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In cardiac muscle, CaM associates with ryanodine receptor 2 (RyR2) and regulates excitation\u2013contraction coupling. Mutations in human genes <jats:italic>CALM1<\/jats:italic>, <jats:italic>CALM2<\/jats:italic>, and <jats:italic>CALM3<\/jats:italic> have been associated with life\u2010threatening heart disorders, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia. A novel <jats:italic>de novo<\/jats:italic> LQTS\u2010associated missense CaM mutation (E105A) was recently identified in a 6\u2010year\u2010old boy, who experienced an aborted first episode of cardiac arrest. Herein, we report the first molecular characterization of the CaM E105A mutation. Expression of the CaM E105A mutant in zebrafish embryos resulted in cardiac arrhythmia and increased heart rate, suggestive of ventricular tachycardia. <jats:italic>In vitro<\/jats:italic> biophysical and biochemical analysis revealed that E105A confers a deleterious effect on protein stability and a reduced Ca<jats:sup>2+<\/jats:sup>\u2010binding affinity due to loss of cooperativity. Finally, the CaM E105A mutation resulted in reduced CaM\u2013RyR2 interaction and defective modulation of ryanodine binding. Our findings suggest that the CaM E105A mutation dysregulates normal cardiac function by a complex mechanism involving alterations in both CaM\u2013Ca<jats:sup>2+<\/jats:sup> and CaM\u2013RyR2 interactions.<\/jats:p>","DOI":"10.1111\/nyas.14033","type":"journal-article","created":{"date-parts":[[2019,4,2]],"date-time":"2019-04-02T07:24:19Z","timestamp":1554189859000},"page":"19-29","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Arrhythmogenic calmodulin E105A mutation alters cardiac RyR2 regulation leading to cardiac dysfunction in zebrafish"],"prefix":"10.1111","volume":"1448","author":[{"given":"Sahar I.","family":"Da'as","sequence":"first","affiliation":[{"name":"Translational Medicine Sidra Medicine  Doha Qatar"},{"name":"College of Health and Life Sciences Hamad Bin Khalifa University  Doha Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelos","family":"Thanassoulas","sequence":"additional","affiliation":[{"name":"National Center for Scientific Research \u201cDemokritos,\u201d  Aghia Paraskevi Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian L.","family":"Calver","sequence":"additional","affiliation":[{"name":"College of Biomedical and Life Sciences Cardiff University  Cardiff UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konrad","family":"Beck","sequence":"additional","affiliation":[{"name":"College of Biomedical and Life Sciences Cardiff University  Cardiff UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rola","family":"Salem","sequence":"additional","affiliation":[{"name":"College of Medicine, Member of QU Health Qatar University  Doha Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaaeldin","family":"Saleh","sequence":"additional","affiliation":[{"name":"College of Medicine, Member of QU Health Qatar University  Doha Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Kontogianni","sequence":"additional","affiliation":[{"name":"National Center for Scientific Research \u201cDemokritos,\u201d  Aghia Paraskevi Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Al\u2010Maraghi","sequence":"additional","affiliation":[{"name":"College of Medicine, Member of QU Health Qatar University  Doha Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gheyath K.","family":"Nasrallah","sequence":"additional","affiliation":[{"name":"Biomedical Research Center Qatar University  Doha Qatar"},{"name":"Department of Biomedical Sciences, College of Health Science Qatar University  Doha Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bared","family":"Safieh\u2010Garabedian","sequence":"additional","affiliation":[{"name":"College of Medicine, Member of QU Health Qatar University  Doha Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egon","family":"Toft","sequence":"additional","affiliation":[{"name":"College of Medicine, Member of QU Health Qatar University  Doha Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Nounesis","sequence":"additional","affiliation":[{"name":"National Center for Scientific Research \u201cDemokritos,\u201d  Aghia Paraskevi Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F. 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