Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome.

ABSTRACT: Adams-Oliver syndrome (AOS) is a rare congenital disorder characterized by scalp, limb, and cardiovascular defects. Although variants in the NOTCH1 receptor, DLL4 ligand, and RBPJ transcription factor have been implicated in AOS, the driving tissue types and molecular mechanisms by which these variants cause pathogenesis are unknown. Here, we used quantitative binding assays to show that AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding. These findings suggest that AOS-associated RBPJ variants do not function as loss-of-function alleles but instead act as dominant-negative proteins that sequester cofactors from DNA. Consistent with this idea, mice carrying an AOS-associated Rbpj allele develop dominant phenotypes that include increased lethality and card

SUBMITTER: Solano AF 

PROVIDER: S-EPMC12646667 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature