Genetic modifiers of polycystic kidney disease in intersubspecific KAT2J mutants.

Polycystic kidney disease (PKD) is a genetically heterogeneous disorder. In addition to the many PKD-causative loci mapped in mouse and human, a number of reports indicate that modifier loci greatly influence the course of disease progression. Recently we reported a new mouse mutation, kat2J, on chromosome (Chr) 8 that causes late-onset PKD and anemia. During the mapping studies it was noted that the severity of PKD in the mutant (C57BL/6J-kat2J/+ x CAST/Ei)F2 generation was more variable than that in the parental C57BL/6J strain. This suggested that genetic background or modifier genes alter the clinical manifestations and progression of PKD. Genome scans using molecular markers revealed three loci that affect the severity of PKD. The CAST-derived modifier on Chr 1 affects both kidney weight and hematocrit. The CAST-derived modifier on Chr 19 affects kidney weight, and the C57BL/6J-derived modifier on Chr 2 affects hematocrit. Additional modifier loci are noted that interact with and modulate the effects of these three loci. The mapping of these modifier genes and their eventual identification will help to uncover factors that can delay disease progression. These, in turn, could be used to design suitable modes of therapy for various forms of human PKD.