Genetic Etiology of Renal Agenesis: Fine Mapping of Renag1 and Identification of Kit as the Candidate Functional Gene

Abstract

Congenital anomalies of the kidney and urogenital tract (CAKUT) occur in approximately 0.5% of live births and represent the most frequent cause of end-stage renal disease in neonates and children. The genetic basis of CAKUT is not well defined. To understand more fully the genetic basis of one type of CAKUT, unilateral renal agenesis (URA), we are studying inbred ACI rats, which spontaneously exhibit URA and associated urogenital anomalies at an incidence of approximately 10%. URA is inherited as an incompletely dominant trait with incomplete penetrance in crosses between ACI and Brown Norway (BN) rats and a single responsible genetic locus, designated Renag1, was previously mapped to rat chromosome 14 (RNO14). The goals of this study were to fine map Renag1, identify the causal genetic variant responsible for URA, confirm that the Renag1 variant is the sole determinant of URA in the ACI rat, and define the embryologic basis of URA in this rat model. Data presented herein localize Renag1 to a 379 kilobase (kb) interval that contains a single protein coding gene, Kit (v-kit Hardy-Zukerman 4 feline sarcoma viral oncogene homolog); identify an endogenous retrovirus-derived long terminal repeat located within Kit intron 1 as the probable causal variant; demonstrate aberrant development of the nephric duct in the anticipated number of ACI rat embryos; and demonstrate expression of Kit and Kit ligand (Kitlg) in the nephric duct. Congenic rats that harbor ACI alleles at Renag1 on the BN genetic background exhibit the same spectrum of urogenital anomalies as ACI rats, indicating that Renag1 is necessary and sufficient to elicit URA and associated urogenital anomalies. These data reveal the first genetic link between Kit and URA and illustrate the value of the ACI rat as a model for defining the mechanisms and cell types in which Kit functions during urogenital development.

Whole genome sequencing and novel candidate genes for CAKUT and altered nephrogenesis in the HSRA rat

“…An obvious hypothesis is that both HSRA and ACI share this common genetic cause and that other factors in the HSRA genome (from the other founders) contribute to increased penetrance of CAKUT (75% in the HSRA vs. 15% in ACI). A major finding of this study is that the HSRA genome contains the insertion within intron 1 of c-Kit linked to CAKUT in the ACI progenitor (72). More so, the region around the c-kit locus [established by linkage analysis (75)] is consistent with the HSRA being derived from the ACI genome, suggesting the models share a common genetic factor that leads to CAKUT.…”

“…Thus, a major focus of the current study was to perform whole genome sequencing (WGS) of the HSRA to map its genetic architecture with respect to the eight progenitor strains that compose the HS model. There were several other objectives, including: 1) query all known genes linked to CAKUT in both human and rodent models to determine if sequence variation in any of these genes underlies CAKUT in the HSRA rat, 2) identify potential novel candidate genes linked to CAKUT/nephron number by investigating all genes genome-wide with high-impact sequence variants, and 3) investigate whether the HSRA contains a long-term repeat (LTR) within exon 1 of c-Kit gene linked to CAKUT in the ACI progenitor (72). In summary, the WGS of the HSRA model provides an important first step in establishing the genetic architecture of the model as well as lays the groundwork for future genetic studies to identity gene/modifier that leads to loss of one kidney and nephron deficiency in the HSRA model.…”

Complex abnormalities of urinary tract in boy with renal agenesis

“…Jest wynikiem braku indukcji pączka moczowodowego do mezodermy nerki ostatecznej, co powoduje brak zawiązka nerki [1]. Agenezja nerki zwykle rozpoznawana jest przypadkowo, może występować rodzinnie i być uwarunkowana genetycznie [3,4,5]. Rozpoznano ponad 20 mutacji u pacjentów z wrodzonym brakiem jednej lub obu nerek [1].…”

“…Jednostronna agenezja nerki jest częstą anomalią rozwojową układu moczowego, która może występować sporadycznie lub rodzinnie. Opisano liczne przypadki rodzinnego występowania jednostronnej i obustronnej agenezji nerki [1,3,13]. Roodhooft i wsp.…”

“…Przesiewowe badania USG członków rodziny opisanego chłopca wykazały agenezję nerki lewej u 18-letniego brata. Przyczyną braku nerki u dorosłego brata mogła być nie tylko agenezja, ale również aplazja i zanik nerki dysplastycznej wielotorbielowatej lub hipodysplastycznej [1,3]. Chłopcy są w trakcie badań genetycznych, w celu określenia mutacji, która mogła być przyczyną złożonej wady układu moczowego u jednego z braci i agenezji nerki u drugiego.…”