{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:34:08Z","timestamp":1791408848318,"version":"4.3.3"},"reference-count":63,"publisher":"Cambridge University Press (CUP)","license":[{"start":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T00:00:00Z","timestamp":1683072000000},"content-version":"unspecified","delay-in-days":122,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007225","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["G2022040006L, DL2022040004L"],"award-info":[{"award-number":["G2022040006L, DL2022040004L"]}],"id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["Expert Rev. Mol. Med."],"published-print":{"date-parts":[[2023]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand\/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative gene<jats:italic>CACNA1C<\/jats:italic>encoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function of<jats:italic>CACNA1C<\/jats:italic>gene encoding Ca<jats:sub>v<\/jats:sub>1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation\u2013transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.<\/jats:p>","DOI":"10.1017\/erm.2023.11","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T07:19:28Z","timestamp":1683098368000},"update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":15,"title":["Current updates on arrhythmia within Timothy syndrome: genetics, mechanisms and therapeutics"],"prefix":"10.1017","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7457-6243","authenticated-orcid":false,"given":"Congshan","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7580-4693","authenticated-orcid":false,"given":"Yanmin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"56","published-online":{"date-parts":[[2023,5,3]]},"reference":[{"key":"S146239942300011X_ref17","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-020-02199-3"},{"key":"S146239942300011X_ref40","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.2010.02913.x"},{"key":"S146239942300011X_ref50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacep.2017.08.007"},{"key":"S146239942300011X_ref25","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2011.05.015"},{"key":"S146239942300011X_ref62","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.314695"},{"key":"S146239942300011X_ref7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.09.011"},{"key":"S146239942300011X_ref53","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.recesp.2021.10.023","article-title":"Use of ranolazine as rescue therapy in a patient with Timothy syndrome type 2","volume":"75","author":"Hermida","year":"2022","journal-title":"Revista Espanola de Cardiologia (English ed.)"},{"key":"S146239942300011X_ref14","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01232-8"},{"key":"S146239942300011X_ref49","doi-asserted-by":"publisher","DOI":"10.1177\/1535370219863149"},{"key":"S146239942300011X_ref12","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.recesp.2019.01.017","article-title":"Cardiac-only Timothy syndrome (COTS): peripartum cardiomyopathy and long QT syndrome","volume":"72","author":"Larra\u00f1aga-Moreira","year":"2019","journal-title":"Revista Espanola de Cardiologia (English Ed.)"},{"key":"S146239942300011X_ref9","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37258"},{"key":"S146239942300011X_ref46","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34355"},{"key":"S146239942300011X_ref43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2012.04.029"},{"key":"S146239942300011X_ref61","article-title":"Characterization of the CACNA1C-R518C missense mutation in the pathobiology of long-QT syndrome using human induced pluripotent stem cell cardiomyocytes shows action potential prolongation and L-type calcium channel perturbation","volume":"12","author":"Estes","year":"2019","journal-title":"Circulation: Genomic and Precision Medicine"},{"key":"S146239942300011X_ref63","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.02.002"},{"key":"S146239942300011X_ref39","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2006.04.024"},{"key":"S146239942300011X_ref22","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.00335"},{"key":"S146239942300011X_ref35","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00741.2003"},{"key":"S146239942300011X_ref13","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38833"},{"key":"S146239942300011X_ref55","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e31826e73b1"},{"key":"S146239942300011X_ref6","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(94)00318-K"},{"key":"S146239942300011X_ref58","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-012-9444-x"},{"key":"S146239942300011X_ref45","doi-asserted-by":"publisher","DOI":"10.1007\/s00392-011-0358-4"},{"key":"S146239942300011X_ref2","first-page":"54","article-title":"The heart-hand syndrome. 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