International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E10 Epistatic Interactions of Loci that Modify the Severity of PKD in the jck Mouse

David R. Beier and Shiei Kuida. Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

We have previously shown that polycystic kidney disease (PKD) progression in the juvenile cystic kidney (jck) mutation can be influenced by an epistatic interaction. This was suggested by the observation that F2 progeny of a C57BL/6 x DBA/2 (B6xD2) intercross have a wide range of disease severity, while affected mice in the parental B6 or D2 backgrounds have mild disease. We have now proven that the severe disease phenotype is a recessive trait, since C57BL/6 x DBA/2 (B6xD2) F1 jck mice have very mild PKD. When heterozygous mice from this cross are intercrossed, the variable phenotype is recapitulated in their F2 progeny, which supports the model that an interaction of parental alleles causes severe PKD.

In our previous study, a B6-derived modifying locus was mapped to chromosome 1 with a highly significant LOD score; however, the interacting D2 locus was not definitively mapped. This was likely due to the fact that the statistical effect of this locus is obscured in an intercross, since the chromosome 1 locus behaves recessively and three-fourths of the mice are therefore not informative for the interaction. To address this, we constructed a D2.B6 jck/+ congenic strain which carries a large interval on chromosome 1 as homozygous B6 and the remainder of the genome as D2 (except for loci linked to jck). When this mouse is crossed with a B6 jck/+ mouse, the congenic region on chromosome 1 is fixed as B6, while the rest of the genome is segregating as in an F2 population. In this cross, all the affected mice should be informative for the interacting D2 locus. Consistent with this hypothesis, we were readily able to localize a D2 locus associated with severe PKD using a strategy of interval haplotype analysis, which requires the analysis of only 2-3 markers per chromosome

The demonstration that a locus on proximal chromosome 4 contributes to severe PKD in the jck mutant mouse is of particular interest because this is the position of the locus Pkdm3 (previously called MOP1), which has been shown to modify the progression of PKD in two different mouse mutations, cpk and pcy. The evidence that the same locus can influence disease progress in three different murine PKD mutations is of considerable significance, since this suggests this gene might influence PKD severity irrespective of its cause. As such, this locus represents a potential target for therapeutic intervention in human PKD.

 


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