Targeted sequencing identifies novel GATA6 variants in a large cohort of patients with conotruncal heart defects
Targeted sequencing identifies novel GATA6 variants in a large cohort of patients with conotruncal heart defects
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靶向测序在一大群圆锥动脉干心脏缺陷患者中发现了新的 GATA6 变异
DOI：
10.1016/j.gene.2017.10.083
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发表时间：
2018
期刊：
影响因子：
3.5
通讯作者：
Sun Kun
中科院分区：
文献类型：
--
作者：
Zhang Erge;Hong Nanchao;Chen Sun;Fu Qihua;Li Fen;Yu Yu;Sun Kun
研究强调了GATA 6在圆锥动脉干心脏缺陷（CTD）中的关键作用。然而，GATA 6变异体与不同CTD之间的关系在很大程度上仍然未知。应用靶向测序技术对542例CTD患者进行GATA 6基因筛查。变异频率为2.0%（11/542）。三种新变体：c.86C > A（p.A29E）、c.296T > A（p.V99D）和c.1254delC（p.S418fs）分别在大动脉转位、右室双出口和永存动脉干患者中检出，而在400例对照组中均未检出。Western blot结果显示，A29 E和V99 D突变体蛋白表达模式与野生型GATA 6蛋白相似，而S418 fs突变体蛋白为截短的双联体。报告基因分析表明，A29 E和V99 D突变蛋白保留了激活BNP和ANF启动子的能力，而S418 fs突变蛋白则不能激活BNP和ANF启动子。野生型、A29 E和V99 D突变体蛋白的亚细胞定位在细胞核中，而S418 fs突变体蛋白在细胞核和细胞质中都有表达。散发性CTD患者GATA 6变异频率高于其他先天性心脏病患者。变异c.1254delC是与CTD，特别是PTA相关的致病性变异，而c.86C > A和c.296T > A应被认为是可能的致病性变异。
Studies have highlighted the critical role of GATA6 in conotruncal heart defects (CTDs). Nevertheless, relationship betweenGATA6variants and different CTDs remains largely unknown. HereGATA6gene was screened in 542 patients with CTDs using targeted sequencing. Variant frequency was 2.0% (11/542). Three novel variants: c.86C > A (p.A29E), c.296T > A (p.V99D) and c.1254delC (p.S418fs) were identified in patients with transposition of the great arteries, double outlet right ventricle and persistent truncus arteriosus, respectively, but in none of the 400 controls. Western blot revealed that A29E and V99D mutant protein had similar expression pattern with wild-typeGATA6protein, but S418fs mutant protein appeared as a truncated doublet. Reporter gene assay demonstrated that A29E and V99D mutant protein retained the ability to activate BNP and ANF promoter, whereas S418fs mutant protein failed to transactivate both of them, compared with wild-type. Subcellular localization of wild-type, A29E and V99D mutant protein were in the nucleus, while S418fs mutant protein was expressed both in the nucleus and cytoplasm. In conclusion,GATA6variant frequency in sporadic CTDs patients was higher than that in other congenital heart diseases. Variant c.1254delC was a pathogenic variant associated with CTDs, especially PTA, whereas c.86C > A and c.296T > A should be considered as likely pathogenic variants.