Localization of genetic loci controlling hydronephrosis in the Brown Norway rat and its association with hematuria.

The aim of this study was to investigate the genetic basis of congenital hydronephrosis (HN), a poorly defined pathological entity, with a rat model. The Brown Norway (BN) strain spontaneously presents a high incidence of apparently asymptomatic HN, whereas the LOU strain does not. A backcross was established between these two strains [BN x (BN x LOU)] and a genomewide scan was performed with 193 microsatellite markers on 121 males and 118 females of this population, which had been phenotyped and scored for HN severity (defined as degree of renal pelvic dilation), followed by linkage analysis with Mapmaker/QTL software. Bilateral HN score was significantly linked to a locus on chromosome 6 (Z scores 4.4 and 4.8 for all rats and for females, respectively). Suggestive loci were identified on chromosomes 2 (for only right-sided HN) and 4. This is the first study in rats to identify genetic loci for HN. Three candidate genes present in these loci were sequenced and insertions detected in Id2 and Agtr1b genes in BN, which did not, however, lead to modified expression as measured by quantitative PCR. Production of a congenic line for part of the chromosome 6 locus confirmed its involvement in HN, but the phenotype was mild. Evidence of hematuria was observed in 9.6% of the backcross rats, mostly males and only in kidneys with HN, but not necessarily in the most severely affected. Hematuria also occurs in the BN colony used here, where it is due to papilloma-like lesions involving pelvic epithelial proliferation, but not in the LOU rat.

Quantitative genetic basis of arterial phenotypes in the Brown Norway rat.

The Brown Norway (BN) rat presents several genetically determined arterial phenotypes of interest, i.e., ruptures of the internal elastic lamina (RIEL) in the abdominal aorta (AA), iliac (IAs), and renal arteries, aortic elastin deficit and higher frequency of persistent ductus arteriosus (PDA) than other strains. We investigated the genetic basis of these phenotypes. We established a backcross between BN and the LOU reference strain and performed a genome-wide scan on 104 males and 105 females with 193 microsatellite markers followed by linkage analysis. RIEL in AA and IAs showed highly significant linkage to a locus on chromosome 5 and suggestive linkage to a locus on chromosome 10, which is syntenic to one linked to a syndrome of thoracic aortic aneurysms with PDA in humans. In contrast, renal artery RIEL mapped to a chromosome 3 locus and thoracic aortic elastic content to two loci on chromosome 2. PDA was significantly linked to two different quantitative trait loci (QTL) on chromosomes 8 and 9. This is the first study in rats to identify genetic loci for PDA. We identified 21 candidate genes by functional relevance or integration of our mapping data with global expression analysis. Sequencing these genes identified 47 single nucleotide polymorphisms, but no functionally relevant amino acid changes. By expression analysis, myosin heavy chain 10, nonmuscle, in the chromosome 10 QTL, emerged as a candidate for RIEL in AA and IAs. Furthermore, production of a congenic line for the chromosome 5 QTL proved implication of this locus in RIEL formation.