Boczek Nicole J, Gomez-Hurtado Nieves, Ye Dan, Calvert Melissa L, Tester David J, Kryshtal Dmytro, Hwang Hyun Seok, Johnson Christopher N, Chazin Walter J, Loporcaro Christina G, Shah Maully, Papez Andrew L, Lau Yung R, Kanter Ronald, Knollmann Bjorn C, Ackerman Michael J
Department Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN.
Department of Medicine, Vanderbilt University, Nashville, TN.
Circ Cardiovasc Genet. 2016 Apr;9(2):136-146. doi: 10.1161/CIRCGENETICS.115.001323. Epub 2016 Mar 11.
Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca(2+) and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants.
Thirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in Ca(2+)-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release.
Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history.
钙调蛋白（CaM）由3个基因CALM1、CALM2和CALM3编码，所有这些基因都含有与早发和严重表型的长QT综合征（LQTS）相关的致病变异。这些导致LQTS的变异降低了CaM对Ca(2+)的亲和力，并改变了心脏L型钙通道（CaV1.2）的特性。CaM还调节NaV1.5和兰尼碱受体RyR2。所有这些相互作用可能在疾病发病机制中起作用。在此，我们确定了一组遗传原因不明的LQTS患者中致病CaM变异的谱系和患病率，并对新发现的变异进行功能特性分析。
对38例遗传原因不明的LQTS患者进行全外显子组测序以鉴定CaM变异。与外显子聚合联盟（0.04%；P<0.0001）相比，非同义CaM变异在这个迄今为止的LQTS队列中显著富集（13.2%）。当将这5例CaM阳性病例的临床后遗症与33例CaM阴性病例进行比较时，CaM阳性病例具有更严重的表型，平均发病年龄为10个月，平均校正QT间期为676毫秒，心脏骤停患病率高。对1个新变异E141G-CaM的功能特性分析显示，其Ca(2+)结合亲和力降低了11倍，CaV1.2中失活功能呈显性丧失，NaV1.5晚期电流轻度增强，但对细胞内RyR2介导的钙释放无影响。
总体而言，我们的遗传原因不明的LQTS队列中有13%的患者CaM存在非同义变异。对于LQTS患者，尤其是那些有幼儿期心脏骤停、QT极度延长和家族史阴性的患者，应进行CALM1-3的基因检测。
