Pathogenetic Mechanisms in Alagille Syndrome

Abstract Alagille syndrome (AGS), also known as arteriohepatic dysplasia, is an autosomal dominant disorder characterised by a paucity of interlobular bile ducts and chronic cholestasis, cardiac and vascular dysfunction, skeletal and ocular abnormalities and a characteristic facial appearance. Most cases of AGS in patients harbour mutations in either the JAGGED‐1 ( JAG1 ) or Notch2 receptor ( NOTCH2 ) gene. The JAG1 gene encodes a ligand for the Notch receptor. The Notch signalling network controls mammalian cell fate during embryonic development and also dictates several cell phenotypes in adult cells. The majority of JAG1 mutations seen in AGS patients are null alleles, suggesting JAG1 haploinsufficiency as a primary cause of this disorder. Key Concepts: Alagille syndrome is an autosomal dominant disorder with variable expression. Alagille syndrome and associated abnormalities include those of the liver, heart, eye, skeleton and kidneys and characteristic facial features. Mild‐to‐moderate mental retardation also may be present. Alagille syndrome is most often caused by a mutation, or defect, in the JAGGED1 (JAG1) or NOTCH2 receptor gene. Alagille syndrome has been mapped to the 20p12‐jagged‐1 locus, JAG1, which encodes a ligand critical to the NOTCH gene–signalling cascade that is important in fetal development. Notch signalling has been found to regulate formation of three‐dimensional intrahepatic biliary architecture in murine models and vascular cell phenotype during development. A minority (6–7%) of patients have complete deletion of JAG1, and approximately 15–50% of mutations are spontaneous. Deaths in people with Alagille syndrome are most often caused by liver failure, heart problems and blood vessel abnormalities.