Alagille syndrome (ALGS) is a rare disease with autosomal dominant inheritance that mainly affects the liver.1 It is characterized by bile duct paucity and consequently bile buildup in the liver. The disease is caused by mutations that disrupt the Notch signaling pathway.
Mutations in the JAG1 and NOTCH2 Genes
Almost 90% of ALGS cases are caused by mutations in the JAG1 gene, which is located on chromosome 20p12.2 The spectrum of mutations in this gene is wide and includes total gene deletions, mutations leading to protein truncation and splicing errors, and missense mutations across the coding region of the gene that result in disrupted function of the Jagged 1 protein.
The most common mutations in the JAG1 gene cause protein truncation.3 The second most common are missense mutations that result in disruption of the amino acid sequence of the protein. The third most common mutations are total deletions of the JAG1 gene. Finally, a small proportion of mutations are splice site mutations that alter function of the Jagged 1 protein.
A very small number of patients with ALGS have a mutation in the NOTCH2 gene, which
encodes the receptor for the Jagged 1 protein. These can be missense, nonsense, or splicing mutations.4
The JAG1/NOTCH2 Signaling Pathway
The JAG1 and NOTCH2 genes both code for single‐pass transmembrane proteins.
The extracellular domain of the Jagged 1 protein binds to a Notch 2 receptor on the surface of an adjacent cell. This causes an ADAM family metalloprotease, ADAM10, to cleave the Notch protein outside the membrane. The intracellular portion of the Notch 2 protein is then further cleaved by another enzyme, called γ-secretase. The cleaved intracellular domain of Notch moves into the nucleus and interacts with transcription factors that regulate downstream gene expression.5
When the JAG1 or NOTCH2 gene is mutated, the JAG1/NOTCH2 signaling pathway is disrupted, resulting in errors of downstream gene expression that cause the symptoms of ALGS. The type of mutation in the JAG1 gene does not appear to correlate with symptom type or severity.3
Genetic Modifiers and Severe Symptoms
The severity of ALGS symptoms often varies significantly among members of the same family, even if they all have the same pathogenic variant of the JAG1 gene.
This can possibly be explained by the presence of genetic modifiers. Research has shown that Lunatic Fringe, Radical Fringe, Manic Fringe, and POGLUT1, which are glycosyltransferases involved in the glycosylation and transport of mature Jagged 1 and Notch 2 proteins to the cell membrane, function as genetic modifiers of Notch and alter ligand-receptor affinity in a dose-dependent manner.3
Another genetic modifier, the thrombospondin 2 gene (THBS2), also appears to affect the severity of liver disease in patients with ALGS.6 This gene encodes an extracellular matrix protein that can interact with Notch signaling and is expressed in bile ducts. Research has shown that people with a pathogenic JAG1 variant and increased THBS2 expression are at higher risk for relatively severe liver disease.
Pathophysiology of Alagille Syndrome
The exact role of the Jagged 1 protein in the development of new bile ducts during infancy is not known. It is also not clear how disruption of the JAG1/NOTCH2 signaling pathways leads to a decreased number of hepatic bile ducts.
According to some researchers, ALGS is primarily a vasculopathy, and at least some of its effects are caused by abnormalities of angiogenesis and the vascular system.2 For example, the abnormal formation of mature bile ducts could be the result of abnormal development of the intrahepatic arterial network.7 It is known that the Notch signaling pathway plays a major role in angiogenesis, providing support for this idea and possibly explaining the pathophysiology of the disease.
Inheritance of Alagille Syndrome
Although ALGS is inherited in an autosomal dominant pattern, meaning that people with a mutated gene have a 50% chance of passing it onto their children, 60% of ALGS cases appear to be the result of de novo mutations that occur during either gametogenesis or early embryonic development.2 Research has shown that germline mosaicism may occur at a frequency of up to 8% in ALGS.8 This fact should be taken into account when genetic counseling is provided.
- Jesina D. Alagille syndrome: an overview. Neonatal Netw. 2017;1;36(6):343-347. doi:10.1891/0730-08184.108.40.2063
- Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20(3):251-257. doi:10.1038/ejhg.2011.181
- Gilbert MA, Bauer RC, Rajagopala R, et al. Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019;40(12):2197-2220. doi:10.1002/humu.23879
- Kamath BM, Bauer RC, Loomes KM, et al. NOTCH2 mutations in Alagille syndrome. J Med Genet. 2012;49(2):138-144. doi:10.1136/jmedgenet-2011-100544
- Groot AJ, Habets R, Yahyanejad S, et al. Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins. Mol Cell Biol. 2014;34(15):2822-2832. doi:10.1128/MCB.00206-14
- Tsai EA, Gilbert MA, Grochowski CM, et al. THBS2 is a candidate modifier of liver disease severity in Alagille syndrome. Cell Mol Gastroenterol Hepatol. 2016;2(5):663-675.e2. doi:10.1016/j.jcmgh.2016.05.013
- Libbrecht L, Cassiman D, Desmet V, Roskams T. The correlation between portal myofibroblasts and development of intrahepatic bile ducts and arterial branches in human liver. Liver. 2002;22(3):252-258. doi:10.1046/j.0106-9543.2002.01674.
- Giannakudis J, Röpke A, Kujat A, et al. Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Eur J Hum Genet. 2001;9(3):209-216. doi:10.1038/sj.ejhg.5200613
Reviewed by Eleni Fitsiou, PhD, on 7/1/2021.