{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:25:50Z","timestamp":1789511150958,"version":"build-2803163510"},"reference-count":39,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2013,4,30]],"date-time":"2013-04-30T00:00:00Z","timestamp":1367280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL-33843\/HL-51618"],"award-info":[{"award-number":["HL-33843\/HL-51618"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL-28958"],"award-info":[{"award-number":["HL-28958"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Columbia University Department of Pediatrics"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cardiovasc electrophysiol"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:title>An LQTS6 M54T Mutation and Sinus Node Dysfunction<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Sinus node (SN) dysfunction is observed in some long\u2010QT syndrome (LQTS) patients, but has not been studied as a function of LQTS genotype. LQTS6 involves mutations in the hERG \u03b2\u2010subunit MiRP1, which also interacts with hyperpolarization\u2010activated, cyclic nucleotide gated (HCN) channels\u2014the molecular correlate of SN pacemaker current (I\n                      <jats:sub>f<\/jats:sub>\n                      ). An LQTS registry search identified a 55\u2010year male with M54T MiRP1 mutation, history of sinus bradycardia (39\u201356 bpm), and prolonged QTc.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      We tested if LQTS6 incorporates sinus bradycardia due to abnormal I\n                      <jats:sub>f<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We transiently co\u2010transfected neonatal rat ventricular myocytes (to study currents in a myocyte background) with human HCN4 (hHCN4, primary SN isoform) or human HCN2 (hHCN2) and one of the following: empty vector, wild\u2010type hMiRP1 (WT), M54T hMiRP1 (M54T). Current amplitude, voltage dependence, and kinetics were measured by whole cell patch clamp.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>M54T co\u2010expression decreased HCN4 current density by 80% compared to hHCN4 alone or with WT, and also slowed HCN4 activation at physiologically relevant voltages. Neither WT nor M54T altered HCN4 voltage dependence. A computer simulation predicts that these changes in HCN4 current would decrease rate and be additive with published effects of M54T mutation on hERG kinetics on rate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We conclude that M54T LQTS6 mutation can cause sinus bradycardia through effects on both hERG and HCN currents. Patients with other LQTS6 mutations should be examined for SN dysfunction, and the effect on HCN current determined.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jce.12163","type":"journal-article","created":{"date-parts":[[2013,4,8]],"date-time":"2013-04-08T07:23:10Z","timestamp":1365405790000},"page":"1021-1027","source":"Crossref","is-referenced-by-count":33,"title":["An LQTS6 MiRP1 Mutation Suppresses Pacemaker Current and is Associated with Sinus Bradycardia"],"prefix":"10.1111","volume":"24","author":[{"given":"POOJA A.","family":"NAWATHE","sequence":"first","affiliation":[{"name":"Columbia University Medical Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YELENA","family":"KRYUKOVA","sequence":"additional","affiliation":[{"name":"Columbia University Medical Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"RONIT 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