Genetic analysis in mouse models is a means to investigate how modifying loci cause variation in phenotypic expression. We have shown that polycystic kidney disease (PKD) progression in the juvenile cystic kidney (jck) mutation can be influenced by different strain backgrounds. We have localized one of these modifier loci to proximal chromosome 4, in a region previously found to modify disease progression in two different mouse PKD mutations. The evidence that the same locus can influence disease progression in three different murine PKD mutations is of considerable significance, since this suggests this gene might influence PKD severity irrespective of its cause. As such, this locus represents a potential target for therapeutic intervention in human PKD. We propose to continue our ongoing high-resolution localization of this PKD modifier in congenic strains. We also propose to test PKD modifier candidate loci by analysis of genetically targeted mutant mice. Lastly, we propose a novel strategy of analysis using outbred mice that will potentially increase the speed and resolution of genetic localization of modifying loci.
It is well known that the same underlying genetic defect in the PKD gene can have different degrees of severity, presumably as a function of the genetic background of the affected individual. This has led to the recognition of potential importance of modifier loci, which can influence the expression of the PKD defect. Positional cloning of such loci may suggest alternative avenues of therapeutic intervention.