GENE MAPPING IN INHERITED MURINE INTERSTITIAL NEPHRITIS

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Interstitial nephritis is the final common pathway to all forms of chronic renal failure. The central pathophysiologic process is a destructive immune reaction directed towards the kidney's own tubulointerstitium. The goal of this project is to identify the gene which causes an inherited form of interstitial nephritis in susceptible mice (termed "kd" for kidney disease). The disease is inherited as an autosomal recessive genotype and the inheritance and phenotype has similarities to a human disease, juvenile nephronophthisis/medullary cystic disease which some have argued has an auto immune component to its expression. The overall strategy used to identify this kd gene will be one that involves positional cloning. Preliminary linkage studies from breedings of backcross progeny has placed the gene between two microsatellite markers on mouse chromosome 10. To further narrow the critical region, additional polymorphisms will be identified by genetically directed representational difference analysis (GDRDA). A contiguous array (contig) of overlapping yeast artificial chromosome (YAC) and bacterial artificial chromosome (BAG) clones will be constructed. Once the contig has been assembled, and the critical region narrowed, candidate genes will be identified by screening of cDNA libraries. The identification of the kd gene 1 and subsequent research into its structure and function will provide an important and novel clue to the mechanism of interstitial injury in the kidney.