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.
Highlights
Congenital anomalies of the kidney and urogenital tract (CAKUT) occur in approximately 0.5% of live births and together represent the most common class of developmental abnormalities in humans [1,2,3,4]
These data are consistent with the published observation that unilateral renal agenesis (URA) and related urogenital abnormalities segregate as an incompletely dominant and incompletely penetrant trait in progeny generated by crossing ACI rats, which exhibit these developmental anomalies, and Brown Norway (BN) rats, which do not [40]
The other renal abnormalities observed in the F2 population were unilateral renal hypoplasia (URH), which was observed in 66 rats (1.3% incidence in F2 population, 18.8% of observed abnormalities), and an enlarged, fluid filled, vestigial kidney and ureter indicative of hydroureteronephrosis (HUN), which was observed in 47 rats (0.9% incidence in F2 population; 13.4% of renal abnormalities)(Figs. 1B and 2)
Summary
Congenital anomalies of the kidney and urogenital tract (CAKUT) occur in approximately 0.5% of live births and together represent the most common class of developmental abnormalities in humans [1,2,3,4]. CAKUT is comprised of an assortment of interrelated phenotypes including bilateral renal agenesis (BRA), unilateral renal agenesis (URA), renal hypodysplasia, hydronephrosis, megaureter and pelviureteric junction obstructions. Together, these anomalies are the most frequent cause of end-stage renal disease in neonates and children [5,6]. Other CAKUT associated genes were first identified in genetic studies of developmental syndromes that include anomalies in urogenital organs as associated phenotypes. Data from multiple genetic linkage and genome wide association studies, many of which were focused on vesicoureteral reflux as the phenotype of interest, further establish the heterogeneous genetic bases of CAKUT [6,10,11,12,13,14,15,16]
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