Pathogenetic Mechanisms in Alagille Syndrome


Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a rare autosomal dominant genetic disorder caused by mutations in the Notch signalling pathway. The Notch pathway controls mammalian cell fate during embryonic development but also dictates several cell phenotypes in adult cells. The most common mutations affect the Notch ligand, JAG1 (ALGS type 1) or the NOTCH2 receptor (ALGS type 2) genes, and have a significant impact on multiple organ systems. ALGS primarily affects the liver, heart, skeleton, eye, face and kidney. Using animal models, loss‐of‐function mutations in JAG1 reveal that JAG‐1 haploinsufficiency promotes disease phenotypes in most target tissues. Expression and conditional gene knockout studies of JAG1 have further correlated with tissue‐specific disease phenotypes and have provided significant insight into disease pathogenesis. The majority of JAG1 mutations present in ALGS patients are null alleles, suggesting that JAG1 haploinsufficiency is the primary cause of this disorder in humans.

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 may also 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 foetal 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.
  • Therapy is focused on the consequences of liver disease, as well as the surgical and medical treatment of congenital heart defects.

Keywords: JAGGED1; NOTCH2; mutation; arteriohepatic dysplasia; vasculogenesis; cardiac and vascular dysfunction

Figure 1. The binding of jagged 1 ligand to the notch receptor leads to the ubiquitination of functional notch ligand in the signal‐sending cell by myristoylated neur1. The ubiquitination of jagged 1 and subsequent endocytosis and recycling mediated by myristoylated neur1 leads to regeneration of the signal/ligand (jagged 1), thus maintaining ligand–receptor interaction. Notch receptors engage with activated ligands and are subsequently cleaved by ADAM and γ‐secretase before translocating to the nucleus and derepressing CBF‐1/RBP‐Jκ‐dependent transactivation of Notch target genes (Hey and Hes). Abbreviation: CoA, coenzyme A; CoRs, corepressor; MAML, mastermind‐like; LNRs, Lin–Notch repeats; Mib, mind bomb; CBF‐1/RBP‐Jκ, recombining binding protein suppressor of hairless; Arp2/3, actin‐related proteins 2, 3; wASP, Wiskott–Aldrich syndrome protein; Rab11, Ras‐related protein; DSL, delta, Serrate and Lag‐2; RAM, RBP‐J‐associated module; HD, heterodimerisation domain; P, A PEST sequence proline; E, glutamic acid; S, serine; T, threonine; TAD, topologically associating domains; ANK, ankyrin repeats domain.


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Further Reading

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Zanotti S and Canalis E (2010) Notch and the skeleton. Molecular and Cellular Biology 30: 886–896.

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Hakimjavadi, Roya, Olayinka, Abidemi, Luca, Mariana Di, Guha, Shaunta, Walls, Dermot, Redmond, Eileen M, and Cahill, Paul A(Nov 2017) Pathogenetic Mechanisms in Alagille Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021440.pub2]