PITX2 Loss-of-Function Mutation Contributes to Congenital Endocardial Cushion Defect and Axenfeld-Rieger Syndrome
PITX2 Loss-of-Function Mutation Contributes to Congenital Endocardial Cushion Defect and Axenfeld-Rieger Syndrome
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DOI：
10.1371/journal.pone.0124409
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发表时间：
2015-04
期刊：
影响因子：
3.7
通讯作者：
Cui-Mei Zhao;Luying Peng;Li Li-Li;Xing-yuan Liu;Juan Wang;Xian-Ling Zhang;Fang Yuan;Ruo-Gu Li
中科院分区：
文献类型：
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作者：
Cui-Mei Zhao;Luying Peng;Li Li-Li;Xing-yuan Liu;Juan Wang;Xian-Ling Zhang;Fang Yuan;Ruo-Gu Li
先天性心脏病（CHD）是最常见的出生缺陷类型，仍然是人类婴儿发病率和死亡率的主要非感染性原因。越来越多的证据表明，遗传缺陷参与了冠心病的发病机制。然而，冠心病是遗传异质性和遗传组成部分支持冠心病在绝大多数患者仍不清楚。在本研究中，对196例无关CHD患者和随后的突变携带者家族成员的PITX 2基因的编码外显子和侧翼内含子进行了测序。PITX 2基因编码一种对心血管形态发生和上颌面部发育至关重要的配对同源结构域转录因子2。结果，在一个患有内膜垫缺陷（ECD）和Axenovirus-Rieger综合征（ARS）的家族中鉴定出一种新的杂合PITX 2突变，PITX 2a的p.Q102X，或PITX 2b的p.Q148X，或PITX 2c的p.Q155X。家系遗传学分析表明，该无义突变与ECD和ARS共分离，呈常染色体显性遗传，完全连锁。该突变在来自种族匹配人群的800条对照染色体中不存在。通过使用双荧光素酶报告分析系统的功能分析显示，突变体PITX 2没有转录活性，并且突变消除了PITX 2和NKX2.5之间的协同转录激活，NKX2.5是心脏发生的另一个关键转录因子。据我们所知，这是第一份关于PITX 2功能缺失突变与ECD和ARS易感性增加相关的报告。这些发现为ECD和ARS的分子机制提供了新的见解，提示了CHD和ARS的产前预防和个性化治疗的潜在意义。
Congenital heart disease (CHD), the most common type of birth defect, is still the leading non-infectious cause of infant morbidity and mortality in humans. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous and the genetic components underpinning CHD in an overwhelming majority of patients remain unclear. In the present study, the coding exons and flanking introns of the PITX2 gene, which encodes a paired-like homeodomain transcription factor 2essential for cardiovascular morphogenesis as well as maxillary facial development, was sequenced in 196 unrelated patients with CHD and subsequently in the mutation carrier’s family members available. As a result, a novel heterozygous PITX2 mutation, p.Q102X for PITX2a, or p.Q148X for PITX2b, or p.Q155X for PITX2c, was identified in a family with endocardial cushion defect (ECD) and Axenfeld-Rieger syndrome (ARS). Genetic analysis of the pedigree showed that the nonsense mutation co-segregated with ECD and ARS transmitted in an autosomal dominant pattern with complete penetrance. The mutation was absent in 800 control chromosomes from an ethnically matched population. Functional analysis by using a dual-luciferase reporter assay system revealed that the mutant PITX2 had no transcriptional activity and that the mutation eliminated synergistic transcriptional activation between PITX2 and NKX2.5, another transcription factor pivotal for cardiogenesis. To our knowledge, this is the first report on the association of PITX2 loss-of-function mutation with increased susceptibility to ECD and ARS. The findings provide novel insight into the molecular mechanisms underpinning ECD and ARS, suggesting the potential implications for the antenatal prophylaxis and personalized treatment of CHD and ARS.