{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:49:25Z","timestamp":1786121365340,"version":"build-2736575974"},"reference-count":33,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation","doi-asserted-by":"crossref","award":["81800293"],"award-info":[{"award-number":["81800293"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Beijing Hospitals Authority Youth Programme","award":["QML2019305"],"award-info":[{"award-number":["QML2019305"]}]},{"award":["QML2019305"],"award-info":[{"award-number":["QML2019305"]}],"id":[{"id":"https:\/\/ror.org\/02jwb5s28","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["0525806Z"],"award-info":[{"award-number":["0525806Z"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["11SDG7470009"],"award-info":[{"award-number":["11SDG7470009"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"award":["0525806Z"],"award-info":[{"award-number":["0525806Z"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"publisher"}]},{"award":["11SDG7470009"],"award-info":[{"award-number":["11SDG7470009"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The cardiac sodium channel NaV1.5, encoded by SCN5A, generates the inward sodium current required for myocardial excitability and impulse conduction. Loss-of-function mutations of NaV1.5 have been implicated in inherited arrhythmia syndromes, including Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The common SCN5A polymorphism H558R has reported minor allele frequencies ranging from 9.2% to 29% across ethnic groups, whereas S524Y has been described in individuals of African ancestry with a minor allele frequency of approximately 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio. We engineered these two polymorphisms in both backgrounds and reported that when S524Y and H558R were expressed in the Q1077del variant, current densities were normal. In the Q1077 variant, however, the current densities showed a dramatic reduction compared to those in the Q1077del variant or WT-Q1077. We previously reported that incubation with the antiarrhythmic drug mexiletine \u201crescued\u201d expression deficiencies in the Brugada syndrome. Cells expressing S524Y\/Q1077 and H558R\/Q1077 were incubated for 48 h with or without mexiletine (500 \u03bcM), followed by drug washout before electrophysiological assessment. Mexiletine significantly increased current density for both S524Y\/Q1077 and H558R\/Q1077 compared with untreated cells, restoring current density to levels comparable to WT-Q1077. Flow cytometry using a FLAG-tagged channel demonstrated that mexiletine-mediated rescue was associated with increased cell-surface expression. The magnitude of the expression defects caused by H558R and S524Y in the Q1077 splice background is similar to that observed with arrhythmia-associated SCN5A mutations, and we show for the first time that the defects for both polymorphisms can be rescued with mexiletine. Although it is unknown whether they result in heightened arrhythmia susceptibility in patients homozygous for the minor allele, our result may have implications for therapy for mutations with loss-of-function phenotypes modified by these common polymorphisms.<\/jats:p>","DOI":"10.3390\/cells15151418","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:14:46Z","timestamp":1785917686000},"page":"1418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expression Defects of SCN5A Common Polymorphisms S524Y and H558R in the Q1077 Splice Variant Can Be Rescued by Mexiletine"],"prefix":"10.3390","volume":"15","author":[{"given":"Rou-Mu","family":"Hu","sequence":"first","affiliation":[{"name":"Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China"},{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2616-0814","authenticated-orcid":false,"given":"Evelyn J.","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, CA 94403, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1224-3088","authenticated-orcid":false,"given":"Carmen R.","family":"Valdivia","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Deschenes","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan C.","family":"Makielski","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi-Hua","family":"Tan","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI 53726, USA"},{"name":"Department of Physiology and Cell Biology, The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/376683a0","article-title":"Molecular mechanism for an inherited cardiac arrhythmia","volume":"376","author":"Bennett","year":"1995","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00424-009-0761-0","article-title":"Cardiac sodium channelopathies","volume":"460","author":"Amin","year":"2010","journal-title":"Pflug. Arch."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s00424-024-02930-3","article-title":"Biophysical mechanisms of myocardium sodium channelopathies","volume":"476","author":"Zaytseva","year":"2024","journal-title":"Pflug. 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