Novel calmodulin mutations associated with congenital arrhythmia susceptibility.
Novel calmodulin mutations associated with congenital arrhythmia susceptibility.
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DOI：
10.1161/circgenetics.113.000459
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发表时间：
2014-08
期刊：
影响因子：
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通讯作者：
George AL Jr
中科院分区：
文献类型：
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作者：
Makita N;Yagihara N;Crotti L;Johnson CN;Beckmann BM;Roh MS;Shigemizu D;Lichtner P;Ishikawa T;Aiba T;Homfray T;Behr ER;Klug D;Denjoy I;Mastantuono E;Theisen D;Tsunoda T;Satake W;Toda T;Nakagawa H;Tsuji Y;Tsuchiya T;Yamamoto H;Miyamoto Y;Endo N;Kimura A;Ozaki K;Motomura H;Suda K;Tanaka T;Schwartz PJ;Meitinger T;Kääb S;Guicheney P;Shimizu W;Bhuiyan ZA;Watanabe H;Chazin WJ;George AL Jr
危及生命的心律失常的遗传易感性，如先天性长QT综合征（LQTS）和儿茶酚胺能多形性室性心动过速（CPVT），是年轻人和儿童心脏性猝死的可治疗原因。最近，钙调蛋白（CALM 1，CALM 2）的突变与严重形式的LQTS和CPVT相关，在生命的早期发生危及生命的心律失常。需要额外的突变阳性病例来辨别与钙调素突变相关的基因型-表型相关性。我们采用了常规和新一代测序方法，包括基因型阴性LQTS先证者的外显子组分析。我们在3例LQTS患者（p.N98S、p.N98I、p.D134H）和2例同时具有LQTS和CPVT临床特征的患者（p.D132E、p.Q136P）中发现了5个新的CALM 2从头错义突变。主要症状（晕厥或心脏骤停）出现的年龄范围为1-9岁。五个先证者中有三个心脏骤停，其中一个没有存活。虽然所有先证者都有LQTS，但两名受试者也表现出与CPVT一致的心电图特征。该系列中受试者的临床严重程度通常低于最初报告的与婴儿期复发性心脏骤停相关的CALM 1和CALM 2。5例先证者中有4例对β受体阻滞剂治疗有反应，而1例携带突变p.Q136P的受试者尽管接受了β受体阻滞剂治疗，但仍在劳累期间突然死亡。突变影响位于钙结合环III（p.N98S，p.N98I）或IV（p.D132E，p.D134H，p.Q136P）内的保守残基，并导致钙结合亲和力降低。CALM 2突变可能与LQTS以及LQTS和CPVT的重叠特征相关。
Genetic predisposition to life-threatening cardiac arrhythmias such as in congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations. We employed conventional and next-generation sequencing approaches including exome analysis in genotype-negative LQTS probands. We identified five novel de novo missense mutations in CALM2 in three subjects with LQTS (p.N98S, p.N98I, p.D134H) and two subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1–9 years. Three of five probands had cardiac arrest and one of these subjects did not survive. Although all probands had LQTS, two subjects also exhibited electrocardiographic features consistent with CPVT. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of five probands responded to β-blocker therapy whereas one subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within calcium binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced calcium binding affinity. CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.