Alagille syndrome (ALGS) is caused by mutations in 1 of the 2 genes — Jagged1 (JAG1) or Notch2 (NOTCH2) — that code for the proteins that are components of the Notch signaling pathway, a highly conserved protein signaling pathway that is crucial for the development of multiple organ systems.1 Mutations in either of these genes disrupt Notch signaling, affecting the normal development of the liver bile ducts, heart, eyes, ears, and spinal column.
Types of Mutations in ALGS
While about 30% to 50% of cases inherit the gene mutation from an affected parent, the majority of cases (50% to 70%) result from random or spontaneous gene mutations and have no family history of the syndrome.2
Read more about ALGS genetic testing.
Most cases of Alagille syndrome (94.3%) are known to be caused by alterations in the JAG1 gene, also referred to as the type 1 (JAG1-associated) mutation.3 About 2.5% of cases are found to be caused by mutations in the NOTCH2 gene, also referred to as the type 2 (NOTCH2-associated) mutation.4 In about 3.2% percent cases, the causative gene mutations have not been characterized.
Pattern of ALGS Inheritance
ALGS is inherited in an autosomal dominant pattern, ie, the mutated copy of the gene dominates over the normal copy of the gene so that the condition is inherited even if only 1 copy of the mutation is present. The offspring of an affected individual has a 50% chance of inheriting the Alagille-associated gene mutation and developing the syndrome.5
The type and severity of signs and symptoms associated with ALGS may differ due to variable expressivity, even when the affected individuals carry the same mutation or belong to the same family. The symptoms may range from mild to severe for different individuals carrying the same mutation.6
Causative Genes in ALGS
Both JAG1 and NOTCH2 proteins are cell-surface proteins that are part of the Notch signaling pathway, which, when activated, alter the transcription of specific genes involved in cellular development and function in a growing embryo. Mutations in either of these proteins’ genes may disrupt Notch signaling, causing errors in embryonic development that result in defective bile ducts in the liver, cardiac defects, and altered vertebral and facial features.
The JAG1 Gene and ALGS
The JAG1 gene codes for the Jagged1 protein, which is expressed on the cellular surface and functions as a ligand for the receptor proteins called Notch receptors (Notch 1, 2, 3, and 4) present on the neighboring cells. When the Jagged1 ligand attaches to its receptors on adjacent cells, it activates the Notch signaling pathway that alters the transcription of specific genes, thereby affecting the cell fate determination and development in a growing embryo, especially in cells being formed for the heart, liver, eyes, ears, and spinal column. The Jagged1 protein also plays a role in hematopoiesis.7
About 694 mutations in the JAG1 gene have been associated with ALGS. While most mutations result in an abnormal shorter Jagged1 protein that is missing the transmembrane domain, other mutations interfere with the transport of the protein to the cell membrane. Due to the lack of Jagged1 protein on the cell surface, there is no activation of Notch signaling that disrupts normal embryonic development. The protein expressed by the normal copy of the JAG1 gene is insufficient in preventing the appearance of syndrome (haploinsufficiency).7
The NOTCH2 Gene and ALGS
The NOTCH2 gene codes for the Notch2 receptor protein that binds to ligand proteins present on adjacent cells. Upon ligand attachment, the Notch2 receptor sends intracellular signals for the normal development and function of cells, especially those of the heart, liver, kidneys, teeth, bones, and other structures in a growing embryo. Following birth, Notch2 signaling plays a role in tissue repair, immune system function, and bone remodeling.
About 19 mutations in the NOTCH2 gene have been identified in individuals with ALGS. Some of these mutations can alter the normal protein shape so that the defective receptor is unable to undergo activation by the Jagged1 ligand protein, thereby disrupting the Notch2 signaling and affecting the development of numerous organs and tissues.8
- Symptoms & causes for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed June 21, 2021.
- Alagille syndrome. MedlinePlus. Updated April 7, 2021. Accessed June 21, 2021.
- 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, Rajagopalan 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
- Alagille syndrome. National Organization for Rare Disorders. Accessed June 21, 2021.
- Spinner NB, Gilbert MA, Loomes KM, Krantz ID. Alagille syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington; 2000. Updated December 12, 2019. Accessed June 21, 2021.
- JAG1 gene. MedlinePlus. Updated August 18, 2020. Accessed June 21, 2021.
- Gilbert MA, Loomes KM. Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts. Transl Gastroenterol Hepatol. 2021;6:22. doi:10.21037/tgh-2020-03
Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.