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An association between <jats:italic>SCN5A<\/jats:italic> and Wnt\/\u03b2-catenin signaling has been recently established. However, the role of Wnt\/\u03b2-catenin signaling in BrS and underlying mechanisms remains unknown.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Three healthy control subjects and one BrS patient carrying a novel frameshift mutation (T1788fs) in the <jats:italic>SCN5A<\/jats:italic> gene were recruited in this study. Control and BrS patient-specific induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts using nonintegrated Sendai virus. All iPSCs were differentiated into cardiomyocytes using monolayer-based differentiation protocol. Action potentials and sodium currents were recorded from control and BrS iPSC-derived cardiomyocytes (iPSC-CMs) by single-cell patch clamp.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>BrS iPSC-CMs exhibited increased burden of arrhythmias and abnormal action potential profile featured by slower depolarization, decreased action potential amplitude, and increased beating interval variation. Moreover, BrS iPSC-CMs showed cardiac sodium channel (Na<jats:sub>v<\/jats:sub>1.5) loss-of-function as compared to control iPSC-CMs. Interestingly, the electrophysiological abnormalities and Na<jats:sub>v<\/jats:sub>1.5 loss-of-function observed in BrS iPSC-CMs were accompanied by aberrant activation of Wnt\/\u03b2-catenin signaling. Notably, inhibition of Wnt\/\u03b2-catenin significantly rescued Na<jats:sub>v<\/jats:sub>1.5 defects and arrhythmic phenotype in BrS iPSC-CMs. Mechanistically, <jats:italic>SCN5A<\/jats:italic>-encoded Na<jats:sub>v<\/jats:sub>1.5 interacts with \u03b2-catenin, and reduced expression of Na<jats:sub>v<\/jats:sub>1.5 leads to re-localization of \u03b2-catenin in BrS iPSC-CMs, which aberrantly activates Wnt\/\u03b2-catenin signaling to suppress <jats:italic>SCN5A<\/jats:italic> transcription.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our findings suggest that aberrant activation of Wnt\/\u03b2-catenin signaling contributes to the pathogenesis of <jats:italic>SCN5A<\/jats:italic>-related BrS and point to Wnt\/\u03b2-catenin as a potential therapeutic target.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13287-023-03477-3","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T01:01:59Z","timestamp":1694134919000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Patient-specific iPSC-derived cardiomyocytes reveal aberrant activation of Wnt\/\u03b2-catenin signaling in SCN5A-related Brugada syndrome"],"prefix":"10.1186","volume":"14","author":[{"given":"Dongsheng","family":"Cai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hangping","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongkuai","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hangyuan","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyu","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6806-3735","authenticated-orcid":false,"given":"Ping","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"3477_CR1","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/0735-1097(92)90253-J","volume":"20","author":"P Brugada","year":"1992","unstructured":"Brugada P, Brugada J. 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Written informed consents were obtained from all participants. This study was approved by the Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (Title of the ethical approved project: Cardiac channelopathies; Approval number: No. 2019-497; Approval date: 2019.02.26).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent form for publication was signed by the patient in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"241"}}