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Alagille syndrome (ALGS) is primarily caused by jagged1 (JAG1) mutations, 70% of which are protein‑truncating mutations. However, no mutation hotspots have been discovered, and the pathogenic mechanism is not fully understood. The aim of the present study was to analyze two protein‑truncating JAG1 mutations detected in three Chinese ALGS patients. Mutation c.1261delT (p.Cys421Valfs) was identified in one patient with hepatic damage, xanthomas, facial abnormalities and cardiovascular defects, which was inherited from his father. The other mutation, c.1382_1383delAC (p.Asp461Glyfs), carried by a pair of monozygotic twins with hepatic damage, facial abnormalities and cardiovascular defects, was de novo. Biological experiments were performed to study the characteristics and function of these mutations. The p.Cys421Valfs and p.Asp461Glyfs mutant proteins appeared to be truncated in western blotting using anti‑Flag bound to the N‑terminus of JAG1. The RBP‑Jκ‑responsive reporter gene assay was used to investigate the ability of mutant JAG1 proteins to activate the Notch signaling pathway. The mutant proteins had a lower luciferase activity than the wild‑type, indicating impaired transcriptional activation ability. Western blotting using soluble JAG1 from the culture medium revealed that the expression levels of the mutant proteins were lower than that of the wild‑type, suggesting that less mutant JAG1 protein underwent proteolytic cleavage than the wild‑type. In conclusion, these two loss‑of‑function JAG1 mutations may be associated with ALGS manifestations in these patients.

JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families