The role of these EGF repeats remains unclear, but several previous studies suggest that these EGF repeats play roles in Notch activation: they are required for the DSL domain of Jagged1 to bind to the mammalian Notch2 receptor in biochemical studies [54]; perturbation of the second EGF repeat interferes with Notch signaling in Drosophila [25]; and mutations in these EGF repeats of human Jagged1 are associated with Alagille syndrome [55]. Here, JAG1 is linked to Alagille syndrome.