Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome

This is the authors' abstract. We don't add key points for this paper.

The loss-of-function mutations of serine protease inhibitor, Kazal type 1 ( SPINK1 ) gene are associated with human chronic pancreatitis, but the underlying mechanisms remain unknown. We previously reported that mice lacking Spink3 , the murine homologue of human SPINK1 , die perinatally due to massive pancreatic acinar cell death, precluding investigation of the effects of SPINK1 deficiency. To circumvent perinatal lethality, we have developed a novel method to integrate human SPINK1 gene on the X chromosome using Cre- lox P technology and thus generated transgenic mice termed “ X-SPINK1 “. Consistent with the fact that one of the two X chromosomes is randomly inactivated, X-SPINK1 mice exhibit mosaic pattern of SPINK1 expression. Crossing of X-SPINK1 mice with Spink3 + / − mice rescued perinatal lethality, but the resulting Spink3 − / − ;XX SPINK1 mice developed spontaneous pancreatitis characterized by chronic inflammation and fibrosis. The results show that mice lacking a gene essential for cell survival can be rescued by expressing this gene on the X chromosome. The Spink3 −/− ;XX SPINK1 mice, in which this method has been applied to partially restore SPINK1 function, present a novel genetic model of chronic pancreatitis.