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.
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.
The Wellcome Trust Centre for Human Genetics, University of Oxford, UK. bihoreau@well.ox.ac.uk
Marie-Thérèse
MT
Bihoreau
Natalia
N
Megel
Joanna H
JH
Brown
Bettina
B
Kränzlin
Laurence
L
Crombez
Yulia
Y
Tychinskaya
John
J
Broxholme
Susanne
S
Kratz
Volker
V
Bergmann
Sigrid
S
Hoffman
Dominique
D
Gauguier
Norbert
N
Gretz
D000818:Animals; D002874:Chromosome Mapping; D017124:Conserved Sequence; D003433:Crosses, Genetic; D005260:Female; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009394:Nephritis, Hereditary / Q000235:genetics*; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D051381:Rats