The murine and human AT2 genes reside on the X chromosome. Embryonal AT2 transcriptional activity is temporally and spatially upregulated in association with the apoptotic event of the mesenchymal cells surrounding the ureter. We have recently found that ≈23% of male mice that are hemizygous for a targeted AT2 null mutation have CUTA. Interestingly, these CUTA are predominantly unilateral and include multicystic dysplastic kidneys (MCDK) and ureteropelvic junction obstruction (UPJO). We, therefore, hypothesized that dysfunction in the AT2 receptor, through an incomplete/delayed mesenchymal cell apoptosis, can cause disruption of normal ureteral growth, and hence CUTA. To determine if AT2 gene alterations are associated with CUTA in humans, we analyzed the AT2 genes from a cohort of Caucasian subjects with MCDK and/or UPJO and controls. Using genomic DNAs as templates, PCR amplicons containing exons 1-3 and introns 1 and 2 of the AT2 gene were obtained. These amplicons were then screened for sequence alterations by dideoxy fingerprinting (ddF) followed by DNA sequencing of those showing an altered ddF pattern. We identified an A to G transition within intron 1 which occurred in 72% of the 18 affected males but only 30% of the 13 control males (X2=5.2, p=0.02). Thus, our study identified a nucleotide transition in the human AT2 gene which exhibits an association with the MCDK and/or UPJO phenotype. This finding along with our observations that AT2 null mutant mice have a variety of CUTA, including vesicoureteral reflux, suggest that the AT2 gene variance in the polymorphic locus identified in the study or a nearby mutation also contributes to other forms of CUTA in humans. Apparently, murine and human CUTA are polygenic diseases resulting from mutations in genes with pleiotropic potentials.