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

• Published in: Clinical genetics Vol. 59; no. 5; pp. 330 - 337
• Main Authors: Yuan, Zr, Okaniwa, M, Nagata, I, Tazawa, Y, Ito, M, Kawarazaki, H, Inomata, Y, Okano, S, Yoshida, T, Kobayashi, N, Kohsaka, T
• Format: Journal Article
• Language: English
• Published: Copenhagen Munksgaard International Publishers 01.05.2001; Blackwell
• Subjects: Alagille syndrome; Alagille Syndrome - genetics; Alagille Syndrome - pathology; Binding Sites - genetics; Biological and medical sciences; Calcium-Binding Proteins; Complex syndromes; Delta/Serrate/Lag-2 domain; DNA - chemistry; DNA - genetics; DNA Mutational Analysis; Family Health; Female; Genotype; human Jagged 1 gene; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Liver - pathology; Male; Medical genetics; Medical sciences; Membrane Proteins; Mutation; Phenotype; Polymorphism, Single-Stranded Conformational; Proteins - genetics; Serrate-Jagged Proteins; Severity of Illness Index; Human; Portal circulation disease; Family study; Pathogenesis; Cardiovascular disease; Arteriohepatic dysplasia; Genotype; Congenital disease; Genetic determinism; Vascular disease; Phenotype; Gene; Digestive diseases; Severity score; Mutation
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1034/j.1399-0004.2001.590506.x

Alagille syndrome (AGS) is a congenital multi‐system anomaly mainly characterized by paucity of intrahepatic bile ducts caused by haploinsufficiency of the Jagged 1 gene (JAG1). To explore the relationship between genotype and 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/Serrate/Lag‐2 (DSL) domain in JAG1 protein played an essential role in determining the severity of the liver disorder. In four sporadic cases, missing an entire DSL domain in mutant JAG1 resulted in progressive liver failure and all 4 patients needed a liver transplant at a very young age. This correlation was further confirmed by statistical analysis (χ2=9.143, p<0.001). Our finding demonstrated that the DSL domain in JAG1 appears to be essential for normal liver development and function.