Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes.
Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes.
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DOI：
10.1371/journal.pone.0130329
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Tanaka T
中科院分区：
文献类型：
--
作者：
Shigemizu D;Aiba T;Nakagawa H;Ozaki K;Miya F;Satake W;Toda T;Miyamoto Y;Fujimoto A;Suzuki Y;Kubo M;Tsunoda T;Shimizu W;Tanaka T
长QT间期综合征(LQTS)是一种可导致猝死的心律失常。到目前为止，已发现15个LQTS易感基因发生突变。然而，大约20%的LQTS患者的遗传原因仍然难以捉摸。在这里，我们对35个家系的59个LQTS和61个未患LQTS的个体和138个无关的LQTS病例进行了全外显子测序，对已知的LQTS基因进行了遗传筛选。我们对家族性病例的系统分析和随后的Sanger测序证实，35个家系中的23个(65.7%)在88个基因中发现了92个候选突变：其中包括11个从头突变，5个隐性突变(2个纯合子和3个复合杂合子)和73个显性突变。虽然除了已知的LQTS基因外，没有发现新的常见突变基因，但蛋白质-蛋白质相互作用(PPI)网络分析发现了10个新的致病候选基因，它们直接或间接地与已知LQTS基因编码的蛋白质相互作用。此外，基于候选基因的关联研究使用了138个无关的LQTS病例和587个对照的独立集合，确定了另一个新的候选对象。这些新的候选基因和已知基因的突变加在一起，解释了37.1%的LQTS家族(35人中有13人)。此外，新发现的候选基因中有一半直接与钙调蛋白相互作用(11个中有5个；与所有基因比较；p=0.042)。随后在138例独立病例中进行的变异分析确定了11个基因中的16个变异，其中14个是钙调素相互作用基因(87.5%)。这些结果提示钙调蛋白及其相互作用蛋白在LQTS的发病机制中起重要作用。
Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20% of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7%): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1% of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5%). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS.