Exome Sequencing in a Family Identifies RECQL5 Mutation Resulting in Early Myocardial Infarction.
Exome Sequencing in a Family Identifies RECQL5 Mutation Resulting in Early Myocardial Infarction.
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一个家族的外显子组测序发现 RECQL5 突变导致早期心肌梗塞。
DOI：
10.1097/md.0000000000002737
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发表时间：
2016-02
期刊：
影响因子：
1.6
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Xie X;Zheng YY;Adi D;Yang YN;Ma YT;Li XM;Fu ZY;Ma X;Liu F;Yu ZX;Chen Y;Huang Y
包括心肌梗死(MI)在内的冠状动脉疾病(CAD)是世界范围内的主要死亡原因，通常是由遗传因素和环境风险相互作用引起的。尽管使用连锁和候选基因方法进行了大量的研究，但大多数具有多代早期CAD/MI易感性的家系的遗传病因尚不清楚。在这项研究中，我们使用了来自1个早期MI家系的10个个体的全外显子测序，其中4个兄弟姐妹在55岁之前被诊断为MI，以确定潜在的易感基因。我们发现了RECQL5基因的突变，RECQL5基因是参与维持基因组稳定性的5个RecQ家族成员之一。这个新的突变是13号染色体上73,626,918位的TG插入，发生在影响RECQL5剪接的第11内含子受体剪接点的最后一个核苷酸之前。RECQL5基因突变患者外显子11~13直接剪接，跳过外显子12。RECQL5基因突变患者外显子12的定量RT-PCR分析显示，突变纯合子个体中仅有微量含有该外显子的基因，而携带杂合子的家系成员的水平仅为对照组的48%~55%。这些发现为MI的发病机制和RECQL5基因在人类疾病中的作用提供了深入的认识。
Coronary artery disease (CAD) including myocardial infarction (MI) is the leading cause of death worldwide and is commonly caused by the interaction between genetic factors and environmental risks. Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multigenerational early CAD /MI predisposition is unknown. In this study, we used whole-exome sequencing of 10 individuals from 1 early MI family, in which 4 siblings were diagnosed with MI before the age of 55, to identify potential predisposing genes. We identified a mutation in the RECQL5 gene, 1 of the 5 members of the RECQ family which are involved in the maintenance of genomic stability. This novel mutation, which is a TG insert at position 73,626,918 on the 13 chromosome and occurs before the last nucleotide of the introns 11 acceptor splice site affecting splicing of RECQL5. RT-PCR suggested the control subject had a full-length mRNA including exon 12, but the patients with RECQL5 mutation had a shorter mRNA form involving splicing of exons 11 to 13 directly, with skipping of exon 12. Quantitative RT-PCR analysis of RECQL5 exon 12 demonstrated that individuals whose genotype is mutant homozygote had only trace amounts of mRNA containing this exon and the family members who carry the heterozygous genotype had a level at 48% to 55% of the control's level. These findings provide insight into both the pathogenesis of MI and the role of RECQL5 gene in human disease.