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

Abstract

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.

Missense Mutation in Sterile α Motif of Novel Protein SamCystin is Associated with Polycystic Kidney Disease in (cy/+) Rat

“…The identification of the mutation that is likely to cause renal cyst development in the PKD/Mhm(cy/ϩ) rat in a novel gene encoding SamCystin provides new opportunities for further dissecting mechanisms that control cystogenesis and modulate PKD severity (11). Both this novel gene and genes that encode proteins that interact with SamCystin call for large-scale genetic and functional studies in human PKD that may have significant implications for the clinical classification of cystic kidney diseases and the development of novel therapeutic strategies.…”

“…A large cohort of 742 first-backcross (BC1) rats was derived from affected F1(cy/ϩ) rats that were mated to BN rats as described previously (11). The BN rat was preferred to other inbred rat strains because of the high level of allele variation observed between BN and PKD/ Mhm(cy/ϩ) strains, which facilitates the detection of recombinant hybrids in the BC1 cohort and therefore increases efficiency of positional cloning the disease gene.…”

“…Kidneys were removed, weighed, fixed in 3% buffered formaldehyde, and then embedded in paraffin for histologic analyses. After hematoxylin/eosin staining of kidney sections, presence of renal cysts was assessed by microscopic examination (11).…”

A Major Gene Locus Links Early Onset Albuminuria with Renal Interstitial Fibrosis in the MWF Rat with Polygenetic Albuminuria

“…Animal models such as the MWF rat represent valuable models to substitute the investigation of the polygenetic basis of common forms of chronic proteinuric nephropathies (1,4). Indeed, susceptibility loci identified in rodent models have been shown to be predictive for human genetic studies using the comparative genomic approach (26,27). Such susceptibility loci may provide target regions for subsequent studies using single nucleotide polymorphisms and linkage disequilibrium mapping in association studies in human patient populations (28 -30).…”

Murine models of polycystic kidney disease: molecular and therapeutic insights

“…In both sexes, renal cystic disease is modulated by genetic background. Genetic mapping studies have identified a rat Chr 8 locus designated Modpkdr1, which exerts a main effect on renal disease severity (10).…”