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Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS). LQTS patients display prolonged ventricular recovery times (QT interval), increasing their risk of incurring life\u2010threatening arrhythmic events. Loss\u2010of\u2010function mutations to Kv7.1 (which drives the slow delayed rectifier potassium current, IKs, a key ventricular repolarising current) are the largest contributor to congenital LQTS (&gt;50% of cases). CaM modulates Kv7.1 to produce a Ca<jats:sup>2+<\/jats:sup>\u2010sensitive IKs, but little is known about the consequences of LQTS\u2010associated CaM mutations on Kv7.1 function. Here, we present novel data characterising the biophysical and modulatory properties of three LQTS\u2010associated CaM variants (D95V, N97I and D131H). We showed that mutations induced structural alterations in CaM and reduced affinity for Kv7.1, when compared with wild\u2010type (WT). Using HEK293T cells expressing Kv7.1 channel subunits (KCNQ1\/KCNE1) and patch\u2010clamp electrophysiology, we demonstrated that LQTS\u2010associated CaM variants reduced current density at systolic Ca<jats:sup>2+<\/jats:sup> concentrations (1\u00a0\u03bc<jats:sc>m<\/jats:sc>), revealing a direct QT\u2010prolonging modulatory effect. Our data highlight for the first time that LQTS\u2010associated perturbations to CaM's structure impede complex formation with Kv7.1 and subsequently result in reduced IKs. This provides a novel mechanistic insight into how the perturbed structure\u2013function relationship of CaM variants contributes to the LQTS phenotype.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15642-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Calmodulin (CaM) is a ubiquitous, highly conserved calcium (Ca<jats:sup>2+<\/jats:sup>) sensor playing a key role in cardiac muscle contraction.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS), a life\u2010threatening cardiac arrhythmia syndrome.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>LQTS\u2010associated CaM variants (D95V, N97I and D131H) induced structural alterations, altered binding to Kv7.1 and reduced IKs.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our data provide a novel mechanistic insight into how the perturbed structure\u2013function relationship of CaM variants contributes to the LQTS phenotype.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp284994","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T17:24:47Z","timestamp":1689009887000},"page":"3739-3764","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Long QT syndrome\u2010associated calmodulin variants disrupt the activity of the slowly activating delayed rectifier potassium 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