Alagille Syndrome and JAGGED1/NOTCH Sequence

Alagille syndrome (AGS) is a highly variable, autosomal dominant disorder that affects the liver, heart, eyes, face, and skeleton. AGS is caused by mutations in JAGGED1, a ligand in the Notch signaling pathway. This pathway is evolutionarily conserved and is involved in cell fate determination. JAGGED1 mutations are identified in more than 90% of clinically diagnosed probands. The majority of the mutations are predicted to result in premature termination of the protein in the extracellular domain. The finding that mutations in JAGGED1 and NOTCH2 cause AGS indicates that Notch signaling is important in the development of the organ systems affected. JAGGED1 expression during normal embryogenesis is widespread in different organ systems and overlaps with the clinical manifestations of AGS. In situ hybridization studies have revealed JAGGED1 expression in the cardiovascular system, renal tubules, eyes, inner ear, pharyngeal arches, mesenchyme of limb buds, and developing nervous system. The study of AGS, in particular in mutant mouse models, has shed enormous light on Jagged–Notch signaling and this in turn has led to further insights into bile duct and cardiac development.