{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:22:20Z","timestamp":1790230940345,"version":"4.1.0"},"reference-count":33,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2004,6]]},"abstract":"<jats:p>\n                    Long QT syndrome (LQTS) is a cardiac repolarization disorder that can lead to arrhythmias and sudden death. Chromosome 7-linked inherited LQTS (LQT2) is caused by mutations in human ether-a-go-go-related gene ( HERG; KCNH2), whereas drug-induced LQTS is caused primarily by HERG channel block. Many common polymorphisms are functionally silent and have been traditionally regarded as benign and without physiological consequence. However, the identification of common nonsynonymous single nucleotide polymorphisms (nSNPs; i.e., amino-acid coding variants) with functional phenotypes in the SCN5A Na\n                    <jats:sup>+<\/jats:sup>\n                    channel and MiRP1 K\n                    <jats:sup>+<\/jats:sup>\n                    channel \u03b2-subunit have challenged this viewpoint. In this report, we test the hypothesis that common missense HERG polymorphisms alter channel physiology. Comprehensive mutational analysis of HERG was performed on genomic DNA derived from a population-based cohort of sudden infant death syndrome and two reference allele cohorts derived from 100 African American and 100 Caucasian individuals. Amino acid-encoding variants were considered common polymorphisms if they were present in at least two of the three study cohorts with an allelic frequency &gt;0.5%. Four nSNPs were identified: K897T, P967L, R1047L, and Q1068R. Wild-type (WT) and polymorphic channels were heterologously expressed in human embryonic kidney cells, and biochemical and voltage-clamp techniques were used to characterize their functional properties. All channel types were processed similarly, but several electrophysiological differences were identified: 1) K897T current density was lower than the other polymorphic channels; 2) K897T channels activated at more negative potentials than WT and R1047L; 3) K897T and Q1068R channels inactivated and recovered from inactivation faster than WT, P967L, and R1047L channels; and 4) K897T channels showed subtle differences compared with WT channels when stimulated with an action potential waveform. In contrast to K897T and Q1068R channels, P967L and R1047L channels were electrophysiologically indistinguishable from WT channels. All HERG channels had similar sensitivity to block by cisapride. Therefore, some HERG polymorphic channels are electrophysiologically different from WT channels.\n                  <\/jats:p>","DOI":"10.1152\/ajpheart.00891.2003","type":"journal-article","created":{"date-parts":[[2004,2,23]],"date-time":"2004-02-23T20:50:34Z","timestamp":1077569434000},"page":"H2434-H2441","source":"Crossref","is-referenced-by-count":104,"title":["Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels"],"prefix":"10.1152","volume":"286","author":[{"given":"Blake D.","family":"Anson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Tester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa L.","family":"Will","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian P.","family":"Delisle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey L.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig T.","family":"January","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.18.2264"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.11.1464"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(03)00342-0"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110204200"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90358-5"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.279.4.H1748"},{"key":"R7","unstructured":"Food and Drug Administration.\n                      Janssen Pharmaceutica Stops Marketing Cisapride in the US\n                      .\n                      Rockville, MD: FDA Talk Paper, 2000."},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1007\/s100380050207"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.42.27231"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1004(200006)15:6<580::AID-HUMU16>3.0.CO;2-0"},{"key":"R11","unstructured":"Larsen LA\n                      , Andersen PS, Kanters J, Svendsen IH, Jacobsen JR, Vuust J, Wettrell G, Tranebjarg L, Bathen J, and Christiansen M.\n                      Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG\/MiRP1 ion channel: implications for acquired and congenital long Q-T syndrome.\n                      Clin Chem\n                      47\n                      : 1390\u20131395, 2001."},{"key":"R12","unstructured":"Lees-Miller JP\n                      , Duan Y, Teng GQ, and Duff HJ.\n                      Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in\n                      Xenopus\n                      oocytes: involvement of S6 sites.\n                      Mol Pharmacol\n                      57\n                      : 367\u2013374, 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