{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T01:51:49Z","timestamp":1772761909079,"version":"3.50.1"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,5,16]],"date-time":"2017-05-16T00:00:00Z","timestamp":1494892800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Seventh Masonic District Association, Inc."},{"name":"KiDS of NYU"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pacing Clinical Electrophis"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Two genetic variants in <jats:italic>SCN5A<\/jats:italic>, encoding the Nav1.5 Na<jats:sup>+<\/jats:sup> channel \u03b1\u2010subunit, were found in a 5\u2010month\u2010old girl who died suddenly in her sleep. The first variant is a missense mutation, resulting in an amino acid change (Q1832E), which has been described (but not characterized) in a patient with Brugada syndrome. The second is a nonsense mutation that produces a premature stop codon and a C\u2010terminal truncation (R1944\u0394).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>To investigate their functional relevance with patch clamp experiments in transfected HEK\u2010293 cells. The Q1832E mutation drastically reduced Nav1.5 current density. The R1944\u0394 C\u2010terminal truncation had negligible effects on Nav1.5 current density. Neither of the mutations affected the voltage dependence of steady activation and inactivation or influenced the late Na<jats:sup>+<\/jats:sup> current or the recovery from inactivation. Biochemical and immunofluorescent approaches demonstrated that the Q1832E mutation caused severe trafficking defects. Polymerase chain reaction cloning and sequencing the victim's genomic DNA allowed us to determine that the two variants were in <jats:italic>trans<\/jats:italic>. We investigated the functional consequences by coexpressing Nav1.5(Q1832E) and Nav1.5(R1944\u0394), which led to a significantly reduced current amplitude relative to wild\u2010type.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These sudden infant death syndrome (SIDS)\u2010related variants caused a severely dysfunctional Nav1.5 channel, which was mainly due to trafficking defects caused by the Q1832E mutation. The decreased current density is likely to be a major contributing factor to arrhythmogenesis in Brugada syndrome and the sudden death of this SIDS victim.<\/jats:p><\/jats:sec>","DOI":"10.1111\/pace.13087","type":"journal-article","created":{"date-parts":[[2017,3,31]],"date-time":"2017-03-31T07:21:20Z","timestamp":1490944880000},"page":"703-712","source":"Crossref","is-referenced-by-count":20,"title":["Infant sudden death: Mutations responsible for impaired Nav1.5 channel trafficking and function"],"prefix":"10.1111","volume":"40","author":[{"given":"Ivan","family":"Gando","sequence":"first","affiliation":[{"name":"Pediatrics NYU School of Medicine  New York NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jace","family":"Morganstein","sequence":"additional","affiliation":[{"name":"Pediatrics NYU School of Medicine  New York NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kundan","family":"Jana","sequence":"additional","affiliation":[{"name":"Pediatrics NYU School of Medicine  New York NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas V.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Medicine Albert Einstein College of Medicine  Bronx NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingying","family":"Tang","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory Office of Chief Medical Examiner  New York NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1522-8326","authenticated-orcid":false,"given":"William A.","family":"Coetzee","sequence":"additional","affiliation":[{"name":"Pediatrics NYU School of Medicine  New York NY"},{"name":"Physiology &amp; Neuroscience NYU School of Medicine  New York NY"},{"name":"Biochemistry and Molecular Pharmacology NYU School of Medicine  New York NY"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,5,16]]},"reference":[{"key":"e_1_2_5_2_1","first-page":"1","article-title":"Death in the United States, 2011","author":"Minino AM","year":"2013","journal-title":"NCHS data brief"},{"key":"e_1_2_5_3_1","unstructured":"Mortality PCCGRPHAtRUSI.Centers for Disease Control and Prevention. 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