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 numbe r of reports indicate that modifier loci greatly influence the course of di sease progression. Recently we reported a new mouse mutation, kat(2J), on c hromosome (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-kat( 2J)/+ x CAST/Ei)F-2 generation was more variable than that in the parental C57BL/6J strain. This suggested that genetic background or modifier genes a lter 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 hel p to uncover factors that can delay disease progression. These, in turn, co uld be used to design suitable modes of therapy for various forms of human PKD. (C) 1999 Academic Press.