Abstract
Congenital heart disease (CHD) is one of the most common birth defects in humans, but its genetic etiology remains largely unknown despite decades of research. The Notch signaling pathway plays critical roles in embryonic cardiogenesis. Mind bomb 1 (Mib1) is a vital protein that activates the Notch signaling pathway through promoting ubiquitination, endocytosis and subsequent activation of Notch ligands. Previous studies show that Mib1 knockout in mice completely abolishes Notch signaling, leading to cardiac deformity. However, the function of MIB1 and its potential disease-causing mutations are poorly studied in human CHD. In this research, we identified four novel non-synonymous heterozygous rare mutations of MIB1 from 417 Han Chinese CHD patients. The following biochemical analyses revealed that mutations p.T312K fs*55 and p.W271G significantly deplete MIB1's function, resulting in a lower level of JAGGED1 (JAG1) ubiquitination and Notch signaling induction. Our results suggest that pathologic variants in MIB1 may contribute to CHD occurrence, shedding new light on the genetic mechanism of CHD in the context of the Notch signaling pathway.