Shandong Provincial Key Laboratory of Cardiac Disease Diagnosis and Treatment, Jining Medical University Affiliated Hospital, Jining Medical University, 79 Guhuai Road, Jining, 272029, Shandong, China.
Mol Cell Biochem. 2013 Oct;382(1-2):121-6. doi: 10.1007/s11010-013-1725-4. Epub 2013 Jun 8.
Congenital heart disease (CHD) is the most common birth defect in humans. Genetic causes for CHD remain largely unknown. T-box transcription factor 18 (TBX18) gene is expressed in the developing heart, including myocardium of the left ventricle and interventricular septum. Epicardial cells expressing TBX18 gene contribute to the cardiac fibroblast and smooth muscle cells. We speculated that the DNA sequence variants (DSVs) within TBX18 gene promoter may mediate CHD development by affecting TBX18 levels and the cardiac gene regulatory network. In this study, we genetically and functionally analyzed the TBX18 gene promoter in patients with ventricular septal defects (VSD) (n = 326) and ethnic-matched healthy controls (n = 327). Three novel heterozygous DSVs (g.85474435del, g.85474418C>T, and g.85473965C>G) and one single nucleotide polymorphism (g.85474871C>T, rs77693245) were identified in VSD patients, but none in the controls. Functional analysis revealed that the DSVs (g.85474871C>T, g.85474435del, and g.85473965C>G) significantly decreased the transcriptional activities of the TBX18 gene promoter. The effect of DSV (g.85474418C>T) on the TBX18 gene promoter was marginal, but not significant. Therefore, the DSVs within the TBX18 gene promoter identified in VSD patients may be involved in the VSD etiology.
先天性心脏病（CHD）是人类最常见的出生缺陷。CHD 的遗传原因在很大程度上尚不清楚。T 盒转录因子 18（TBX18）基因在心脏发育中表达，包括左心室心肌和室间隔。表达 TBX18 基因的心外膜细胞有助于心脏成纤维细胞和平滑肌细胞。我们推测，TBX18 基因启动子内的 DNA 序列变异（DSVs）可能通过影响 TBX18 水平和心脏基因调控网络来介导 CHD 发育。在这项研究中，我们对室间隔缺损（VSD）患者（n=326）和种族匹配的健康对照者（n=327）的 TBX18 基因启动子进行了遗传和功能分析。在 VSD 患者中发现了三个新的杂合性 DSVs（g.85474435del、g.85474418C>T 和 g.85473965C>G）和一个单核苷酸多态性（g.85474871C>T，rs77693245），但在对照组中均未发现。功能分析表明，DSVs（g.85474871C>T、g.85474435del 和 g.85473965C>G）显著降低了 TBX18 基因启动子的转录活性。DSV（g.85474418C>T）对 TBX18 基因启动子的影响较小，但无统计学意义。因此，在 VSD 患者中鉴定的 TBX18 基因启动子内的 DSV 可能与 VSD 的病因有关。
