated SUNDS pathogenesis.
Main Methods:
- Genotyping of VCL D841H in SUNDS cases and controls.
- Expression studies in HEK293 cells and human induced pluripotent stem-cell-derived cardiomyocytes.
- Whole-cell patch-clamp electrophysiology to assess sodium channel function.
- Immunofluorescence and co-immunoprecipitation to study protein interactions.
Main Results:
- The VCL D841H variant was detected in 8 of 120 SUNDS cases.
- An increased odds ratio (5.226) for SUNDS was observed with the H841 allele compared to the general population.
- VCL-D841H reduced peak sodium current (INa) by 29% at physiological pH and 43% under acidic conditions (pH 7.0).
- VCL-D841H caused a negative shift in sodium channel inactivation, particularly under acidosis.
- VCL interacts with SCN5A at the intercalated disk, and D841H does not disrupt this interaction.
Conclusions:
- The common VCL variant D841H is genetically and biophysically associated with Chinese SUNDS.
- VCL-D841H exacerbates loss-of-function of SCN5A under acidosis.
- Nocturnal respiratory disorders with acidosis may be crucial in SUNDS pathogenesis.
Background:
We 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 Results:
In 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 INa 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 INa 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.
Conclusions:
A 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.