title: Digenic inheritance novel mutations in SCN5a and SNTA1 increase late I(Na) contributing to LQT syndrome.
abstract: SCN5A and SNTA1 are reported susceptible genes for long QT syndrome (LQTS). This study was designed to elucidate a plausible pathogenic arrhythmia mechanism for the combined novel mutations R800L-SCN5A and A261V-SNTA1 on cardiac sodium channels. A Caucasian family with syncope and marginally prolonged QT interval was screened for LQTS-susceptibility genes and found to harbor the R800L mutation in SCN5A and A261V mutation in SNTA1, and those with both mutations had the strongest clinical phenotype. The mutations were engineered into the most common splice variant of human SCN5A and SNTA1 cDNA, respectively, and sodium current (INa) was characterized in human embryonic kidney 293 cells cotransfected with neuronal nitric oxide synthase (nNOS) and the cardiac isoform of the plasma membrane Ca-ATPase (PMCA4b). Peak INa densities were unchanged for wild-type (WT) and for mutant channels containing R800L-SCN5A, A261V-SNTA1, or R800L-SCN5A plus A261V-SNTA1. However, late INa for either single mutant was moderately increased two- to threefold compared with WT. The combined mutations of R800L-SCN5A plus A261V-SNTA1 significantly enhanced the INa late/peak ratio by 5.6-fold compared with WT. The time constants of current decay of combined mutant channel were markedly increased. The gain-of-function effect could be blocked by the N(G)-monomethyl-l-arginine, a nNOS inhibitor. We conclude that novel mutations in SCN5A and SNTA1 jointly exert a nNOS-dependent gain-of-function on SCN5A channels, which may consequently prolong the action potential duration and lead to LQTS phenotype.
authors: Center for Arrhythmia Diagnosis and Treatment, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Rou-Mu
authors: RM
authors: Hu
authors: Bi-Hua
authors: BH
authors: Tan
authors: Kate M
authors: KM
authors: Orland
authors: Carmen R
authors: CR
authors: Valdivia
authors: Amber
authors: A
authors: Peterson
authors: Jielin
authors: J
authors: Pu
authors: Jonathan C
authors: JC
authors: Makielski
mesh_terms: D000200:Action Potentials / Q000235:genetics*; D000328:Adult; D000368:Aged; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013575:Syncope / Q000235:genetics; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C091825:syntrophin alpha1; D019323:omega-N-Methylarginine; D012964:Sodium; D019001:Nitric Oxide Synthase; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases
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