A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death.
A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death.
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DOI：
10.1016/j.cca.2010.09.035
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发表时间：
2011-01-14
期刊：
影响因子：
--
通讯作者：
Wang QK
中科院分区：
文献类型：
--
作者：
Ouyang P;Saarel E;Bai Y;Luo C;Lv Q;Xu Y;Wang F;Fan C;Younoszai A;Chen Q;Tu X;Wang QK
转录因子NKX2.5的突变会导致先天性心脏病（CHD）。我们发现了一个患有房间隔缺损（ASDs）、房室传导阻滞、心室致密化不全、晕厥和猝死的先天性心脏病家族。我们的目的是确定该先天性心脏病家族中的致病突变。
采用直接DNA序列分析来确定先天性心脏病突变。通过荧光素酶报告基因检测和免疫染色来表征突变的功能影响。
在NKX2.5的第2外显子中发现了一种新的、从头发生的2个碱基插入（c.512insGC）。突变c.512insGC与该家族中的先天性心脏病共分离，且在200名对照者中不存在。功能研究表明，c.512insGC突变阻碍NKX2.5的核定位，并导致NKX2.5的转录激活活性完全丧失。此外，在125名中国散发性先天性心脏病患者中未发现NKX2.5突变。
（1）NKX2.5突变c.512insGC与房间隔缺损、晕厥和猝死相关。它是在NKX2.5中发现的第二种从头突变。（2）NKX2.5突变在散发性先天性心脏病患者中罕见。（3）本研究首次确定了NKX2.5突变与心室致密化不全之间的关联。我们的研究结果显著扩展了NKX2.5突变的表型谱。
Mutations in transcription factor NKX2.5 cause congenital heart disease (CHD). We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death. Our objective is to identify the disease-causing mutation in the CHD family. Direct DNA sequence analysis was used to identify the CHD mutation. The functional effects of the mutation were characterized by a luciferase reporter assay and immunostaining. A novel, de novo 2-bp insertion (c.512insGC) was identified in exon 2 of NKX2.5. Mutation c.512insGC co-segregates with CHD in the family, and is not present in 200 controls. Functional studies indicate that the c.512insGC mutation impedes nuclear localization of NKX2.5 and causes a total loss of transactivation activity of NKX2.5. Furthermore, no NKX2.5 mutation was identified in 125 sporadic Chinese CHD patients. (1) NKX2.5 mutation c.512insGC is associated with ASDs, syncope and sudden death. It is the second de novo mutation identified in NKX2.5. (2) NKX2.5 mutations are rare in sporadic CHD patients. (3) This study for the first time identifies association between a NKX2.5 mutation and ventricular noncompaction. Our results significantly expand the phenotypic spectrum of NKX2.5 mutations.
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