Abstract：
Bicuspid aortic valve (BAV), the most common congenital heart defect affecting 1% to 2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and mechanisms of BAV etiology and pathogenesis remain largely undefined.
Cardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS (Genome Wide Association Study). GATA6 expression was determined in mice and human tissues using quantitative real-time polymerase chain reaction and immunohistochemistry. Mechanistic studies were carried out in cultured cells.
Gata6 heterozygous mice have highly penetrant right-left (RL)-type BAV, the most frequent type in humans. GATA6 transcript levels are lower in human BAV compared with normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules, including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes because loss of 1 Gata6 allele from Isl- 1-positive cells-but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice.
The data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.
Cardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS (Genome Wide Association Study). GATA6 expression was determined in mice and human tissues using quantitative real-time polymerase chain reaction and immunohistochemistry. Mechanistic studies were carried out in cultured cells.
Gata6 heterozygous mice have highly penetrant right-left (RL)-type BAV, the most frequent type in humans. GATA6 transcript levels are lower in human BAV compared with normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules, including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes because loss of 1 Gata6 allele from Isl- 1-positive cells-but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice.
The data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.
摘要：
二叶主动脉瓣(BAV),最常见的先天性心脏病影响1%至2%的人口，是早发主动脉瓣疾病的主要危险因素，占瓣膜置换术的大多数。BAV病因和发病机制的遗传基础和机制在很大程度上仍不明确。
在缺乏Gata6等位基因的小鼠中评估心脏结构和功能。在来自BAV联盟的452个BAV病例和来自FraminghamGWAS（全基因组关联研究）的1849个对照中分析了人类GATA6基因变体。使用定量实时聚合酶链反应和免疫组织化学测定小鼠和人体组织中的GATA6表达。在培养的细胞中进行了机理研究。
Gata6杂合子小鼠具有高度渗透的右左（RL）型BAV，人类中最常见的类型。与正常三尖瓣相比，人BAV中的GATA6转录物水平较低。机械上,Gata6单倍体功能不全通过重要信号分子的失调破坏瓣膜重塑和细胞外基质组成,包括基质金属蛋白酶9。Gata6的细胞特异性失活揭示了GATA6在次级心脏视野肌细胞中的重要作用，因为来自Isl-1阳性细胞而不是内皮或神经c细胞的1Gata6等位基因的丢失概括了Gata6杂合小鼠的表型。
这些数据确定了一种新的BAV潜在的细胞和分子机制。最常见的人类BAV动物模型的可用性为阐明BAV发病机理和开发急需的疗法开辟了道路。
在缺乏Gata6等位基因的小鼠中评估心脏结构和功能。在来自BAV联盟的452个BAV病例和来自FraminghamGWAS（全基因组关联研究）的1849个对照中分析了人类GATA6基因变体。使用定量实时聚合酶链反应和免疫组织化学测定小鼠和人体组织中的GATA6表达。在培养的细胞中进行了机理研究。
Gata6杂合子小鼠具有高度渗透的右左（RL）型BAV，人类中最常见的类型。与正常三尖瓣相比，人BAV中的GATA6转录物水平较低。机械上,Gata6单倍体功能不全通过重要信号分子的失调破坏瓣膜重塑和细胞外基质组成,包括基质金属蛋白酶9。Gata6的细胞特异性失活揭示了GATA6在次级心脏视野肌细胞中的重要作用，因为来自Isl-1阳性细胞而不是内皮或神经c细胞的1Gata6等位基因的丢失概括了Gata6杂合小鼠的表型。
这些数据确定了一种新的BAV潜在的细胞和分子机制。最常见的人类BAV动物模型的可用性为阐明BAV发病机理和开发急需的疗法开辟了道路。
