Abstract
Obstructive uropathy is the leading cause of chronic renal failure and ESRD in children. Understanding the genetic and molecular control of urinary tract development is critical for making an impact on obstructive uropathy. Presently, little is known about the specific molecular causes of obstructive uropathy.
The congenital progressive hydronephrosis (cph) mouse was described as having a random recessive mutation in the C57Bl/6J strain of mice in 1978 and was crudely mapped to mouse chromosome 15 between the visible markers belted (bt) (now ADAMTS20) and Caracul (Ca) (now Krt2–6g). The cph mutant provides an excellent model of obstructive uropathy that closely mimics the process in humans. The renal phenotype of homozygous cph mutants is not grossly visible at day 1 of age but can be detected microscopically with abnormalities of the renal papillae indicating onset in-utero. Radiographic analysis demonstrates profound hydronephrosis with obstruction at the level of the UPJ.
We hypothesize that the identification of the cph gene and mutation therein, will provide novel insight into the mechanism of development of congenital progressive hydronephrosis and allow identification of important signaling molecules required for both normal and abnormal genitourinary tract development.
Obligate heterozygote mice for cph, were mated to the 129Ola strain of mice to generate F1 progeny containing the cph mutation. Random F1 animal matings has resulted in the generation of F2 mice homozygous for the cph mutation. DNA samples from F2 mice homozygous for the cph mutation have been used for analysis. We have obtained multiple cph mutants on this F2 background and we have begun linkage analysis using SSLP markers in the candidate region on Chromosome 15. Through cross-over analysis using MIT markers we have narrowed the region of the mutation on Chromosome 15. We have found a marker, D15Mit172, very close to the proposed genomic location of the cph gene that is consistently inherited as homozygous for the B6 allele in all affected F2 animals genotyped, giving 100% concordance with this marker and the cph phenotype in seven of fifty-one F2 mice to date. This finding leads us to believe that the D15Mit172 marker can be used as a proxy locus for genotyping embryos in the F2 genetic background for in-utero analyses. Simultaneous candidate gene sequencing and Real Time RT-PCR analysis has been performed and narrowed the candidate field. A promising gene has been identified.
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Brophy, P., Clarke, J. & Raymond, R. 6 Identifying the Mouse Gene Responsible for Congenital Progressive Hydronephrosis (CPH).. Pediatr Res 58, 817 (2005). https://doi.org/10.1203/00006450-200510000-00036
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DOI: https://doi.org/10.1203/00006450-200510000-00036