GENETIC ANALYSIS OF MODIFIER EFFECTS ON POLYCYSTIC KIDNEY DISEASE

Massachusetts General Hospital, Boston MA

Investigators

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a very common genetic disease affecting 1:1,000. The majority of cases are caused by mutations in PKD1, the gene that encodes polycystin. A striking feature of ADPKD is the marked variation of the phenotype both within and between families. This variability strongly suggests the presence of ' modifier' genes that influence the PKD1-mutant phenotype. Identification of these PKD1 modifiers will enhance our understanding of the molecular pathways that lead to cyst formation and could provide novel targets for therapy of disease. Identification of modifier genes in man is likely to prove a formidable task because of the non-ideal structures of human pedigrees and difficulties in sampling human kidneys to quantitate the phenotype. By contrast, modifier effects can be readily mapped in the mouse where selective mating and inbreeding can be arranged. The Principal Investigator has recently generated a mouse model of PKD1 mutation by targeting a mutation to its murine homologue, Pkd1. Homozygous mice die of severe polycystic disease in utero. When the Pkd1 mutation is bred onto different genetic background, a significant difference in phenotype is observed, strongly suggesting the influence of modifier genes. The co-PI has extensive experience in mapping modifiers of murine cystic diseases. The PI and co-PI will collaborative to map the modifier genes of Pkd1 by canning the mouse genome with a large array of genetic markers. Further refinements of the map positions of these loci will be achieved by genetic mapping of modifier effects on congenic mice. Finally, candidate genes from the genomic interval shown to contain the modifiers will be screened by indirect and direct sequencing methods to identify allelic differences that account for the modifier effects. Once such mouse modifier have been identified, it will be possible to determine the syntenic human genomic regions and to study the role of these modifiers in human disease populations.