The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome

Alagille syndrome (AGS) is a congenital multi-system anomaly mainly charact erized by paucity of intrahepatic bile ducts caused by haploin-sufficiency of the Jagged 1 gene (JAG1). To explore the relationship between genotype a nd phenotype, we analyzed the JAG1 gene in 25 Japanese AGS families at the genomic DNA level and identified 15 point mutations and one large deletion. Analysis of the genotype and phenotype strongly indicated that the Delta/S errate/Lag-2 (DSL) domain in JAG1 protein played an essential role in deter mining the severity of the liver disorder. In four sporadic cases, missing an entire DSL domain in mutant JAG1 resulted in progressive liver failure a nd all 4 patients needed a liver transplant at a very young age. This corre lation was further confirmed by statistical analysis (chi (2) = 9.143, p < 0.001). Our finding demonstrated that the DSL domain in JAG1 appears to be essential for normal liver development and function.