@Article{chd.2025.064366,
AUTHOR = {Hongqun Xiang, Jian Zhuang, Luoning Bao, Yan Shi},
TITLE = {Variants and Molecular Mechanism of NOTCH1 in Congenital Heart Disease},
JOURNAL = {Structural and Congenital Heart Disease},
VOLUME = {20},
YEAR = {2025},
NUMBER = {2},
PAGES = {245--263},
URL = {http://www.techscience.com/schd/v20n2/60824},
ISSN = {3071-1738},
ABSTRACT = { Congenital heart disease (CHD) is the most common birth defect, with 34% of cases attributed to genetic variants. NOTCH1, a multi-domain transmembrane protein, regulates heart development by controlling the differentiation and migration of myocardial mesoderm cells, and different variants are present in different types of CHD. In this review, we aim to provide a detailed description of NOTCH1 structural domains and their functions, highlighting NOTCH1 variants in CHD and the molecular mechanisms through which they contribute to CHD occurrence. NOTCH1 has two main domains, the NOTCH extracellular domain (NECD) and the NOTCH intracellular domain (NICD). NECD facilitates ligand binding and NICD formation, while the NICD functions as a transcription factor, forming complexes with co-factors in the nucleus to initiate gene transcription. Among the NOTCH1 variants associated with CHD occurrence, most are loss-of-function variants. Moreover, most of the variants are located in the EGF-like domain. The molecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to a loss-of-function or missense variant. In the loss-of-function mutations, NOTCH1 haploinsufficiency is noted and directly reduces the NICD production, causing CHD occurrence. In the less common case of missense variant, only a mild NOTCH1 malfunction 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 environmental toxin, the cumulative effect can lead to CHD. Understanding the genetic and molecular mechanisms linking NOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.},
DOI = {10.32604/chd.2025.064366}
}