{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:47:11Z","timestamp":1791352031564,"version":"4.3.1"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2011,8,30]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>\n                      The D1275N\n                      <jats:italic>SCN5A<\/jats:italic>\n                      mutation has been associated with a range of unusual phenotypes, including conduction disease and dilated cardiomyopathy, as well as atrial and ventricular tachyarrhythmias. However, when D1275N is studied in heterologous expression systems, most studies show near-normal sodium channel function. Thus, the relationship of the variant to the clinical phenotypes remains uncertain.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      We identified D1275N in a patient with atrial flutter, atrial standstill, conduction disease, and sinus node dysfunction. There was no major difference in biophysical properties between wild-type and D1275N channels expressed in Chinese hamster ovary cells or tsA201 cells in the absence or presence of \u03b21 subunits. To determine D1275N function in vivo, the\n                      <jats:italic>Scn5a<\/jats:italic>\n                      locus was modified to knock out the mouse gene, and the full-length wild-type (H) or D1275N (DN) human\n                      <jats:italic>SCN5A<\/jats:italic>\n                      cDNAs were then inserted at the modified locus by recombinase mediated cassette exchange. Mice carrying the DN allele displayed slow conduction, heart block, atrial fibrillation, ventricular tachycardia, and a dilated cardiomyopathy phenotype, with no significant fibrosis or myocyte disarray on histological examination. The DN allele conferred gene-dose\u2013dependent increases in\n                      <jats:italic>SCN5A<\/jats:italic>\n                      mRNA abundance but reduced sodium channel protein abundance and peak sodium current amplitudes (H\/H, 41.0\u00b12.9 pA\/pF at \u221230 mV; DN\/H, 19.2\u00b13.1 pA\/pF,\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.001 vs H\/H; DN\/DN, 9.3\u00b11.1 pA\/pF,\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.001 versus H\/H).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>Although D1275N produces near-normal currents in multiple heterologous expression experiments, our data establish this variant as a pathological mutation that generates conduction slowing, arrhythmias, and a dilated cardiomyopathy phenotype by reducing cardiac sodium current.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.110.987248","type":"journal-article","created":{"date-parts":[[2011,8,9]],"date-time":"2011-08-09T00:16:10Z","timestamp":1312848970000},"page":"1001-1011","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":132,"title":["Striking In Vivo Phenotype of a Disease-Associated Human\n                    <i>SCN5A<\/i>\n                    Mutation Producing Minimal Changes in Vitro"],"prefix":"10.1161","volume":"124","author":[{"given":"Hiroshi","family":"Watanabe","sequence":"first","affiliation":[{"name":"From the Departments of Medicine and Pharmacology (H.W., T.Y., D.M.S., J.S.L., T.C.A., D.W.W., B.L., L.H., S.K., N.K., B.C.K., A.L.G., D.M.R.) and Molecular Physiology and Biophysics (S.B.H., M.A.M.), Vanderbilt University School of Medicine, Nashville, TN; Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (H.W.); Division of Cardiology, University of Toronto, Canada (L.H.); Department of Medicine, The First Affiliated Hospital of Nanjing..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine and Pharmacology (H.W., T.Y., D.M.S., J.S.L., T.C.A., D.W.W., B.L., L.H., S.K., N.K., B.C.K., A.L.G., D.M.R.) and Molecular Physiology and Biophysics (S.B.H., M.A.M.), Vanderbilt University School of Medicine, Nashville, TN; Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (H.W.); Division of Cardiology, University of Toronto, Canada (L.H.); Department of Medicine, The First Affiliated Hospital of Nanjing..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina Myers","family":"Stroud","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine and Pharmacology (H.W., T.Y., D.M.S., J.S.L., T.C.A., D.W.W., B.L., L.H., S.K., N.K., B.C.K., A.L.G., D.M.R.) and Molecular Physiology and Biophysics (S.B.H., M.A.M.), Vanderbilt University School of Medicine, Nashville, TN; Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (H.W.); Division of Cardiology, University of Toronto, Canada (L.H.); Department of Medicine, The First Affiliated Hospital of Nanjing..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Lowe","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine and Pharmacology (H.W., T.Y., D.M.S., J.S.L., T.C.A., D.W.W., B.L., L.H., S.K., N.K., B.C.K., A.L.G., D.M.R.) and Molecular Physiology and Biophysics (S.B.H., M.A.M.), Vanderbilt University School of Medicine, Nashville, TN; Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (H.W.); Division of Cardiology, University of Toronto, Canada (L.H.); Department of Medicine, The First Affiliated Hospital of Nanjing..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Harris","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine and Pharmacology (H.W., T.Y., D.M.S., J.S.L., T.C.A., D.W.W., B.L., L.H., S.K., N.K., B.C.K., A.L.G., D.M.R.) and Molecular Physiology and Biophysics (S.B.H., M.A.M.), Vanderbilt University School of Medicine, Nashville, TN; 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