Human Molecular Genetics, 2002, Vol. 11, No. 18 2165-2173
© 2002 Oxford University Press
Characterization of a major modifier locus for polycystic kidney disease (Modpkdr1) in the Han:SPRD(cy/+) rat in a region conserved with a mouse modifier locus for Alport syndrome
1The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, 2Medical Research Centre, Klinikum Mannheim, University of Heidelberg, D-68167 Mannheim, Germany and 3Institute of Veterinary Pathology, Free University of Berlin, D-14163 Berlin, Germany
Received May 9, 2002; Accepted June 28, 2002
The genetic analysis of rodent disease models provides a powerful tool to investigate how modifier loci cause variation in the phenotypic expression of a disease. In order to test the existence of modifier loci influencing polycystic kidney disease (PKD) phenotypes, we derived a backcross between PKD susceptible Han:SPRD(cy/+) and control Brown Norway (BN) rats, and performed a whole-genome scan in 182 PKD affected hybrids showing different grades of disease severity. The genetic dissection of PKD in the cross allowed us to detect a modifier locus, Modpkdr1, on rat chromosome 8 that controls PKD severity, kidney mass and plasma urea concentration. Results from database searches and computational analyses demonstrated that the Modpkdr1 locus shows strong evidence of synteny conservation with human and mouse chromosomal regions controlling kidney diseases, including disease progression of Alport syndrome. Comparative genome mapping also provided an inventory of potential candidate genes for modifier(s) of PKD. Analyses of the coding regions for four strong candidates (Ctsh, Bcl2a1, Trpc1 and Slc21a2) in (cy/+), BN and Lewis rat strains did not reveal sequence variants that could be associated with PKD. The characterization of Modpkdr1 may provide new insights into modulating mechanisms involved in the pathogenesis of PKD that could delay disease progression in humans. It may also have strong implications in the identification of pathophysiological factors common to different renal disorders.
* To whom correspondence should be addressed. Tel: +44 1865287648; Fax: +44 1865287533; Email: bihoreau{at}well.ox.ac.uk
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