@article{oai:shiga-med.repo.nii.ac.jp:00004186,
 author = {加藤, 浩一 and 伊藤, 英樹 and KATO, Koichi and ISBELL, Holly M. and FRESSART, Véronique and DENJOY, Isabelle and DEBBICHE, Amal and ITOH, Hideki and POINSOT, Jacques and GEORGE Jr, Alfred L. and COULOMBE, Alain and SHEA, Madeline A. and GUICHENEY, Pascale},
 issue = {3},
 journal = {Circulation. Arrhythmia and electrophysiology},
 month = {Mar},
 note = {Background:
CaM (calmodulin), encoded by 3 separate genes (CALM1, CALM2, and CALM3), is a multifunctional Ca2+-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 CALM3 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—a variant associated with a severe LQTS phenotype., Methods:
We performed whole exome sequencing for a large, 4-generation family affected by LQTS. To assess the effect of the detected CALM3 variant, the intrinsic Ca2+-binding affinity was measured by stoichiometric Ca2+ titrations and equilibrium titrations. L-type Ca2+ and slow delayed rectifier potassium currents (ICaL and IKs) were recorded by whole-cell patch-clamp. Cav1.2 and Kv7.1 membrane expression were determined by optical fluorescence assays., Results:
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 Ca2+-binding affinity of the CaM C-terminal domain was 10-fold lower for p.N138K-CaM compared with wild-type-CaM. ICaL inactivation was slowed in cells expressing p.N138K-CaM but less than in p.D130G-CaM cells. Unexpectedly, a larger IKs current density was observed in cells expressing p.N138K-CaM, but not for p.D130G-CaM, compared with wild-type-CaM., Conclusions:
The p.N138K CALM3 variant impairs Ca2+-binding affinity of CaM and ICaL inactivation but potentiates IKs. The variably expressed phenotype of this variant compared with previously published de novo LQTS-CaM variants is likely explained by a milder impairment of ICaL inactivation combined with IKs augmentation., Journal Article},
 title = {Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family},
 volume = {15},
 year = {2022}
}