{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T02:25:40Z","timestamp":1791080740716,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Sudden infant death syndrome (SIDS) is a leading cause of death during the first 6 months after birth. About 5% to 10% of SIDS may stem from cardiac channelopathies such as long-QT syndrome. We recently implicated mutations in \u03b11-syntrophin (SNTA1) as a novel cause of long-QT syndrome, whereby mutant SNTA1 released inhibition of associated neuronal nitric oxide synthase by the plasma membrane Ca-ATPase PMCA4b, causing increased peak and late sodium current (\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>Na<\/jats:sub>\n            ) via S-nitrosylation of the cardiac sodium channel. This study determined the prevalence and functional properties of SIDS-associated\n            <jats:italic>SNTA1<\/jats:italic>\n            mutations.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing of\n            <jats:italic>SNTA1<\/jats:italic>\n            \u2019s open reading frame, 6 rare (absent in 800 reference alleles) missense mutations (G54R, P56S, T262P, S287R, T372M, and G460S) were identified in 8 (\u22483%) of 292 SIDS cases. These mutations were engineered using polymerase chain reaction\u2013based overlap extension and were coexpressed heterologously with SCN5A, neuronal nitric oxide synthase, and PMCA4b in HEK293 cells.\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>Na<\/jats:sub>\n            was recorded using the whole-cell method. A significant 1.4- to 1.5-fold increase in peak\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>Na<\/jats:sub>\n            and 2.3- to 2.7-fold increase in late\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>Na<\/jats:sub>\n            compared with controls was evident for S287R-, T372M-, and G460S-SNTA1 and was reversed by a neuronal nitric oxide synthase inhibitor. These 3 mutations also caused a significant depolarizing shift in channel inactivation, thereby increasing the overlap of the activation and inactivation curves to increase window current.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            Abnormal biophysical phenotypes implicate mutations in\n            <jats:italic>SNTA1<\/jats:italic>\n            as a novel pathogenic mechanism for the subset of channelopathic SIDS. Functional studies are essential to distinguish pathogenic perturbations in channel interacting proteins such as \u03b11-syntrophin from similarly rare but innocuous ones.\n          <\/jats:p>","DOI":"10.1161\/circep.109.891440","type":"journal-article","created":{"date-parts":[[2009,9,13]],"date-time":"2009-09-13T00:25:32Z","timestamp":1252801532000},"page":"667-676","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":79,"title":["\u03b11-Syntrophin Mutations Identified in Sudden Infant Death Syndrome Cause an Increase in Late Cardiac Sodium Current"],"prefix":"10.1161","volume":"2","author":[{"given":"Jianding","family":"Cheng","sequence":"first","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Van Norstrand","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argelia","family":"Medeiros-Domingo","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Valdivia","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi-hua","family":"Tan","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Ye","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacie","family":"Kroboth","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Vatta","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig T.","family":"January","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan C.","family":"Makielski","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (J.C., C.V., B.T., B.Y., S.K., C.T.J., J.C.M.), Department of Medicine, University of Wisconsin, Madison; the Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics (D.W.V., A.M.-D., D.J.T., M.J.A.), Mayo Clinic, Rochester, Minn; and the Section of Pediatric Cardiology (M.V.), Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, Tex."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.114.1.234"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/dev.20367"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp048194"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/dev.20369"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61662-6"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.17.2124"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199806113382401"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200007273430405"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.18.2264"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000115205.70330.05"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.646513"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.658021"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2006.11.030"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e3181841eca"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2005.02.013"},{"key":"e_1_3_2_16_2","first-page":"S94.","volume":"5","year":"2008","unstructured":"Van Norstrand DW, Pundi KN, Tester DJ, Medeiros-Domingo A, Valdivia CR, Makielski JC, Ackerman MJ. 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