{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:19:20Z","timestamp":1781669960201,"version":"3.54.5"},"reference-count":56,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,6,30]],"date-time":"2024-06-30T00:00:00Z","timestamp":1719705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007458","name":"Qatar Foundation","doi-asserted-by":"publisher","award":["HSREP02\u20101125\u2010190004"],"award-info":[{"award-number":["HSREP02\u20101125\u2010190004"]}],"id":[{"id":"10.13039\/100007458","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007458","name":"Qatar Foundation","doi-asserted-by":"publisher","award":["UREP26\u2010097\u20103\u2010040"],"award-info":[{"award-number":["UREP26\u2010097\u20103\u2010040"]}],"id":[{"id":"10.13039\/100007458","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004252","name":"Qatar University","doi-asserted-by":"publisher","award":["QUCG\u2010CMED\u201019\/20\u20102"],"award-info":[{"award-number":["QUCG\u2010CMED\u201019\/20\u20102"]}],"id":[{"id":"10.13039\/501100004252","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004252","name":"Qatar University","doi-asserted-by":"publisher","award":["QUCG\u2010CMED\u201022\/23\u2010514"],"award-info":[{"award-number":["QUCG\u2010CMED\u201022\/23\u2010514"]}],"id":[{"id":"10.13039\/501100004252","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Calmodulin (CaM) is a ubiquitous, small cytosolic calcium (Ca<jats:sup>2+<\/jats:sup>)\u2010binding sensor that plays a vital role in many cellular processes by binding and regulating the activity of over 300 protein targets. In cardiac muscle, CaM modulates directly or indirectly the activity of several proteins that play a key role in excitation\u2010contraction coupling (ECC), such as ryanodine receptor type 2 (RyR2),\u00a0<jats:sc>l<\/jats:sc>\u2010type Ca<jats:sup>2+<\/jats:sup> (Ca<jats:sub>v<\/jats:sub>1.2), sodium (NaV1.5) and potassium (KV7.1) channels. Many recent clinical and genetic studies have reported a series of CaM mutations in patients with life\u2010threatening arrhythmogenic syndromes, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently showed that four arrhythmogenic CaM mutations (N98I, D132E, D134H, and Q136P) significantly reduce the binding of CaM to RyR2. Herein, we investigate in vivo functional effects of these CaM mutations on the normal zebrafish embryonic heart function by microinjecting complementary RNA corresponding to CaM<jats:sup>N98I<\/jats:sup>, CaM<jats:sup>D132E<\/jats:sup>, CaM<jats:sup>D134H<\/jats:sup>, and CaM<jats:sup>Q136P<\/jats:sup> mutants. Expression of CaM<jats:sup>D132E<\/jats:sup> and CaM<jats:sup>D134H<\/jats:sup> mutants results in significant reduction of the zebrafish heart rate, mimicking a severe form of human bradycardia, whereas expression of CaM<jats:sup>Q136P<\/jats:sup> results in an increased heart rate mimicking human ventricular tachycardia. Moreover, analysis of cardiac ventricular rhythm revealed that the CaM<jats:sup>D132E<\/jats:sup> and CaM<jats:sup>N98I<\/jats:sup> zebrafish groups display an irregular pattern of heart beating and increased amplitude in comparison to the control groups. Furthermore, circular dichroism spectroscopy experiments using recombinant CaM proteins reveals a decreased structural stability of the four mutants compared to the wild\u2010type CaM protein in the presence of Ca<jats:sup>2+<\/jats:sup>. Finally, Ca<jats:sup>2+<\/jats:sup>\u2010binding studies indicates that all CaM mutations display reduced CaM Ca<jats:sup>2+<\/jats:sup>\u2010binding affinities, with CaM<jats:sup>D132E<\/jats:sup> exhibiting the most prominent change. Our data suggest that CaM mutations can trigger different arrhythmogenic phenotypes through multiple and complex molecular mechanisms.<\/jats:p>","DOI":"10.1002\/jcb.30619","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T06:54:47Z","timestamp":1719816887000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Divergent Biochemical Properties and Disparate Impact of Arrhythmogenic Calmodulin Mutations on Zebrafish Cardiac Function"],"prefix":"10.1002","volume":"125","author":[{"given":"Sahar I.","family":"Da'as","sequence":"first","affiliation":[{"name":"Department of Human Genetics Sidra Medicine Doha Qatar"},{"name":"College of Health and Life Sciences Hamad Bin Khalifa University Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelos","family":"Thanassoulas","sequence":"additional","affiliation":[{"name":"College of Medicine QU Health, Qatar University Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Calver","sequence":"additional","affiliation":[{"name":"Sir Geraint Evans Wales Heart Research Institute, College of Biomedical and Life Science Cardiff University Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaaeldin","family":"Saleh","sequence":"additional","affiliation":[{"name":"College of Medicine QU Health, Qatar University Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doua","family":"Abdelrahman","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Sidra Medicine Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waseem","family":"Hasan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Sidra Medicine Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bared","family":"Safieh\u2010Garabedian","sequence":"additional","affiliation":[{"name":"College of Medicine QU Health, Qatar University Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Kontogianni","sequence":"additional","affiliation":[{"name":"National Centre for Scientific Research \u201cDemokritos\u201d Agia Paraskevi Greece"},{"name":"National Technical University of Athens Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gheyath K.","family":"Nasrallah","sequence":"additional","affiliation":[{"name":"Biomedical Research Center Qatar University Doha Qatar"},{"name":"Department of Biological Sciences, College of Health Sciences QU Health, Qatar University Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Nounesis","sequence":"additional","affiliation":[{"name":"National Centre for Scientific Research \u201cDemokritos\u201d Agia Paraskevi Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. Anthony","family":"Lai","sequence":"additional","affiliation":[{"name":"College of Medicine QU Health, Qatar University Doha Qatar"},{"name":"Sir Geraint Evans Wales Heart Research Institute, College of Biomedical and Life Science Cardiff University Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9761-6327","authenticated-orcid":false,"given":"Michail","family":"Nomikos","sequence":"additional","affiliation":[{"name":"College of Medicine QU Health, Qatar University Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/19336950.2023.2165278"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.05.025"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20180755"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2017.12.004"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2012.03.019"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)92938-8"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1993.1211"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)37497-0"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.001216"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.122.011387"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.113.000459"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.07.091"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.08.015"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrcr.2016.09.004"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.116.004161"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.303391"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.04.022"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2014.07.007"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.4103\/tcmj.tcmj_182_20"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2015.07.001"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010771200"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29515"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302857"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.14033"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2023.130313"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20180545"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi401502x"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00624a033"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(72)26005-0"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.9.8.1519"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002114"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(83)80234-4"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00033a044"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00004a011"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20180685"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23168840"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29441"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micron.2020.102876"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.79.2.358"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP284994"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04165-w"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP279307"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.1100992"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.11601"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(02)75286-7"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrcr.2016.02.002"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz311"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2014.10.035"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00396"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20020400"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.758680"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.115.001323"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13184"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00019.2020"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242115630"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14969"}],"container-title":["Journal of Cellular Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcb.30619","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T11:49:28Z","timestamp":1723463368000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcb.30619"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,30]]},"references-count":56,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1002\/jcb.30619"],"URL":"https:\/\/doi.org\/10.1002\/jcb.30619","archive":["Portico"],"relation":{},"ISSN":["0730-2312","1097-4644"],"issn-type":[{"value":"0730-2312","type":"print"},{"value":"1097-4644","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,30]]},"assertion":[{"value":"2023-12-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e30619"}}