Shandong Provincial Key Laboratory of Cardiac Disease Diagnosis and Treatment, Jining Medical College Affiliated Hospital, Jining Medical College, Jining, Shandong 272029, China.
Transl Res. 2012 May;159(5):376-82. doi: 10.1016/j.trsl.2011.10.012. Epub 2011 Nov 23.
Ventricular septal defects (VSDs) are the most common type of congenital heart diseases (CHDs). To date, the genetic causes for sporadic VSDs remain largely unknown. GATA transcription factor 4 (GATA4) is a zinc-finger transcription factor that is expressed in developing heart and adult cardiomyocytes. Mutations in the coding region of the GATA4 gene have been identified in CHD patients, including VSD. As the GATA4 factor is a dosage-sensitive regulator, we hypothesized that the promoter region variants of the GATA4 gene may be genetic causes of VSD. In this study, we analyzed the promoter region of the GATA4 gene by bidirectional sequencing in 172 VSD patients and 171 healthy controls. The results showed that 5 heterozygous sequence variants (NG_008177:g.4071T>C, NG_008177:g.4148C>A, NG_008177:g.4566C>T, NG_008177:g.4653G>T, and NG_008177:g.4690G>deletion) within the promoter region of the GATA gene were identified in 5 VSD patients, but in none of controls. One heterozygous sequence variant (g.4762C>A) was found only in one control, which may have no functional significance. A functional analysis revealed that the transcriptional activity of variant NG_008177:g.4566C>T was reduced significantly, whereas the transcriptional activities of the variants (NG_008177:g.4071T>C, NG_008177:g.4148C>A, NG_008177:g.4653G>T, and NG_008177:g.4690G>deletion) were increased significantly compared with the wild-type GATA4 gene promoter. As GATA4 is a dosage-sensitive regulator during development, our data suggest that these sequence variants within the promoter region of the GATA4 gene may contribute to the VSD etiology by altering its gene expression. Additional studies in experimental animals will deepen our understanding of the genetic basis of VSD and shed light on designing novel molecular therapies for adult VSD patients carrying these variants.
室间隔缺损（VSD）是最常见的先天性心脏病（CHD）类型。迄今为止，散发性 VSD 的遗传原因仍知之甚少。GATA 转录因子 4（GATA4）是一种锌指转录因子，在心脏发育和成年心肌细胞中表达。在 CHD 患者中已发现 GATA4 基因突变，包括 VSD。由于 GATA4 因子是一种剂量敏感的调节因子，我们假设 GATA4 基因启动子区域的变体可能是 VSD 的遗传原因。在这项研究中，我们通过双向测序分析了 172 名 VSD 患者和 171 名健康对照者的 GATA4 基因启动子区域。结果显示，在 5 名 VSD 患者中发现了 5 种杂合性序列变异（NG_008177：g.4071T>C、NG_008177：g.4148C>A、NG_008177：g.4566C>T、NG_008177：g.4653G>T 和 NG_008177：g.4690G>缺失），但在对照组中均未发现。在一名对照者中仅发现了一种杂合性序列变异（g.4762C>A），可能没有功能意义。功能分析表明，变体 NG_008177：g.4566C>T 的转录活性显著降低，而变体（NG_008177：g.4071T>C、NG_008177：g.4148C>A、NG_008177：g.4653G>T 和 NG_008177：g.4690G>缺失）的转录活性显著高于野生型 GATA4 基因启动子。由于 GATA4 是发育过程中的一种剂量敏感调节因子，我们的数据表明，GATA4 基因启动子区域内的这些序列变异可能通过改变其基因表达而导致 VSD 发病机制。在实验动物中的进一步研究将加深我们对 VSD 遗传基础的理解，并为携带这些变异的成年 VSD 患者设计新型分子治疗方法提供启示。
