Alagille syndrome (ALGS) is a rare genetic disease possibly affecting multiple systems throughout the body, including the hepatic, cardiovascular, skeletal, and renal. The underlying cause of the disease has been linked to problems in the Notch signaling pathway found in numerous cells. Alagille Syndrome pathophysiology is characterized in part by a wide range in the phenotypic manifestations of the disease, even within similar genotypes, indicating other mechanisms’ involvement in the severity of the disease as well.
The Notch signaling pathway involves 4 transmembrane proteins (Notch 1 through Notch 4) and 5 transmembrane ligands, including Jagged1 (JAG1), JAG2, Delta-like1 (DLL1), DLL3, and DLL4.1 The pathway is used in intercellular signaling, where a transmembrane ligand-expressing cell activates a Notch receptor on a neighboring cell, upregulating the expression of the ligand on the signaling cell and the receptor on the receiving cell.2 Binding of the ligand and receptor initiates a series of enzyme cleavages that results in the intracellular domain of the Notch receptor translocating to the nucleus, where it interacts with a number of transcriptional factors. The Notch pathway appears to play a role in lateral inhibition and boundary formation,2 which can help drive morphogenesis and ultimately organogenesis in different types of cells.3
In patients with ALGS, the predominant mutations (94%-96%) involve the JAG1 gene, whereas 2% to 3% involve the NOTCH2 gene.4
Liver Symptoms in ALGS
Liver-related symptoms, including bile duct paucity and cholestasis, are some of the major clinical features presented in patients with ALGS. The exact mechanism leading to a paucity of bile ducts is not fully elucidated, but ex vivo and animal studies indicate it is related to the formation of the ductal plate from hepatoblasts located close to the portal veins.5 During the first 7 to 10 weeks of fetal development, portal vein mesenchymal cells begin expressing JAG1 and the surrounding liver-progenitor cells (hepatoblasts) begin expressing NOTCH2.5 Notch-dependent signaling between these cells then prompts the hepatoblasts to differentiate into cholangiocytes, the cells that line the bile ducts, and form ductal plates.
Under normal conditions, these ductal plates then develop into the intrahepatic bile ducts (IHBD) through tubulogenesis as gestation and infancy progress. In animal models of ALGS, the ductal plates often appear too disorganized to form ducts, and the cells lack expression of the transcriptional factor SRY-related HMG box 9 (SOX-9), which is a biomarker of ductal plate formation.5 Notch signaling may also play a role in the differentiation of smooth muscle cells in the vasculature, as evidenced by lower levels of alpha smooth muscle actin-positive cells in the hepatic arteries and portal veins of murine models of ALGS.5 The lack of these cells could contribute to the lack of SOX-9–expressing ductal plate cells.5
Some evidence suggests there may be some Notch-independent pathways that can attempt to compensate for the lack of IHBDs, through conversion of some hepatocytes into cholangiocytes in an attempt to form de novo IHBDs.5 The exact mechanism of this action is unknown but may involve signaling of transforming growth factor β, yes-associated protein, and beta-catenin.5 This de novo formation could contribute to the variable severity of bile duct paucity among patients with the same genetic mutations.
Bile duct paucity results in a number of symptoms seen in patients with ALGS. The backup of bile leads to chronic cholestasis that can present as jaundice, pruritus, and xanthomas.6 Cholestasis can also lead to malnutrition through malabsorption of dietary fats and fat-soluble vitamins, ultimately leading to failure to thrive.6
Cardiovascular Symptoms in ALGS
Several cardiovascular symptoms have been seen in patients with ALGS. The 2 most commonly reported in the literature are peripheral pulmonary stenosis and tetralogy of Fallot.7 Studies in animals have suggested that JAG1 and/or NOTCH2 signaling may be involved in the development of neural crest cells and the smooth muscles of the pulmonary arteries.2 Studies in mice have also shown that ablation of the Hey2 gene, a downstream target of the Notch signaling pathway, resulted in tetralogy of Fallot and pulmonary stenosis, implicating its involvement in ALGS as well.
Patients with ALGS may exhibit extracardiac vascular issues as well. JAG1 has been shown to be present in angiogenic stalk cells and expressed in endothelial and smooth muscle cells during vascular remodeling.8 However, the exact mechanisms of JAG1 mutations leading to the vascular issues seen in ALGS are not fully known.
