GENETIC IDENTIFICATION OF 2 MAJOR MODIFIER LOCI OF POLYCYSTIC KIDNEY-DISEASE PROGRESSION IN PCY MICE

Unlike the uniform disease progression in inbred animals, polycystic k idney disease (PKD) progression within human families can be highly va riable, This may be due to environmental or genetic factors or both, T o determine if PKD severity can be influenced by modifier genes, we ca rried out an intercross between DBA/2-pcy/pcy and Mus m. castaneous in volving 3,105 6-wk-old F2 mice. Large differences in PKD severity were observed in this cross. In addition, 23/800 phenotypically normal mic e were pcy/pcy genotypically. These results demonstrated that PKD prog ression in pcy/pcy mice is a quantitative trait that is strongly modul ated by modifier genes. Whole genome quantitative trait loci mapping o f 114 selected pcy/pcy mice (68 with the mild PKD and 46 with severe P KD) identified two loci, MOP1 and MOP2 that strongly modulate PKD prog ression. MOP1 (max LOD score = 10.3 at D4Mit111) and MOP2 (max LOD sco re = 13.8 at D16Mit1) accounted for 36.7 and 46.8% of the phenotypic v ariance, respectively. Two-factor ANOVA of the phenotypes and genotype s of all 673 pcy/pcy mice from our cross indicated that MOP1 and MOP2 alleles regulate PKD progression in a complex additive manner. Charact erization of these novel modifying loci may provide additional insight s into the pathogenesis of polycystic kidney diseases.