在一个4代家族中引起钙调蛋白病的新CALM3变异具有可变表达性

K. Kato, Holly M. Isbell, V. Fressart, I. Denjoy, A. Debbiche, H. Itoh, J. Poinsot, Alfred L. George, A. Coulombe, M. A. Shea, P. Guicheney
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引用次数: 10

摘要

背景:CaM (calmodulin)是一种多功能Ca2+结合蛋白,由3个独立的基因(CALM1、CALM2和CALM3)编码,参与包括离子通道调节在内的许多信号转导事件。CaM变异可能表现为早发性长QT综合征(LQTS)、儿茶酚胺能多形性室性心动过速或心源性猝死。大多数报告的变异都是从头发生的。我们在一个与LQTS分离的4代家族中发现了一种新的CALM3变体p.Asn138Lys (N138K)。本研究的目的是阐明其致病性,并将其与p.d 130g - cam(一种与严重LQTS表型相关的变异)的致病性进行比较。方法:我们对一个受LQTS影响的4代大家庭进行了全外显子组测序。为了评估检测到的CALM3变异的影响,通过化学计量Ca2+滴定和平衡滴定来测量固有的Ca2+结合亲和力。全细胞膜片钳记录l型Ca2+和慢延迟整流钾电流(ICaL和IKs)。光学荧光法检测Cav1.2和Kv7.1膜表达。结果:我们在一个发生2例儿童猝死的家庭中鉴定出14例p.N138K-CaM携带者。与迄今文献中描述的CaM-LQTS患者相比,一些成员仅轻度受影响。与野生型CaM相比,p.N138K-CaM的c端结构域的内在Ca2+结合亲和力降低了10倍。表达p.N138K-CaM的细胞的ICaL失活减慢,但低于p.D130G-CaM细胞。出乎意料的是,与野生型cam相比,在表达p.N138K-CaM的细胞中观察到更大的ik电流密度,而在表达p.D130G-CaM的细胞中则没有。结论:p.N138K CALM3变异体损害CaM和ICaL的Ca2+结合亲和力,但增强IKs。与先前发表的新生LQTS-CaM变体相比,该变体的可变表达表型可能是由于ICaL失活和IKs增强的轻微损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family
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.
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