Skeletal and Craniofacial Anomalies in ALGS
Patients with ALGS often experience skeletal abnormalities and characteristic facies. The most common skeletal anomaly found in patients with ALGS is ‘butterfly’: ≥1 vertebrae9 that involves 2 hemivertebrae, with a cartilaginous cleft between.10 Other spinal abnormalities reported include spina bifida occulta, narrowing of the lumbar interpedicular distances, vertebral fusions, and the absence of the 12th rib.1 The exact mechanism underlying these congenital bone defects is unknown, although evidence has shown that the Notch signaling pathway plays a role in skeletal homeostasis as well as bone development through the genesis of chondrocytes, osteoclasts, and osteoblasts.11
Patients with ALGS often exhibit very characteristic facies, including deep-set and widely spaced eyes, a prominent forehead, triangular face shape, and a pointed chin.12 Some initial hypotheses proposed these facial characteristics may be a result of cholestasis; however, other disorders that result in cholestasis do not have similar facial features.13 The Notch signaling pathway has been shown to be active in embryonic neural crest cells that give rise to the cranial bones.11 Studies in mice found that deletion of JAG1 in these crest cells resulted in a reduced maxilla.14 Loss of JAG1 in zebrafish resulted in changes to their facial patterns, too.11 Research has also shown that JAG1 is important in the correct closure of the cranial suture, and its loss can result in craniosynostosis, another feature seen in some patients with ALGS.11
Renal Symptoms in ALGS
A number of different renal abnormalities have also been seen in patients with ALGS, including renal tubular acidosis, renal dysplasia, vesicoureteral reflux, and urinary obstruction.15 The Notch pathway has been shown to be expressed during renal development in murine models and plays a role in downstream regulation of nephron segmentation and glomerular segmentation.12
- Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20(3):251-257. doi:10.1038/ejhg.2011
- Niessen K, Karsan A. Notch signaling in cardiac development. Circ Res. 2008;102(10):1169-1181. doi:10.1161/CIRCRESAHA.108.174318
- Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770-776. doi:10.1126/science.284.5415.770
- Mitchell E, Gilbert M, Loomes KM. Alagille syndrome. Clin Liver Dis. 2018;22(4):625-641. doi:10.1016/j.cld.2018.06.001
- Huppert SS, Campbell KM. Bile duct development and the notch signaling pathway. In: Kamath BM, Loomes KM, eds. Alagille Syndrome. Springer International Publishing; 2018:11-31. Accessed June 22, 2021.
- Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67(2):148-156. doi:10.1097/MPG.0000000000001958
- McElhinney DB, Krantz ID, Bason L, et al. Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome. Circulation. 2002;106(20):2567-2574. doi:10.1161/01.cir.0000037221.45902.69
- Hofmann JJ, Iruela-Arispe ML. Notch signaling in blood vessels: who is talking to whom about what? Circ Res. 2007;100(11):1556-1568. doi:10.1161/01.RES.0000266408.42939.e4
- Sanderson E, Newman V, Haigh SF, Baker A, Sidhu PS. Vertebral anomalies in children with Alagille syndrome: an analysis of 50 consecutive patients. Pediatr Radiol. 2002;32(2):114-119. doi:10.1007/s00247-001-0599-x
- Katsuura Y, Kim HJ. Butterfly vertebrae: a systematic review of the literature and analysis. Global Spine J. 2019;9(6):666-679. doi:10.1177/2192568218801016
- Pakvasa M, Haravu P, Boachie-Mensah M, et al. Notch signaling: Its essential roles in bone and craniofacial development. Genes Dis. 2021;8(1):8-24. doi:10.1016/j.gendis.2020.04.006
- Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol. 2012;23(4):450-457. doi:10.1016/j.semcdb.2012.01.010
- Kamath BM, Loomes KM, Oakey RJ, et al. Facial features in Alagille syndrome: specific or cholestasis facies? Am J Med Genet. 2002;112(2):163-170. doi:10.1002/ajmg.10579
- Humphreys R, Zheng W, Prince LS, et al. Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients. Hum Mol Genet. 2012;21(6):1374-1383. doi:10.1093/hmg/ddr575
- Kamath BM, Podkameni G, Hutchinson AL, et al. Renal anomalies in Alagille syndrome: a disease-defining feature. Am J Med Genet A. 2012;158A(1):85-89. doi:10.1002/ajmg.a.34369
Reviewed by Eleni Fitsiou, PhD, on 7/1/2021.