Quantitative trait loci modulate renal cystic disease severity in the mouse bpk model

Numerous mouse models of polycystic kidney disease (PKD) have been describe d in which the mutant phenotypes closely resemble human PKD with regard to morphology, cyst localization, and disease progression. As in human PKD, ge netic background affects the disease phenotype in mouse PKD models. Using e xperimental crosses, these modifying effects can be dissected into discrete genetic factors referred to as quantitative trait loci. The locus for the mouse bpk model was recently mapped to chromosome (Chr) 10. In the course o f these studies, marked variability was observed in the renal cystic diseas e expressed in F2 bpk/bpk homozygotes of a (BALB/c-+/bpk x CAST/Ei)F1 inter cross. The current study was undertaken to further characterize the renal c ystic disease as quantitative trait in this F2 cohort and to map the geneti c modifiers that modulate this phenotype. Whole-genome scans revealed a CAS T-derived locus on distal Chr 6, near D6Mit14, that affects renal cystic di sease severity. Additional analyses identified loci on Chr 1, Chr 2, and Ch r 4, as well as a possible interaction between the Chr 6 locus and a locus on distal Chr 1, near D1Mit17. Interestingly, the gene encoding RGS7, a reg ulator of G protein signaling that binds to polycystin-1, was mapped to the same Chr 1 interval. It is concluded that the severity of the bpk renal cy stic disease phenotype is modulated by multiple loci and possibly by epista tic interaction among them. It is hypothesized that the gene encoding the p olycystin-binding partner RGS7 is a candidate for the Chr 1 genetic modifie r.