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Genetic modifiers of polycystic kidney disease in intersubspecific KAT2J mutants
P Upadhya1, G Churchill, E H Birkenmeier
1The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, USA. pupadhya@aretha.jax.org p6
Abstract:
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.
Insights
Genetic background significantly impacts polycystic kidney disease (PKD) severity. Identifying modifier genes offers potential therapeutic targets for delaying PKD progression.
Area of Science:
- Genetics
- Nephrology
- Molecular Biology
Background:
- Polycystic kidney disease (PKD) is a complex genetic disorder with variable disease progression.
- Modifier genes are known to influence the clinical manifestations and severity of PKD.
- A novel mouse mutation, kat2J, on chromosome 8 causes late-onset PKD and anemia, providing a model for studying genetic modifiers.
Purpose of the Study:
- To identify genetic loci that modify the severity of polycystic kidney disease (PKD).
- To investigate the influence of genetic background on PKD progression and associated phenotypes like anemia.
- To lay the groundwork for discovering therapeutic targets to delay PKD progression.
Main Methods:
- Genome-wide scans using molecular markers in a mouse cross (C57BL/6J-kat2J/+ x CAST/Ei) F2 generation.
- Analysis of kidney weight and hematocrit levels as indicators of PKD severity and anemia.
- Quantitative trait locus (QTL) mapping to identify modifier loci on different chromosomes.
Main Results:
- Three major modifier loci influencing PKD severity were identified: one on chromosome 1 (CAST-derived), one on chromosome 19 (CAST-derived), and one on chromosome 2 (C57BL/6J-derived).
- The chromosome 1 modifier affects both kidney weight and hematocrit.
- The chromosome 19 modifier impacts kidney weight, while the chromosome 2 modifier influences hematocrit.
- Evidence for additional interacting modifier loci modulating the effects of these primary loci was observed.
Conclusions:
- Genetic background plays a critical role in modulating polycystic kidney disease (PKD) severity.
- The identified modifier loci represent key genetic factors influencing PKD progression and associated anemia.
- Mapping and identification of these modifier genes are crucial steps toward developing targeted therapies for human PKD.