{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:24:34Z","timestamp":1791307474287,"version":"4.3.1"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2013,3,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either\n                      <jats:italic>CALM1<\/jats:italic>\n                      or\n                      <jats:italic>CALM2<\/jats:italic>\n                      , 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.112.001216","type":"journal-article","created":{"date-parts":[[2013,2,6]],"date-time":"2013-02-06T23:50:27Z","timestamp":1360194627000},"page":"1009-1017","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":387,"title":["Calmodulin Mutations Associated With Recurrent Cardiac Arrest in Infants"],"prefix":"10.1161","volume":"127","author":[{"given":"Lia","family":"Crotti","sequence":"first","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher N.","family":"Johnson","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Graf","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano M.","family":"De Ferrari","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina F.","family":"Cuneo","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ovadia","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Papagiannis","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Feldkamp","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subodh G.","family":"Rathi","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer D.","family":"Kunic","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Pedrazzini","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Wieland","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Lichtner","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britt-Maria","family":"Beckmann","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Clark","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Shaffer","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Woodrow","family":"Benson","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"K\u00e4\u00e4b","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Meitinger","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim M.","family":"Strom","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"Chazin","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy (L.C., G.M.D.F., M.P., P.J.S.); Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, Neuherberg, Germany (L.C., E.G., T.W., P.L., T.M., T.M.S.); Department of Biochemistry, Center for Structural Biology (C.N.J., M.D.F., S.G.R., W.J.C.), Division of Genetic Medicine, Department of Medicine (J.D.K..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Alfred L.","family":"George","sequence":"additional","affiliation":[{"name":"From the Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C., G.M.D.F., P.J.S.); Department of Cardiology, Fondazione IRCCS Policlinico S. 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