Novel and functional DNA sequence variants within the GATA5 gene promoter in ventricular septal defects
Novel and functional DNA sequence variants within the GATA5 gene promoter in ventricular septal defects
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DOI：
10.1007/s12519-014-0511-z
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发表时间：
2014-11-01
影响因子：
8.7
通讯作者：
Yan, Bo
中科院分区：
文献类型：
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作者：
Shan, Ji-Ping;Wang, Xiao-Li;Yan, Bo
背景：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仍然未知。加塔转录因子5（加塔5）是心脏发育的重要调节因子。据报道，各种CHD患者均存在GATA 5基因突变。由于基因表达失调与人类疾病有关，我们推测心脏转录因子GATA 5水平的改变可能介导了CUD的发生。方法：在本研究中，我们对室间隔缺损（VSD）患者（n=343）和种族匹配的健康对照（n=348）的加塔5基因启动子进行了遗传和功能分析。结果：两个新的和杂合的DNA序列变异体（DSV），g.61051165A>G和g.61051463delC，在三个VSD患者中被确定，但在对照组中没有。在培养的心肌细胞中，DSV g.61051165 A>G显著降低加塔5基因启动子活性，而DSV g.61051463 delC显著增加GATA 5基因启动子活性。此外，携带相同DSV的VSD患者的父亲左室舒张功能降低。三个SNP，g.61051279C>T（rs77067995），g.61051327A>C（rs145936691）和g.61051373G>A在VSD患者和对照组中均发现了一种新的杂合子型DSV（g.61051227C>T），其频率相似。我们的数据表明，GATA 5基因启动子中的DSV可能增加了VSD发展的易感性，作为一个危险因素。
Background: Congenital heart disease (CHD) is the most common human birth defect. Genetic causes for CHD) remain largely unknown. GATA transcription factor 5 (GATA 5) is an essential regulator for the heart development. Mutations in the GATA5 gene have been reported in patients with a variety of CHD. Since misregulation of gene expression have been associated with human diseases, we speculated that changed levels of cardiac transcription factors, GATA5, may mediate the development of CUD.Methods: In this study, GATA 5 gene promoter was genetically and functionally analyzed in large cohorts of patients with ventricular septal defect (VSD) (n=343) and ethnic-matched healthy controls (n=348).Results: Two novel and heterozygous DNA sequence variants (DSVs), g.61051165A>G and g.61051463delC, were identified in three VSD patients, but not in the controls. In cultured cardiomyocytes, GATA 5 gene promoter activities were significantly decreased by DSV g.61051165A>G and increased by DSV g.61051463delC. Moreover, fathers of the VSD patients carrying the same DSVs had reduced diastolic function of left ventricles. Three SNPs, g.61051279C>T (rs77067995), g.61051327A>C (rs145936691) and g.61051373G>A (rs80197101), and one novel heterozygous DSV, g.61051227C>T, were found in both VSD patients and controls with similar frequencies.Conclusion: Our data suggested that the DSVs in the GATA5 gene promoter may increase the susceptibility to the development of VSD as a risk factor.