{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T07:10:24Z","timestamp":1764141024181,"version":"3.46.0"},"reference-count":33,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Congenital long QT syndrome (LQTS) is an inherited arrhythmia characterized by QT prolongation and increased risk of ventricular arrhythmias. Type 2 LQTS (LQT2) results from mutations in the\n                      <jats:italic>KCNH2<\/jats:italic>\n                      gene encoding the hERG potassium channel. With the widespread use of next\u2010generation sequencing, many\n                      <jats:italic>KCNH2<\/jats:italic>\n                      variants have been identified but remain classified as variants of uncertain significance (VUS), including p.L693P, requiring functional validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A proband with recurrent syncope and prolonged QTc underwent whole\u2010exome and family\u2010based Sanger sequencing, which detected a heterozygous\n                      <jats:italic>KCNH2<\/jats:italic>\n                      \u2010L693P mutation. HEK293 cells were transiently transfected with wild\u2010type (WT) and\/or mutant hERG plasmids. Western blotting, immunofluorescence, and whole\u2010cell patch clamp were performed to assess protein maturation, trafficking, and channel kinetics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Western blot showed reduced levels of the 155\u2009kDa mature hERG and accumulation of the 135\u2009kDa immature form, consistent with trafficking defects. Immunofluorescence confirmed endoplasmic reticulum (ER) retention. Electrophysiology revealed complete current loss in homozygotes and ~39% residual WT current in heterozygotes, indicating dominant\u2010negative\u2010like suppression. The mutation shifted steady\u2010state inactivation and delayed recovery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>KCNH2<\/jats:italic>\n                      \u2010L693P mutation impairs hERG maturation and function, supporting its reclassification from variants of uncertain significance (VUS) to pathogenic and providing evidence for improved clinical management.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.70155","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T11:22:41Z","timestamp":1763378561000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>KCNH2<\/i>\n                    \u2010\n                    <scp>L693P<\/scp>\n                    Causes Long\n                    <scp>QT<\/scp>\n                    Syndrome Type 2 Through\n                    <scp>hERG<\/scp>\n                    Channel Dysfunction: Functional Validation of a Variant of Uncertain Significance"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9167-4514","authenticated-orcid":false,"given":"Xi\u2010Fan","family":"Zheng","sequence":"first","affiliation":[{"name":"Kunming Medical University  Kunming People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Yan'an Hospital Affiliated to Kunming Medical University  Kunming People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang\u2010Ting","family":"Lu","sequence":"additional","affiliation":[{"name":"Kunming Medical University  Kunming People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4744-818X","authenticated-orcid":false,"given":"Hai\u2010Long","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Yan'an Hospital Affiliated to Kunming Medical University  Kunming People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue\u2010Feng","family":"Guang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Yan'an Hospital Affiliated to Kunming Medical University  Kunming People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2016.08.008"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2015.07.002"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.04.003"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci35337"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.105.570200"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6535"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.15.10113"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2000.1263"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201042331\u20106"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.107.708818"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2014.1827"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.109.863076"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.05.021"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.743138"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.86.5.507"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2012.09.053"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2019.4049"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/350232a0"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018273"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.83.4.415"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10081144"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0287206"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2012.23"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.5.2208"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.88.2.782"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.1.89"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joa.2015.11.009"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.102.10.1178"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00304.2013"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029885"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl\u20102020\u2010318259"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac262"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.33.21061"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.70155","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T07:06:13Z","timestamp":1764140773000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.70155"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":33,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1002\/mgg3.70155"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.70155","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"type":"print","value":"2324-9269"},{"type":"electronic","value":"2324-9269"}],"subject":[],"published":{"date-parts":[[2025,11]]},"assertion":[{"value":"2025-04-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70155"}}