Makita Naomasa, Yagihara Nobue, Crotti Lia, Johnson Christopher N, Beckmann Britt-Maria, Roh Michelle S, Shigemizu Daichi, Lichtner Peter, Ishikawa Taisuke, Aiba Takeshi, Homfray Tessa, Behr Elijah R, Klug Didier, Denjoy Isabelle, Mastantuono Elisa, Theisen Daniel, Tsunoda Tatsuhiko, Satake Wataru, Toda Tatsushi, Nakagawa Hidewaki, Tsuji Yukiomi, Tsuchiya Takeshi, Yamamoto Hirokazu, Miyamoto Yoshihiro, Endo Naoto, Kimura Akinori, Ozaki Kouichi, Motomura Hideki, Suda Kenji, Tanaka Toshihiro, Schwartz Peter J, Meitinger Thomas, Kääb Stefan, Guicheney Pascale, Shimizu Wataru, Bhuiyan Zahurul A, Watanabe Hiroshi, Chazin Walter J, George Alfred L
Circ Cardiovasc Genet. 2014 Aug;7(4):466-74. doi: 10.1161/CIRCGENETICS.113.000459. Epub 2014 Jun 10.
Genetic predisposition to life-threatening cardiac arrhythmias such as 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 used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 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 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. 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 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.
CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
危及生命的心律失常，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）的遗传易感性是年轻成年人和儿童心脏性猝死的可治疗原因。最近，钙调蛋白（CALM1、CALM2）突变与严重形式的LQTS和CPVT相关，危及生命的心律失常在生命早期就会发生。需要更多的突变阳性病例来识别与钙调蛋白突变相关的基因型-表型相关性。
我们对基因型阴性的LQTS先证者采用了传统和新一代测序方法，包括外显子组分析。我们在3例LQTS患者（p.N98S、p.N98I、p.D134H）和2例具有LQTS和CPVT临床特征的患者（p.D132E、p.Q136P）中鉴定出5个新的CALM2新发错义突变。主要症状（晕厥或心脏骤停）的发病年龄为1至9岁。5例先证者中有3例发生心脏骤停，其中1例未存活。该系列患者的临床严重程度一般低于最初报道的与婴儿期反复心脏骤停相关的CALM1和CALM2。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p.Q136P突变的患者尽管接受了这种治疗仍在运动时突然死亡。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。
CALM2突变可能与LQTS以及LQTS和CPVT的重叠特征相关。
