{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:43:38Z","timestamp":1776339818057,"version":"3.51.2"},"reference-count":44,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,28]],"date-time":"2021-11-28T00:00:00Z","timestamp":1638057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital long QT syndrome (LQTS) is a cardiac channelopathy characterized by a prolongation of the QT interval and T-wave abnormalities, caused, in most cases, by mutations in KCNQ1, KCNH2, and SCN5A. Although the predominant pattern of LQTS inheritance is autosomal dominant, compound heterozygous mutations in genes encoding potassium channels have been reported, often with early disease onset and more severe phenotypes. Since the molecular mechanisms underlying severe phenotypes in carriers of compound heterozygous mutations are unknown, it is possible that these compound mutations lead to synergistic or additive alterations to channel structure and function. In this study, all-atom molecular dynamic simulations of KCNQ1 and hERG channels were carried out, including wild-type and channels with compound mutations found in two patients with severe LQTS phenotypes and limited family history of the disease. Because channels can likely incorporate different subunit combinations from different alleles, there are multiple possible configurations of ion channels in LQTS patients. This analysis allowed us to establish the structural impact of different configurations of mutant channels in the activated\/open state. Our data suggest that channels with these mutations show moderate changes in folding energy (in most cases of stabilizing character) and changes in channel mobility and volume, differentiating them from each other and from WT. This would indicate possible alterations in K+ ion flow. Hetero-tetrameric mutant channels showed intermediate structural and volume alterations vis-\u00e0-vis homo-tetrameric channels. These findings support the hypothesis that hetero-tetrameric channels in patients with compound heterozygous mutations do not necessarily lead to synergistic structural alterations.<\/jats:p>","DOI":"10.3390\/ijms222312861","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T23:22:28Z","timestamp":1638314548000},"page":"12861","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Structural Modelling of KCNQ1 and KCNH2 Double Mutant Proteins, Identified in Two Severe Long QT Syndrome Cases, Reveals New Insights into Cardiac Channelopathies"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4526-6705","authenticated-orcid":false,"given":"William A.","family":"Agudelo","sequence":"first","affiliation":[{"name":"Fundaci\u00f3n Instituto de Inmunolog\u00eda de Colombia (FIDIC), Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5974-1431","authenticated-orcid":false,"given":"Sebastian Ramiro","family":"Gil-Qui\u00f1ones","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular y Pruebas Diagn\u00f3sticas de Alta Complejidad, Fundaci\u00f3n Cardioinfantil-Instituto de Cardiolog\u00eda, Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandra","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular y Pruebas Diagn\u00f3sticas de Alta Complejidad, Fundaci\u00f3n Cardioinfantil-Instituto de Cardiolog\u00eda, Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvaro","family":"Arenas","sequence":"additional","affiliation":[{"name":"Department of Pediatric Electrophysiology, Congenital Heart Institute, Fundaci\u00f3n Cardioinfantil-Instituto de Cardiolog\u00eda, Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Pediatric Electrophysiology, Congenital Heart Institute, Fundaci\u00f3n Cardioinfantil-Instituto de Cardiolog\u00eda, Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana Carolina","family":"Sierra-D\u00edaz","sequence":"additional","affiliation":[{"name":"Center for Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4751-2500","authenticated-orcid":false,"given":"Manuel A.","family":"Patarroyo","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Instituto de Inmunolog\u00eda de Colombia (FIDIC), Bogot\u00e1 111221, Colombia"},{"name":"Health Sciences Division, Main Campus, Universidad Santo Tom\u00e1s, Bogot\u00e1 111221, Colombia"},{"name":"Microbiology Department, Faculty of Medicine, Universidad Nacional de Colombia, Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Laissue","sequence":"additional","affiliation":[{"name":"Center for Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogot\u00e1 111221, Colombia"},{"name":"Orphan Diseases Unit, Biopas Laboratories, BIOPAS Group, Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8423-408X","authenticated-orcid":false,"given":"Carlos F.","family":"Su\u00e1rez","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Instituto de Inmunolog\u00eda de Colombia (FIDIC), Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5731-1788","authenticated-orcid":false,"given":"Rodrigo","family":"Cabrera","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular y Pruebas Diagn\u00f3sticas de Alta Complejidad, Fundaci\u00f3n Cardioinfantil-Instituto de Cardiolog\u00eda, Bogot\u00e1 111221, Colombia"},{"name":"Center for Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogot\u00e1 111221, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3109","DOI":"10.1093\/eurheartj\/eht089","article-title":"The long QT syndrome: A transatlantic clinical approach to diagnosis and therapy","volume":"34","author":"Schwartz","year":"2013","journal-title":"Eur. 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