title: Vinculin variant M94I identified in sudden unexplained nocturnal death syndrome decreases cardiac sodium current.
abstract: Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative disorder with unclear etiology. Vinculin (VCL) was linked to sudden arrhythmia death in VCL knockout mice prior to the appearance of cardiomyopathy. We hypothesized VCL mutations underlie risk for SUNDS. A rare heterozygous variant VCL-M94I was found in a SUNDS victim who suffered sudden nocturnal tachypnea and lacked pathogenic variants in known arrhythmia-causing genes. VCL was identified to interact with SCN5A in vitro/vivo. The VCL-M94I was co-expressed with the cardiac sodium channel in HEK293 cells and also overexpressed in induced pluripotent stem cells derived cardiomyocytes (iPSCs-CM). In HEK293 cells with pH 7.4, VCL-M94I caused ~30% decrease in peak sodium current (INa) amplitude compared to WT; under acidotic conditions (pH 7.0) typically found with hypoxia during sleep apnea, M94I resulted in 37% reduction in peak INacompared to WT and the combination of VCL-M94I and pH 7.0 decreased peak INaby ~56% compared to WT at pH 7.4. In iPSCs-CM, similar effects of M94I on reduction of peak INawere observed. This study initially shows both physical and functional interaction between VCL and cardiac sodium channel, and suggests an important role for respiratory acidosis in triggering the fatal arrhythmia underlying SUNDS.
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jianding
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Kyle
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Brandi
authors.initials: B
authors.lastname: Wiedmeyer
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Lang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vaidyanathan
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics / Q000473:pathology*; D005260:Female; D005838:Genotype; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D016596:Vinculin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D016596:Vinculin