Alagille syndrome (ALGS) is a rare, autosomal dominant genetic disease characterized by a paucity of intrahepatic bile ducts.1 The disease is caused by mutations in the Jagged 1 (JAG1) or Notch 2 (NOTCH2) gene.2 Depending on which gene is affected, the condition is classified as ALGS1 or ALGS2.3
The Notch Signaling Pathway
The Notch signaling pathway plays a key role in the development of multiple organs.4 Humans have 4 Notch receptors, which are cell surface proteins consisting of covalently linked extracellular and intracellular peptides. The receptors have 5 ligands: Jagged 1, Jagged 2, Delta 1, Delta 3, and Delta 4. The ligands are also cell surface proteins with extracellular, transmembrane, and intracellular domains.5
Binding of these ligands to a Notch receptor triggers cleavage of the intracellular domain of the Notch protein, which moves into the nucleus and interacts with transcription factors that regulate downstream gene expression.6
ALGS1 is the most common type of the disease, accounting for more than 95% of all cases.3 It is caused by mutations in the JAG1 gene, which is located on chromosome 20p12 and encodes the Jagged 1 protein. Jagged 1 protein acts as the ligand of the Notch 2 receptor.7
The types of mutations in the JAG1 gene that have been recorded include whole or partial gene deletions, nonsense and frameshift mutations leading to protein truncation, mutations causing splicing errors, and missense mutations across the coding region of the gene.5 These mutations can lead to the synthesis of nonfunctional Jagged 1 protein. They can also interfere with the trafficking of the Jagged 1 protein to the cell surface, so that it cannot interact with the Notch 2 receptor.
Some researchers have proposed a dominant-negative mechanism in which proteins encoded by mutated JAG1 still interact with Notch 2 but cannot trigger downstream gene expression, thereby blocking interaction of the receptor with healthy Jagged 1 protein and thus the entire signaling cascade.8 This would explain why a single copy of the mutation is sufficient to cause the disease (ie, autosomal dominant inheritance).
Fewer than 1% of patients have ALGS2. This type is caused by a mutation in NOTCH2, which is located on chromosome 1p12.9 Studies have recorded missense mutations, splicing errors, and nonsense mutations in the NOTCH2 gene in patients with ALGS2. These mutations can occur in the portion of the gene encoding either the intracellular or the extracellular domain of the Notch 2 protein.5
The exact mechanism of action of NOTCH2 mutations is not clear, but it is thought that they impair the signaling ability of the protein.
Symptoms of ALGS1 and ALGS2
The symptoms of ALGS1 and ALGS2 overlap and include pruritus, jaundice, xanthomas, congenital heart defects, posterior embryotoxon, butterfly vertebrae, kidney dysplasia, renal tubular acidosis, vesicoureteral reflux, hepatomegaly, splenomegaly, and typical facial features, such as a large forehead, deep-set eyes, and a pointed chin and nose.2
Some researchers think the phenotypic profile of ALGS caused by mutations in the NOTCH2 gene may differ from that of ALGS caused by JAG1 mutations.10 However, not enough data are available to make a clear distinction between the 2 types of this disease on the basis of symptoms alone. The only definitive way to identify ALGS1 and ALGS2 is by genetic testing.
Genetic Testing for ALGS1 and ALGS2
The diagnosis of ALGS can be confirmed with molecular genetic testing for mutations in the JAG1 and NOTCH2 genes.
Although genetic testing for these mutations is now widely available and increasingly reliable, it may not show any mutations on either the JAG1 or NOTCH2 gene in some of the patients who meet the classic criteria for a diagnosis of ALGS.11 These include a paucity of intrahepatic bile ducts plus 3 of the following: cholestasis, typical facial features, congenital heart disease, skeletal abnormalities (including “butterfly” vertebrae), and posterior embryotoxon.12
If molecular genetic testing reveals a mutation in either JAG1 or NOTCH2, a genetic test to detect the same mutation in the parents or other family members of the patient is recommended.13 This can ensure that adequate genetic counseling is provided to help the patient and family members understand how the test results will affect their lives and guide their future reproductive choices. Genetic counseling can also be offered before genetic testing so that families can decide whether or not they wish to proceed with genetic testing. The fact that approximately 60% of cases of ALGS occur as a result of de novo mutations, and that germline mosaicism occurs at a frequency up to 8%, should be taken into account when genetic counseling is provided.14
- Jesina D. Alagille syndrome: an overview. Neonatal Netw. 2017;1;36(6):343-347. doi:10.1891/0730-08126.96.36.1993
- Symptoms & causes for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Reviewed January 2019. Accessed June 14, 2021.
- Singh SP, Pati GK. Alagille syndrome and the liver: current insights. Euroasian J Hepatogastroenterol. 2018;8(2):140-147. doi:10.5005/jp-journals-10018-1280
- Siebel C, Lendahl U. Notch signaling in development, tissue homeostasis, and disease. Physiol Rev. 2017;1;97(4):1235-1294. doi:10.1152/physrev.00005.2017
- Gilbert MA, Spinner NB. Alagille syndrome: genetics and functional models. Curr Pathobiol Rep. 2017;5(3):233-241. doi:10.1007/s40139-017-0144-8
- Bray SJ. Notch signalling in context. Nat Rev Mol Cell Biol. 2016;17(11):722-735. doi:10.1038/nrm.2016.94
- JAG1 gene. MedlinePlus. Updated August 18, 2020. Accessed June 14, 2021.
- Boyer-Di Ponio J, Wright-Crosnier C, Groyer-Picard MT, et al. Biological function of mutant forms of JAGGED1 proteins in Alagille syndrome: inhibitory effect on Notch signaling. Hum Mol Genet. 2007;15;16(22):2683-2692. doi:10.1093/hmg/ddm222
- 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
- McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79(1):169-173. doi:10.1086/505332
- Alagille syndrome. National Organization for Rare Disorders. Accessed June 14, 2021.
- Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75-82. doi:10.2147/TACG.S86420
- Diagnosis for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Reviewed January 2019. Accessed June 14, 2021.
- 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.