{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:30:52Z","timestamp":1790836252893,"version":"4.1.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R324-2019-1933"],"award-info":[{"award-number":["R324-2019-1933"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008367","name":"Statens Naturvidenskabelige Forskningsrad","doi-asserted-by":"publisher","award":["2032-00333B"],"award-info":[{"award-number":["2032-00333B"]}],"id":[{"id":"10.13039\/100008367","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Missense variants in <jats:italic>CALM<\/jats:italic> genes encoding the Ca<jats:sup>2+<\/jats:sup>-binding protein calmodulin (CaM) cause severe cardiac arrhythmias. The disease mechanisms have been attributed to dysregulation of RyR2, for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and\/or Ca<jats:sub>V<\/jats:sub>1.2, for Long-QT Syndrome (LQTS). Recently, a novel <jats:italic>CALM2<\/jats:italic> variant, G114R, was identified in a mother and two of her four children, all of whom died suddenly while asleep at a young age. The G114R variant impairs closure of Ca<jats:sub>V<\/jats:sub>1.2 and RyR2, consistent with a CPVT and\/or mild LQTS phenotype. However, the children carrying the <jats:italic>CALM2<\/jats:italic> G114R variant displayed a phenotype commonly observed with variants in Na<jats:sub>V<\/jats:sub>1.5<jats:italic>,<\/jats:italic> i.e., Brugada Syndrome (BrS) or LQT3, where death while asleep is a common feature. We therefore hypothesized that the G114R variant specifically would interfere with Na<jats:sub>V<\/jats:sub>1.5 binding. Here, we demonstrate that CaM binding to the Na<jats:sub>V<\/jats:sub>1.5 IQ-domain is severely impaired for two CaM variants G114R and G114W. The impact was most severe at low and intermediate Ca<jats:sup>2+<\/jats:sup> concentrations (up to 4\u00a0\u00b5M) resulting in more than a 50-fold reduction in Na<jats:sub>V<\/jats:sub>1.5 binding affinity, and a smaller 1.5 to 11-fold reduction at high Ca<jats:sup>2+<\/jats:sup> concentrations (25\u2013400\u00a0\u00b5M). In contrast, the arrhythmogenic CaM-N98S variant only induced a 1.5-fold reduction in Na<jats:sub>V<\/jats:sub>1.5 binding and only at 4\u00a0\u00b5M Ca<jats:sup>2+<\/jats:sup>. A non-arrhythmogenic I10T variant in CaM did not impair Na<jats:sub>V<\/jats:sub>1.5 IQ binding. These data suggest that the interaction between Na<jats:sub>V<\/jats:sub>1.5 and CaM is decreased with certain CaM variants, which may alter the cardiac sodium current, I<jats:sub>Na<\/jats:sub>. Overall, these results suggest that the phenotypic spectrum of calmodulinopathies may likely expand to include BrS- and\/or LQT3-like traits.<\/jats:p>","DOI":"10.3389\/fphar.2023.1210140","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T13:36:54Z","timestamp":1692279414000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Calmodulin mutations affecting Gly114 impair binding to the NaV1.5 IQ-domain"],"prefix":"10.3389","volume":"14","author":[{"given":"Malene","family":"Brohus","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana-Octavia","family":"Busuioc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Wimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Nyegaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Toft","family":"Overgaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1016\/j.hrthm.2013.07.030","article-title":"Fever-induced Brugada pattern: how common is it and what does it mean?","volume":"10","author":"Adler","year":"2013","journal-title":"Heart rhythm."},{"key":"B2","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.bbamcr.2013.10.021","article-title":"The many faces of calmodulin in cell proliferation, programmed cell death, autophagy, and cancer","volume":"1843","author":"Berchtold","year":"2014","journal-title":"Biochimica Biophysica Acta"},{"key":"B3","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1006\/geno.1993.1211","article-title":"Localization of the human bona fide calmodulin genes CALM1, CALM2, and CALM3 to chromosomes 14q24-q31, 2p21.1-p21.3, and 19q13.2-q13.3, 4611-P21.3, and 19q13.2-Q13.3","volume":"16","author":"Berchtold","year":"1993","journal-title":"Genomics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1161\/CIRCGENETICS.115.001323","article-title":"Spectrum and prevalence of CALM1-CALM2-and CALM3-encoded calmodulin variants in long QT syndrome and functional characterization of a novel long QT syndrome-associated calmodulin missense variant, E141G","volume":"9","author":"Boczek","year":"2016","journal-title":"Circ. 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