{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:30:39Z","timestamp":1790836239699,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T00:00:00Z","timestamp":1594080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pacing Clinical Electrophis"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Telethonin (<jats:italic>TCAP<\/jats:italic>) is a Z\u2010disk protein that maintains cytoskeletal integrity and various signaling pathways in cardiomyocytes. <jats:italic>TCAP<\/jats:italic> is shown to modulate \u03b1\u2010subunit of the human cardiac sodium channel (hNa<jats:sub>v<\/jats:sub>1.5) by direct interactions. Several <jats:italic>TCAP<\/jats:italic> variants are found in cardiomyopathies. We sought to investigate whether TCAP variants are associated with arrhythmia syndromes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mutational analyses for <jats:italic>TCAP<\/jats:italic> were performed in 303 Japanese patients with Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, and J\u2010wave pattern ECG. Using patch\u2010clamp techniques, electrophysiological characteristics of hNa<jats:sub>v<\/jats:sub>1.5 were studied in HEK\u2010293 cells stably expressing hNa<jats:sub>v<\/jats:sub>1.5 and transiently transfected with wild\u2010type (WT) or variant <jats:italic>TCAP<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified two <jats:italic>TCAP<\/jats:italic> variants, c.145G&gt;A:p.E49K and c.458G&gt;A:p.R153H, in four individuals. p.E49K was found in two patients with ARVC or BrS. p.R153H was found in two patients with BrS or J\u2010wave pattern ECG. No patient had variant hNa<jats:sub>v<\/jats:sub>1.5. Patch\u2010clamp experiments demonstrated that peak sodium currents were significantly reduced in cells expressing p.R153H and p.E49K compared with WT\u2010<jats:italic>TCAP<\/jats:italic> (66%, p.R153H; 72%, p.E49K). Voltage dependency of peak IV curve was rightward\u2010shifted by 5\u00a0mV in cells expressing p.E49K compared with WT\u2010<jats:italic>TCAP<\/jats:italic>. Voltage dependency of activation was not leftward\u2010shifted by p.R153H, while voltage dependency of steady\u2010state inactivation was leftward\u2010shifted by p.E49K.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We found two <jats:italic>TCAP<\/jats:italic> variants in the patients with BrS, J\u2010wave pattern ECG, and ARVC that can cause loss\u2010of\u2010function of the hNa<jats:sub>v<\/jats:sub>1.5 in heterologous expression systems. Our observation suggests that these variants might impair I<jats:sub>Na<\/jats:sub> and be associated with the patients\u2019 electrophysiological phenotypes. Further studies linking our experimental data to clinical phenotypes are warranted.<\/jats:p><\/jats:sec>","DOI":"10.1111\/pace.13996","type":"journal-article","created":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T03:35:10Z","timestamp":1593142510000},"page":"838-846","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<i>Telethonin<\/i> variants found in Brugada syndrome, J\u2010wave pattern ECG, and ARVC reduce peak Na<sub>v<\/sub>1.5 currents in HEK\u2010293 cells"],"prefix":"10.1111","volume":"43","author":[{"given":"Isik","family":"Turker","sequence":"first","affiliation":[{"name":"Department of Medicine Krannert Institute of Cardiology Indiana University School of Medicine  Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Makiyama","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine Kyoto University Graduate School of Medicine  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Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Vatta","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Horie","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Respiratory Medicine Shiga University of Medical Science  Shiga Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0376-0227","authenticated-orcid":false,"given":"Tomohiko","family":"Ai","sequence":"additional","affiliation":[{"name":"Department of Medicine Krannert Institute of Cardiology Indiana University School of Medicine  Indianapolis Indiana"},{"name":"Department of Clinical Laboratory Medicine Juntendo University School of Medicine  Tokyo 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