Variants and Molecular Mechanism of NOTCH1 in Congenital HeartDiseaseOA

Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation and migration of myocardial mesoderm cells,and different variants are presentin differnt types of CHD.In this review,we aim to provide a detailed description of NOTCH1 structuraldomains and their functions,highlighting NOTCH1 variants in CHD and the molecular mechanisms throughwhich they contribute to CHD occurrence,NOTCH1 has two main domains,the NOTCH extracellulardomain(NBCD)and the NOTCH intracellular domain(NICD).NECD facilitates ligand binding and NICDformation,while the NICD functions as a transcrip tion factor,forming complexes with co-factors in thenucleus to initiate gene transcription.Amnong the NOTCH1 variants associated with CHD occurrence,most are loss-of-function variants.Moreover,most of the variants are located in theEGF-like domain.Themolecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to aloss-of-function or missense variant.In the loss-of-function mutations,NOTCH1 haploinsufficiency is notedand directly reduces theNICD production,causing CHD ocaurrence.In the less common case of missensevariant,only a mild NOTCH1 malfuncticn is observed,but insufficient to directly lead to CHD occurrence.However,when a missense variant is combined with a risk factor,such as exposure to an environmentaltoxin,the cumulative effect can lead to CHD.Understanding the genetic and molecular mechanisms linkingNOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.