{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:53:51Z","timestamp":1787018031410,"version":"build-2736575974"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2022,3]]},"abstract":"\n Background:<\/jats:title>\n \n CaM (calmodulin), encoded by 3 separate genes (\n CALM1<\/jats:italic>\n ,\n CALM2<\/jats:italic>\n , and\n CALM3<\/jats:italic>\n ), is a multifunctional Ca\n 2+<\/jats:sup>\n -binding protein involved in many signal transduction events including ion channel regulation. CaM variants may present with early-onset long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia, or sudden cardiac death. Most reported variants occurred de novo. We identified a novel\n CALM3<\/jats:italic>\n variant, p.Asn138Lys (N138K), in a 4-generation family segregating with LQTS. The aim of this study was to elucidate its pathogenicity and to compare it with that of p.D130G-CaM\u2014a variant associated with a severe LQTS phenotype.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n We performed whole exome sequencing for a large, 4-generation family affected by LQTS. To assess the effect of the detected\n CALM3<\/jats:italic>\n variant, the intrinsic Ca\n 2+<\/jats:sup>\n -binding affinity was measured by stoichiometric Ca\n 2+<\/jats:sup>\n titrations and equilibrium titrations. L-type Ca\n 2+<\/jats:sup>\n and slow delayed rectifier potassium currents (I\n CaL<\/jats:sub>\n and I\n Ks<\/jats:sub>\n ) were recorded by whole-cell patch-clamp. Cav1.2 and Kv7.1 membrane expression were determined by optical fluorescence assays.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n We identified 14 p.N138K-CaM carriers in a family where 2 sudden deaths occurred in children. Several members were only mildly affected compared with CaM-LQTS patients to date described in literature. The intrinsic Ca\n 2+<\/jats:sup>\n -binding affinity of the CaM C-terminal domain was 10-fold lower for p.N138K-CaM compared with wild-type-CaM. I\n CaL<\/jats:sub>\n inactivation was slowed in cells expressing p.N138K-CaM but less than in p.D130G-CaM cells. Unexpectedly, a larger I\n Ks<\/jats:sub>\n current density was observed in cells expressing p.N138K-CaM, but not for p.D130G-CaM, compared with wild-type-CaM.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n The p.N138K\n CALM3<\/jats:italic>\n variant impairs Ca\n 2+<\/jats:sup>\n -binding affinity of CaM and I\n CaL<\/jats:sub>\n inactivation but potentiates I\n Ks<\/jats:sub>\n . The variably expressed phenotype of this variant compared with previously published de novo LQTS-CaM variants is likely explained by a milder impairment of I\n CaL<\/jats:sub>\n inactivation combined with I\n Ks<\/jats:sub>\n augmentation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circep.121.010572","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T10:51:15Z","timestamp":1646045475000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Novel\n CALM3<\/i>\n Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6125-0789","authenticated-orcid":true,"given":"Koichi","family":"Kato","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, UMRS-1166, Paris, France (K.K., V.F., I.D., A.D., A.C., P.G.)."},{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan (K.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4055-2016","authenticated-orcid":true,"given":"Holly M.","family":"Isbell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Carver College of Medicine, University of Iowa (H.M.I., M.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-1428","authenticated-orcid":true,"given":"V\u00e9ronique","family":"Fressart","sequence":"additional","affiliation":[{"name":"AP-HP, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Functional Unit of Cardiogenetics and Myogenetics, Paris, France (V.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1786-9461","authenticated-orcid":true,"given":"Isabelle","family":"Denjoy","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, UMRS-1166, Paris, France (K.K., V.F., I.D., A.D., A.C., P.G.)."},{"name":"Cardiology Department, Referring Center for Heritable or Rare Cardiac Diseases, AP-HP, Bichat Hospital, HUPNVS, Referring Center for Rare Cardiac Diseases, Sorbonne University, Paris, France (I.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3702-6373","authenticated-orcid":true,"given":"Amal","family":"Debbiche","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, UMRS-1166, Paris, France (K.K., V.F., I.D., A.D., A.C., P.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5104-3313","authenticated-orcid":true,"given":"Hideki","family":"Itoh","sequence":"additional","affiliation":[{"name":"Division of Patient Safety, Hiroshima University Hospital, Japan (H.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8338-0122","authenticated-orcid":true,"given":"Jacques","family":"Poinsot","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de cardio-pediatrie, service de medecine pediatrique, Centre Hospitalier Universitaire de Tours, Tours, France (J.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3993-966X","authenticated-orcid":true,"suffix":"Jr","given":"Alfred L.","family":"George","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Northwestern University Feinberg School of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.L.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Coulombe","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, UMRS-1166, Paris, France (K.K., V.F., I.D., A.D., A.C., P.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0814-7069","authenticated-orcid":true,"given":"Madeline A.","family":"Shea","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Carver College of Medicine, University of Iowa (H.M.I., M.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7663-2050","authenticated-orcid":true,"given":"Pascale","family":"Guicheney","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, UMRS-1166, Paris, France (K.K., V.F., I.D., A.D., 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