title: 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.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Nyssa Becker
authors.initials: NB
authors.lastname: Samanas
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Tessa W
authors.initials: TW
authors.lastname: Commers
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Dennison
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Quincy Eckert
authors.initials: QE
authors.lastname: Harenda
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Kurz
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Lachel
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America; Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Kristen Leland
authors.initials: KL
authors.lastname: Wavrin
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Bowler
authors.affiliation: Hubrecht Institute, Utrecht, The Netherlands.
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.affiliation: Hubrecht Institute, Utrecht, The Netherlands.
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.affiliation: Hubrecht Institute, Utrecht, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Max Delbruck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.affiliation: Research Animal Resources Center, Graduate School, University of Wisconsin, Madison, Wisconsin, United States of America; University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Ruth
authors.initials: R
authors.lastname: Sullivan
authors.affiliation: University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America; Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Vezina
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America; Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: James D
authors.initials: JD
authors.lastname: Shull
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D000013:Congenital Abnormalities / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D007668:Kidney / Q000002:abnormalities* / Q000473:pathology; D007674:Kidney Diseases / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D020161:Physical Chromosome Mapping / Q000379:methods*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D051381:Rats; D011912:Rats, Inbred ACI; D019089:Stem Cell Factor / Q000235:genetics
chemical_list: D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit