Novel and functional DNA sequence variants within the GATA6 gene promoter in ventricular septal defects.
Novel and functional DNA sequence variants within the GATA6 gene promoter in ventricular septal defects.
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室间隔缺损中 GATA6 基因启动子内的新型功能性 DNA 序列变异体
DOI：
10.3390/ijms150712677
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发表时间：
2014-07-17
影响因子：
5.6
通讯作者：
Yan B
中科院分区：
文献类型：
--
作者：
Li C;Li X;Pang S;Chen W;Qin X;Huang W;Zeng C;Yan B
先天性心脏病（CHD）是人类最常见的出生缺陷。孤立性CHD的遗传原因和潜在的分子机制在很大程度上仍然未知。研究表明，加塔转录因子6（GATA 6）在心脏发育过程中起重要作用。GATA6基因突变与多种类型的CHD相关。由于GATA 6以剂量依赖性方式发挥作用，我们推测基因调节区内DNA序列变异（DSV）导致的GATA 6水平变化可能介导CHD的发生。在本研究中，GATA6基因启动子的遗传和功能分析在大组室间隔缺损（VSD）患者（n = 359）和种族匹配的健康对照组（n = 365）。在VSD患者和对照组中共鉴定出11个DSV，包括4个SNP。两个新的和杂合子DSV，g.22169190A>T和g.22169311C>G，在两个VSD患者中被鉴定，但在对照组中没有。在培养的心肌细胞中，GATA 6基因启动子的活性被DSV g.22169190A>T和g.22169311C>G显著降低。因此，我们的研究结果表明，在VSD患者中鉴定的GATA 6基因启动子内的DSV可能会改变GATA 6水平，作为一个危险因素促进VSD的发展。
Congenital heart disease (CHD) is the most common birth defect in humans. Genetic causes and underlying molecular mechanisms for isolated CHD remain largely unknown. Studies have demonstrated that GATA transcription factor 6 (GATA6) plays an essential role in the heart development. Mutations in GATA6 gene have been associated with diverse types of CHD. As GATA6 functions in a dosage-dependent manner, we speculated that changed GATA6 levels, resulting from DNA sequence variants (DSVs) within the gene regulatory regions, may mediate the CHD development. In the present study, GATA6 gene promoter was genetically and functionally analyzed in large groups of patients with ventricular septal defect (VSD) (n = 359) and ethnic-matched healthy controls (n = 365). In total, 11 DSVs, including four SNPs, were identified in VSD patients and controls. Two novel and heterozygous DSVs, g.22169190A>T and g.22169311C>G, were identified in two VSD patients, but in none of controls. In cultured cardiomyocytes, the activities of the GATA6 gene promoter were significantly reduced by the DSVs g.22169190A>T and g.22169311C>G. Therefore, our findings suggested that the DSVs within the GATA6 gene promoter identified in VSD patients may change GATA6 levels, contributing to the VSD development as a risk factor.
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影响因子：
7.7
作者：
De Franco E;Shaw-Smith C;Flanagan SE;Shepherd MH;International NDM Consortium;Hattersley AT;Ellard S
通讯作者：
Ellard S
影响因子：
5.8
作者：
Ho, CKM;Wood, JR;Strauss, JF
通讯作者：
Strauss, JF
影响因子：
30.8
作者：
Cordell, Heather J.;Bentham, Jamie;Topf, Ana;Zelenika, Diana;Heath, Simon;Mamasoula, Chrysovalanto;Cosgrove, Catherine;Blue, Gillian;Granados-Riveron, Javier;Setchfield, Kerry;Thornborough, Chris;Breckpot, Jeroen;Soemedi, Rachel;Martin, Ruairidh;Rahman, Thahira J.;Hall, Darroch;van Engelen, Klaartje;Moorman, Antoon F. M.;Zwinderman, Aelko H.;Barnett, Phil;Koopmann, Tamara T.;Adriaens, Michiel E.;Varro, Andras;George, Alfred L., Jr.;dos Remedios, Christobal;Bishopric, Nanette H.;Bezzina, Connie R.;O'Sullivan, John;Gewillig, Marc;Bu'Lock, Frances A.;Winlaw, David;Bhattacharya, Shoumo;Devriendt, Koen;Brook, J. David;Mulder, Barbara J. M.;Mital, Seema;Postma, Alex V.;Lathrop, G. Mark;Farrall, Martin;Goodship, Judith A.;Keavney, Bernard D.
通讯作者：
Keavney, Bernard D.
影响因子：
2.7
作者：
Laforest, Brigitte;Nemer, Mona
通讯作者：
Nemer, Mona
影响因子：
14.9
作者：
Heinemeyer, T;Wingender, E;Kolchanov, NA
通讯作者：
Kolchanov, NA