Alagille syndrome (AGS; Mendelian Inheritance in Man 118450) was described more than 30 years ago as a genetic entity characterized by five major features: chronic cholestasis owing to paucity of interlobular bile ducts, peripheral pulmonary stenosis, butterfly-like vertebrae, posterior embryotoxon, and peculiar facies. Alagille syndrome is inherited in an autosomal dominant manner. The high variability of phenotypic findings led rapidly to a modification of the definition. It is widely accepted that individuals presenting with three of the five main features are considered to have AGS. As initial descriptions, minor less-frequent features were added to the list of criteria including other manifestations involving previously identified targets such as the vascular system, the bones, and the eye, and those involving previously unspecified organs or tissues such as the ear, the pancreas, the kidney, and the intestine. The disease-causing gene is Jagged1 that encodes a protein belonging to the family of Notch ligands. There are now more than 226 described intragenic mutations of the JAGGED1 (JAG1) gene, none corresponding to the intracellular part of the protein. JAG1 mutations are identified in roughly 70% of patients meeting criteria for AGS leaving 30% of patients with no detectable alteration of the coding sequence. As most often in human disease there is no genotype/phenotype correlation.
The expression pattern of JAG1 had enabled the manifestations already observed to be explained and to open a field for investigations to evidence other system involvement. The role of the Notch signaling pathway during normal liver and bile duct development is still unclear and the mechanism of action of the mutated JAG1 gene remains to be elucidated. Haploinsufficiency is supported by the entire deletion of JAG1 in few patients, but a dominant negative effect of a truncated JAG1 protein cannot be excluded.
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