Association between the Angiotensin Type 2 Receptor (AT2) Genotype and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) • 1812

The murine and human AT2 genes are in the X chromosome. We have recently found that mice that are hemizygous for a targeted AT2 null mutation have CAKUT. Experimental evidence suggested that delay of the apoptosis of the mesenchymal cells surrounding the ureter underlies this murine CAKUT. Moreover, a study on the human AT2 gene revealed an A to G transition within the lariat branchpoint motif of intron 1, which has a significant linkage disequilibrium with the incidence of ureteropelvic junction obstruction and dysplastic kidneys. Of interest, posterior urethral valves (PV), another form of human CAKUT, was not observed as a part of the phenotype in AT2 null mutants. In this regard, AT2 is expressed around the ureter but not the urethra in embryos. Therefore, to further verify the significance of the AT2 gene variant in human CAKUT, we analyzed the AT2 genes from a cohort of male German caucasian subjects with primary megaureter (PM, n=16) or PV (n=19) and anonymous controls (n=19). Using genomic DNAs, PCR amplicons containing exon 1- intron 2 of the AT2 gene were obtained. The A to G transition occurred in 69% of PM, but only 37% of PV. While the former is significantly higher than controls (42%, X2=3.6, P<0.05), the latter is similar to controls(X2=0.47, P>0.4). Thus, our studies identified a nucleotide transition in the human AT2 gene which exhibits an association with primary megaureter (i.e, upper urinary tract lesion) but not posterior urethral valves(i.e., lower urinary tract lesion). The findings are, therefore, in concernt with the notion that the AT2 gene mutation contributes to formation of CAKUT not only in mice but also humans, and that normal embryonic expression of AT2 is critically important for the ontogeny of the ureter.

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