{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T05:28:02Z","timestamp":1771306082403,"version":"3.50.1"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Heterologous functional validation studies of putative long-QT syndrome subtype 2\u2013associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous\n              <jats:italic>KCNH2<\/jats:italic>\n              variants seemingly associated with sudden infant death syndrome.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Genetic testing of 292 sudden infant death syndrome cases identified 9\n              <jats:italic>KCNH2<\/jats:italic>\n              variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R. Previous studies show R181Q-, P967L-, and R1047L-Kv11.1 channels function similar to wild-type Kv11.1 channels, whereas Q1068R-Kv11.1 channels accelerate inactivation gating. We studied the biochemical and biophysical properties for E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels expressed in human embryonic kidney 293 cells; examined the electronic health records of patients who were genotype positive for the sudden infant death syndrome\u2013linked\n              <jats:italic>KCNH2<\/jats:italic>\n              variants; and simulated their functional impact using computational models of the human ventricular action potential.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Western blot and voltage-clamping analyses of cells expressing E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels demonstrated these variants express and generate peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels, but R791W- and R1005W-Kv11.1 channels accelerated deactivation and activation gating, respectively. Electronic health records of patients with the sudden infant death syndrome\u2013linked\n              <jats:italic>KCNH2<\/jats:italic>\n              variants showed that the patients had median heart rate\u2013corrected QT intervals &lt;480 ms and none had been diagnosed with long-QT syndrome or experienced cardiac arrest. Simulating the impact of dysfunctional gating variants predicted that they have little impact on ventricular action potential duration.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>We conclude that these rare Kv11.1 missense variants are not long-QT syndrome subtype 2\u2013causative variants and therefore do not represent the pathogenic substrate for sudden infant death syndrome in the variant-positive infants.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.117.005859","type":"journal-article","created":{"date-parts":[[2018,5,11]],"date-time":"2018-05-11T09:15:18Z","timestamp":1526030118000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Functional Invalidation of Putative Sudden Infant Death Syndrome\u2013Associated Variants in the\n            <i>KCNH2<\/i>\n            -Encoded Kv11.1 Channel"],"prefix":"10.1161","volume":"11","author":[{"given":"Jennifer L.","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Center, Center for Muscle Biology, University of Kentucky, Lexington (J.L.S., A.R.H., D.E.B., B.P.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Diseases, Pediatrics, and Molecular Pharmacology &amp; Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (D.J.T., M.J.A.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison R.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Center, Center for Muscle Biology, University of Kentucky, Lexington (J.L.S., A.R.H., D.E.B., B.P.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Don E.","family":"Burgess","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Center, Center for Muscle Biology, University of Kentucky, Lexington (J.L.S., A.R.H., D.E.B., B.P.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Chun","family":"Hsu","sequence":"additional","affiliation":[{"name":"School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taiwan (C.-C.H.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samy","family":"Claude Elayi","sequence":"additional","affiliation":[{"name":"University of Kentucky, Gill Heart Institute and VAMC, Cardiology, Lexington (S.C.E.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corey L.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmias Research Program, Department of Medicine, University of Wisconsin, Madison (C.L.A., C.T.J.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig T.","family":"January","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmias Research Program, Department of Medicine, University of Wisconsin, Madison (C.L.A., C.T.J.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan Z.","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Molecular and Functional Genomics and Genomic Medicine Institute, Geisinger Clinic, Danville, PA (J.Z.L., D.N.H., U.L.M., M.F.M., T.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dustin N.","family":"Hartzel","sequence":"additional","affiliation":[{"name":"Department of Molecular and Functional Genomics and Genomic Medicine Institute, Geisinger Clinic, Danville, PA (J.Z.L., D.N.H., U.L.M., M.F.M., T.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uyenlinh L.","family":"Mirshahi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Functional Genomics and Genomic Medicine Institute, Geisinger Clinic, Danville, PA (J.Z.L., D.N.H., U.L.M., M.F.M., T.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael F.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Molecular and Functional Genomics and Genomic Medicine Institute, Geisinger Clinic, Danville, PA (J.Z.L., D.N.H., U.L.M., M.F.M., T.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tooraj","family":"Mirshahi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Functional Genomics and Genomic Medicine Institute, Geisinger Clinic, Danville, PA (J.Z.L., D.N.H., U.L.M., M.F.M., T.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Diseases, Pediatrics, and Molecular Pharmacology &amp; Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (D.J.T., M.J.A.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian P.","family":"Delisle","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Center, Center for Muscle Biology, University of Kentucky, Lexington (J.L.S., A.R.H., D.E.B., 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