PDF(Pubmed)
Abstract：
Genome-wide association studies and experimental mouse models implicate the MIB1 and GATA6 genes in congenital heart disease (CHD). Their close physical proximity and conserved synteny suggest that these two genes might be involved in analogous cardiac developmental processes. Heterozygous Gata6 loss-of-function mutations alone or humanized Mib1 mutations in a NOTCH1-sensitized genetic background cause bicuspid aortic valve (BAV) and a membranous ventricular septal defect (VSD), consistent with MIB1 and NOTCH1 functioning in the same pathway. To determine if MIB1-NOTCH and GATA6 interact in valvular and septal development, we generated compound heterozygote mice carrying different Mib1 missense (Mib1K735R and Mib1V943F) or nonsense (Mib1R530X) mutations with the Gata6STOP/+ heterozygous null mutation. Combining Mib1R530X/+ or Mib1K735R/+ with Gata6STOP/+ does not affect Gata6STOP/+ single mutant phenotypes. In contrast, combining Mib1V943F/+ with Gata6STOP/+ decreases the incidence of BAV and VSD by 50%, suggesting a suppressive effect of Mib1V943F/+ on Gata6STOP/+. Transcriptomic and functional analyses revealed that while the EMT pathway term is depleted in the Gata6STOP/+ mutant, introducing the Mib1V943F variant robustly enriches this term, consistent with the Mib1V943F/+ phenotypic suppression of Gata6STOP/+. Interestingly, combined Notch1 and Gata6 insufficiency led to a nearly fully penetrant VSD but did not affect the BAV phenotype, underscoring the complex functional relationship between MIB1, NOTCH, and GATA6 in valvular and septal development.
摘要：
全基因组关联研究和实验性小鼠模型表明MIB1和GATA6基因与先天性心脏病（CHD）有关。它们的紧密物理接近性和保守性表明这两个基因可能参与类似的心脏发育过程。NOTCH1致敏遗传背景中的杂合Gata6功能丧失突变或人源化Mib1突变导致二叶主动脉瓣（BAV）和膜性室间隔缺损（VSD），与MIB1和NOTCH1在同一途径中的功能一致。为了确定MIB1-NOTCH和GATA6在瓣膜和间隔发育中是否相互作用，我们产生了携带不同Mib1错义(Mib1K735R和Mib1V943F)或无义(Mib1R530X)突变的复合杂合子小鼠,其具有Gata6STOP/+杂合子无效突变.将Mib1R530X/+或Mib1K735R/+与Gata6STOP/+组合不影响Gata6STOP/+单突变表型。相比之下,Mib1V943F/+与Gata6STOP/+联合使用可使BAV和VSD的发生率降低50%,提示Mib1V943F/+对Gata6STOP/+有抑制作用。转录组学和功能分析显示，虽然在Gata6STOP/+突变体中EMT途径术语被耗尽，引入Mib1V943F变体有力地丰富了这个术语，与Gata6STOP/+的Mib1V943F/+表型抑制一致。有趣的是,联合Notch1和Gata6功能不全导致几乎完全渗透的VSD，但不影响BAV表型，强调MIB1、NOTCH、和GATA6在瓣膜和间隔发育中。
