High-resolution genetic localization of a modifying locus affecting disease severity in the juvenile cystic kidneys (jck) mouse model of polycystic kidney disease

We have previously demonstrated that a locus on proximal Chr 4 modifies disease severity in the juvenile cystic kidney (jck) mouse, a model of polycystic kidney disease (PKD) that carries a mutation of the Nek8 serine-threonine kinase. In this study, we used QTL analysis of independently constructed B6.D2 congenic lines to confirm this and showed that this locus has a highly significant effect. We constructed sub-congenic lines to more specifically localize the modifier and have determined it resides in a 3.2 Mb interval containing 28 genes. These include Invs and Anks6, which are both excellent candidates for the modifier as mutations in these genes result in PKD and both genes are known to genetically and physically interact with Nek8. However, examination of strain-specific DNA sequence and kidney expression did not reveal clear differences that might implicate either gene as a modifier of PKD severity. The fact that our high-resolution analysis did not yield an unambiguous result highlights the challenge of establishing the causality of strain-specific variants as genetic modifiers, and suggests that alternative strategies be considered.