An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population
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...
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Wiley
2017-04-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.116.005330 |
| _version_ | 1811275150184677376 |
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| author | Jianding Cheng John W. Kyle Di Lang Brandi Wiedmeyer Jian Guo Kun Yin Lei Huang Ravi Vaidyanathan Terry Su Jonathan C. Makielski |
| author_facet | Jianding Cheng John W. Kyle Di Lang Brandi Wiedmeyer Jian Guo Kun Yin Lei Huang Ravi Vaidyanathan Terry Su Jonathan C. Makielski |
| author_sort | Jianding Cheng |
| collection | DOAJ |
| description | 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 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. 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. |
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| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-12T23:32:55Z |
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| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-982e60b47f024bfeb22492f5f3ab95792022-12-22T03:12:14ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802017-04-016410.1161/JAHA.116.005330An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han PopulationJianding Cheng0John W. Kyle1Di Lang2Brandi Wiedmeyer3Jian Guo4Kun Yin5Lei Huang6Ravi Vaidyanathan7Terry Su8Jonathan C. Makielski9Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat‐sen University, Guangzhou, ChinaDivision of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WIDivision of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WIDivision of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WIBGI‐Shenzhen, Shenzhen, ChinaDepartment of Forensic Pathology, Zhongshan School of Medicine, Sun Yat‐sen University, Guangzhou, ChinaDepartment of Forensic Pathology, Zhongshan School of Medicine, Sun Yat‐sen University, Guangzhou, ChinaDivision of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WIDepartment of Forensic Pathology, Zhongshan School of Medicine, Sun Yat‐sen University, Guangzhou, ChinaDivision of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WIBackgroundWe 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 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. 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.https://www.ahajournals.org/doi/10.1161/JAHA.116.005330cardiac sodium channelsudden cardiac deathsudden unexplained nocturnal death syndromevinculin |
| spellingShingle | Jianding Cheng John W. Kyle Di Lang Brandi Wiedmeyer Jian Guo Kun Yin Lei Huang Ravi Vaidyanathan Terry Su Jonathan C. Makielski An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease cardiac sodium channel sudden cardiac death sudden unexplained nocturnal death syndrome vinculin |
| title | An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population |
| title_full | An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population |
| title_fullStr | An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population |
| title_full_unstemmed | An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population |
| title_short | An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population |
| title_sort | east asian common variant vinculin p asp841his was associated with sudden unexplained nocturnal death syndrome in the chinese han population |
| topic | cardiac sodium channel sudden cardiac death sudden unexplained nocturnal death syndrome vinculin |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.116.005330 |
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