International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

G21. Chromosomal Localization of the Modifier Genes that Influence the Phenotypic Expression of orpk in the FVB/N and C3HeB/FEJLe Genetic Backgrounds

Carla Sommardahl1, Marilyn Cottrell1, J. Erby Wilkinson1, Dabney K. Johnson2
1The Department of Pathology, University of Tennessee College of Veterinary Medicine, PO Box 1071, Knoxville, TN, USA, 37901-1071;
Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, USA, 37831

In both dominant and recessive PKD in humans, there is extreme phenotypic variability in disease progression and extrarenal manifestations. We have found marked differences in the phenotypic expression of the orpk mutation when bred on different inbred backgrounds. In the FVB/N genetic background, the phenotype is very severe in the kidney, pancreas, and liver lesions. To better evaluate how genetic background might influence the expressivity of the orpk phenotype, we have made the transgene congenic on the inbred C3H genetic background. Congenic C3H-orpk mutant mice have a much less severe phenotype identical to that initially observed in the first generation backcross to C3H. The kidney lesions in the C3H-orpk mutant mice are morphologically similar to the FVB/N-orpk mutant mice, but renal cysts develop at a slower rate and there are fewer cysts at all stages of cyst development. The liver lesions in the C3H-orpk mutant mice are less aggressive and are characterized by multifocal biliary hyperplasia, dysplasia, and portal fibrosis isolated to the portal triad regions. Significant differences in the lesions when the orpk mutation is on a different genetic background suggest the presence of important modifier genes that vary in the FVB/N and C3H genetic backgrounds. We performed a genome wide scan using backcross and intercross populations with more than 150 markers to map the chromosomal location of the modifier genes that affect the severity of the kidney disease in the orpk mouse between the FVB/N and C3H genetic backgrounds. Analysis of separate populations of severely affected and mildly affected mice in the backcross progeny identified possible modifying loci on chromosomes 4, 13 and 17. A significant association with cystic kidney disease severity was found for a recessively inherited FVB/N-related locus on all three chromosomes. Low-resolution interval mapping was performed using the Map Manager QTb program. The interval that explains most of the variance is at the distal end of chromosome 4. This interval was also identified when analyzing the genotyping and the kidney score data from the F2 progeny using the Map Manager QTb program for linkage analysis. The fact that the markers for this interval segregated with the severe kidney scores with both populations makes it a strong candidate to contain a modifier gene.

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