Genetic background of nonmutant Piebald-Virol-Glaxo rats does not influence nephronophthisis phenotypes

Abstract

BackgroundNephronophthisis (NPHP), which affects multiple organs, is a hereditary cystic kidney disease (CKD), characterized by interstitial fibrosis and numerous fluid-filled cysts in the kidneys. It is caused by mutations in NPHP genes, which encode for ciliary proteins known as nephrocystins. The disorder affects many people across the world and leads to end-stage renal disease. The aim of this study was to determine if the genetic background of the nonmutant female Piebald-Virol-Glaxo (PVG/Seac–/–) rat influences phenotypic inheritance of NPHP from mutant male Lewis polycystic kidney rats.MethodsMating experiments were performed between mutant Lewis polycystic kidney male rats with CKD and nonmutant PVG and Wistar Kyoto female rats without cystic kidney disease to raise second filial and backcross 1 progeny, respectively. Rats that developed cystic kidneys were identified. Systolic blood pressure was determined in each rat at 12 weeks of age using the tail and cuff method. After euthanasia, blood samples were collected and chemistry was determined. Histological examination of the kidneys, pancreas, and liver of rats with and without cystic kidney disease was performed.ResultsIt was established that the genetic background of nonmutant female PVG rats did not influence the phenotypic inheritance of the CKD from mutant male Lewis polycystic kidney rats. The disease arose as a result of a recessive mutation in a single gene (second filial generation, CKD = 13, non-CKD = 39, χ2 = 0.00, P ≥ 0.97; backcross 1 generation, CKD = 67, non-CKD = 72, χ2 = 0.18, P > 0.05) and inherited as NPHP. The rats with CKD developed larger fluid-filled cystic kidneys, higher systolic blood pressure, and anemia, but there were no extrarenal cysts and disease did not lead to early pup mortality.ConclusionThe genetic background of the nonmutant PVG rats does not influence the genetic and phenotypic inheritance of CKD from mutant Lewis polycystic kidney rats. A single recessive mutation incapacitated the gene, which relaxed its functional constraints, and led to formation of multiple cysts in the kidneys of the homozygous mutant rats.

Modifier loci in non-mutant, female Wistar Kyoto rats influence cellular pathogenesis of nephronophthisis in Lewis polycystic kidney rats

“…The current work is a further extension of the study in which a genome-wide linkage scan analysis identified a mutation in the Nek8 gene as the cause of NPHP in LPK rats [10,25,31]. It is now reported that this mutation is influenced by genetic modifier loci in the non-mutant, female WKY rats.…”

“…This finding was established by the use of a dense set of polymorphic simple sequence repeat markers that mapped the genetic loci. Previously, we identified mutation in the Nek8 gene, located on the RCC1 on chromosome 10q25, as the cause of pathogenesis of NPHP [10,18]. Later, we observed that the BC1 progeny had much more variable phenotypes than the LPK parental strain.…”

“…All the animals were kept in a 12-hour light/dark cycle and they had free access to the same food and water. The experiments were performed in accordance with the guidelines of the Animal Ethic Committees of Murdoch University and the Animal Resources Center of Western Australia [18].…”

“…This variability is attributed to individual genetic heterogeneity, but importantly to the genetic background of the parental strains [17]. Regardless of the different genetic mutations that lead to cellular pathogenesis of NPHP, it is now accepted that NPHP is a less common form of ARPKD [18,19].…”