{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:27:35Z","timestamp":1790515655171,"version":"4.1.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2016,5,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Transient receptor potential melastatin member 4 (\n              <jats:styled-content style=\"fixed-case\">TRPM<\/jats:styled-content>\n              4) is a nonselective cation channel.\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">TRPM<\/jats:styled-content>\n                4\n              <\/jats:italic>\n              mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying\n              <jats:styled-content style=\"fixed-case\">TRPM<\/jats:styled-content>\n              4\u2010dependent conduction slowing are not fully understood. The aim of this study was to characterize\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">TRPM<\/jats:styled-content>\n                4\n              <\/jats:italic>\n              genetic variants found in patients with congenital or childhood atrioventricular block.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Ninety\u2010one patients with congenital or childhood atrioventricular block were screened for candidate genes. Five rare\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">TRPM<\/jats:styled-content>\n                4\n              <\/jats:italic>\n              genetic variants were identified and investigated. The variants were expressed heterologously in\n              <jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>\n              293 cells. Two of the variants, A432T and A432T\/G582S, showed decreased expression of the protein at the cell membrane; inversely, the G582S variant showed increased expression. Further functional characterization of these variants using whole\u2010cell patch\u2010clamp configuration showed a loss of function and a gain of function, respectively. We hypothesized that the observed decrease in expression was caused by a folding and trafficking defect. This was supported by the observation that incubation of these variants at lower temperature partially rescued their expression and function. Previous studies have suggested that altered\n              <jats:styled-content style=\"fixed-case\">SUMO<\/jats:styled-content>\n              ylation of\n              <jats:styled-content style=\"fixed-case\">TRPM<\/jats:styled-content>\n              4 may cause a gain of function; however, we did not find any evidence that supports\n              <jats:styled-content style=\"fixed-case\">SUMO<\/jats:styled-content>\n              ylation as being directly involved for the gain\u2010of\u2010function variant.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              This study underpins the role of\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">TRPM<\/jats:styled-content>\n                4\n              <\/jats:italic>\n              in the cardiac conduction system. The loss\u2010of\u2010function variants A432T\/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding\u2010dependent altered trafficking. The ability to rescue this variant with lower temperature may provide a novel use of pharmacological chaperones in treatment strategies.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.114.001625","type":"journal-article","created":{"date-parts":[[2016,5,23]],"date-time":"2016-05-23T16:25:46Z","timestamp":1464020746000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block"],"prefix":"10.1161","volume":"5","author":[{"given":"Ninda","family":"Syam","sequence":"first","affiliation":[{"name":"Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Chatel","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et 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