title: An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population.
abstract: 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 whetherVCLcommon variant D841H is associated with SUNDS.
  
  
  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 peakINaamplitude 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 onINawere 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.
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China chengjd@mail.sysu.edu.cn.
authors.forename: Jianding
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: John W
authors.initials: JW
authors.lastname: Kyle
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: Di
authors.initials: D
authors.lastname: Lang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: Brandi
authors.initials: B
authors.lastname: Wiedmeyer
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yin
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vaidyanathan
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Terry
authors.initials: T
authors.lastname: Su
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics*; D053840:Brugada Syndrome / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002681:China; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D014162:Transfection; D016596:Vinculin / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C488955:VCL protein, human; D016596:Vinculin
keywords: cardiac sodium channel; sudden cardiac death; sudden unexplained nocturnal death syndrome; vinculin