Qi Jia-Le, Chen Huan-Xin, Hou Hai-Tao, Chen Zhuo, Liu Li-Xin, Yang Qin, He Guo-Wei
Department of Cardiovascular Surgery & The Institute of Cardiovascular Diseases, TEDA International Cardiovascular Hospital, Tianjin University, No.61, the 3rd Ave, TEDA, Tianjin, 300457, China.
Tianjin Key Laboratory of Molecular Regulation of Cardiovascular Diseases and Translational Medicine, Tianjin, China.
Mol Cell Biochem. 2025 Mar;480(3):1657-1667. doi: 10.1007/s11010-024-05088-9. Epub 2024 Aug 6.
Ventricular septal defect (VSD) is the most common type of congenital heart disease. HAND1 gene plays a crucial role in the development of the heart, but the role of the variants in the HAND1 gene promoter region in patients with VSD has not been explored yet. From 588 participants (300 with isolated and sporadic VSD and 288 healthy controls), DNA was extracted from blood samples. Variants at the HAND1 gene promoter region were analyzed through Sanger sequencing. Subsequently, cell functional validation was conducted through cell experiments, including dual-luciferase reporter gene analysis, electrophoretic mobility shift analysis, and bioinformatics analysis was also conducted. The promoter region of HAND1 gene had a total of 9 identified variant sites. Among them, 4 variants were exclusively found in VSD patients, and 1 variant (g.3631A>C) was newly discovered. Cell functional experiments indicated that all four variants decreased the transcriptional activity of HAND1 gene promoter with three of them reached statistical significance (p < 0.05). Subsequent analysis using JASPAR (a transcription factor binding profile database) suggests that these variants may alter the binding sites of transcription factors, potentially contributing to the formation of VSD. Our study for the first time identified variants in the promoter region of HAND1 gene in Chinese patients with isolated and sporadic VSD. These variants significantly decreased the expression of HAND1 gene, impacting transcription factor binding sites, and thereby demonstrating pathogenicity. This study offers new insights into the role of HAND1 gene promoter region, contributing to a better understanding of the genetic basis of VSD formation.
室间隔缺损（VSD）是最常见的先天性心脏病类型。HAND1基因在心脏发育中起关键作用，但HAND1基因启动子区域变异在室间隔缺损患者中的作用尚未得到探索。从588名参与者（300例孤立性散发性室间隔缺损患者和288名健康对照）的血样中提取DNA。通过桑格测序分析HAND1基因启动子区域的变异。随后，通过细胞实验进行细胞功能验证，包括双荧光素酶报告基因分析、电泳迁移率变动分析，并进行了生物信息学分析。HAND1基因启动子区域共鉴定出9个变异位点。其中，4个变异仅在室间隔缺损患者中发现，1个变异（g.3631A>C）为新发现。细胞功能实验表明，所有4个变异均降低了HAND1基因启动子的转录活性，其中3个达到统计学意义（p < 0.05）。随后使用JASPAR（一个转录因子结合谱数据库）进行的分析表明，这些变异可能改变转录因子的结合位点，可能导致室间隔缺损的形成。我们的研究首次在中国孤立性散发性室间隔缺损患者中鉴定出HAND1基因启动子区域的变异。这些变异显著降低了HAND1基因的表达，影响转录因子结合位点，从而证明具有致病性。本研究为HAND1基因启动子区域的作用提供了新的见解，有助于更好地理解室间隔缺损形成的遗传基础。
