Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China.
Int J Med Sci. 2013 Aug 22;10(10):1422-9. doi: 10.7150/ijms.6809. eCollection 2013.
Congenital heart disease (CHD) is the most common form of developmental anomaly and is the leading non-infectious cause of infant mortality. A growing body of evidence demonstrates that genetic risk factors are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic determinants for CHD in most patients remain unclear. In the present study, the entire coding region and splice junction sites of the PITX2c gene, which encodes a homeobox transcription factor crucial for normal cardiovascular genesis, was sequenced in 150 unrelated patients with various CHDs. The 200 unrelated control individuals were subsequently genotyped. The functional characteristics of the mutations were explored using a dual-luciferase reporter assay system. As a result, two novel heterozygous PITX2c mutations, p.H98Q and p.M119T, were identified in 2 unrelated patients with atrial septal defects, respectively. The variations were absent in 400 control chromosomes and the affected amino acids were completely conserved evolutionarily. The two variants were both predicted to be disease-causing by MutationTaster and PolyPhen-2, and the functional analysis revealed that the PITX2c mutants were consistently associated with significantly reduced transcriptional activity compared with their wild-type counterpart. These findings firstly link PITX2c loss-of-function mutations to atrial septal defects in humans, which provide novel insight into the molecular mechanism responsible for CHD, suggesting potential implications for the early prophylaxis and allele-specific treatment of CHD.
先天性心脏病（CHD）是最常见的发育异常形式，也是婴儿死亡的主要非传染性原因。越来越多的证据表明，遗传风险因素与 CHD 的发病机制有关。然而，CHD 是一种遗传异质性疾病，大多数患者的 CHD 遗传决定因素仍不清楚。在本研究中，对编码心脏发生过程中至关重要的同源盒转录因子的 PITX2c 基因的整个编码区和剪接连接位点进行了测序，共涉及 150 名患有各种 CHD 的无血缘关系的患者。随后对 200 名无血缘关系的对照个体进行了基因分型。使用双荧光素酶报告基因检测系统对突变的功能特征进行了探索。结果在 2 名无血缘关系的房间隔缺损患者中分别发现了 2 个新的杂合性 PITX2c 突变，p.H98Q 和 p.M119T。这两种变异在 400 个对照染色体中均不存在，受影响的氨基酸在进化上完全保守。突变分析预测这两种变体都是致病的，并且功能分析表明，与野生型相比，PITX2c 突变体的转录活性明显降低。这些发现首次将 PITX2c 功能丧失性突变与人类房间隔缺损联系起来，为 CHD 的分子机制提供了新的见解，表明其可能对 CHD 的早期预防和等位基因特异性治疗具有重要意义。
