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oai:repisalud.isciii.es:20.500.12105/258162025-12-18T13:00:45Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Piñeiro-Sabarís, Rebeca author MacGrogan, Donal author de la Pompa, José Luis author Piñeiro-Sabarís, Rebeca author MacGrogan, Donal author de la Pompa, José Luis author 2024-07-15 Genome-wide association studies and experimental mouse models implicate the and 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 loss-of-function mutations alone or humanized 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 ( and ) or () mutations with the heterozygous null mutation. Combining or with does not affect single mutant phenotypes. In contrast, combining with decreases the incidence of BAV and VSD by 50%, suggesting a suppressive effect of on . Transcriptomic and functional analyses revealed that while the EMT pathway term is depleted in the mutant, introducing the variant robustly enriches this term, consistent with the phenotypic suppression of . Interestingly, combined and 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. J Cardiovasc Dev Dis. 2024 Jul 15;11(7):223. https://hdl.handle.net/20.500.12105/25816 39057643 Journal of Cardiovascular Development and Disease BAV CHD GATA6 MIB1 NOTCH1 VSD genetic interactions Intricate MIB1-NOTCH-GATA6 Interactions in Cardiac Valvular and Septal Development.