MIB2 and spina bifida cystica: In two cases with anencephaly and spina bifida cystica, missense mutations were found In two Notch signaling pathway genes; one in the E3 ubiquitin-protein ligase MIB2, which positively regulates the Delta-mediated Notch signaling, and the other in JAG1, a ligand for multiple Notch receptors (2/2 vs. 16/225 controls, P = 0.028; Fig. 7c).