Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of increased apoptosis in fetal kidneys of Pax2(1Neu) +/- mutant mice

PAX2 mutations cause renal-coloboma syndrome (RCS), a rare multi-system dev elopmental abnormality involving optic nerve colobomas and renal abnormalit ies. End-stage renal failure is common in RCS, but the mechanism by which P AX2 mutations lead to renal failure is unknown. PAX2 is a member of a famil y of developmental genes containing a highly conserved 'paired box' DNA-bin ding domain, and encodes a transcription factor expressed primarily during fetal development in the central nervous system, eye, ear and urogenital tr act. Presently, the role of PAX2 during kidney development is poorly unders tood. To gain insight into the cause of renal abnormalities in patients wit h PAX2 mutations, kidney anomalies were analyzed in patients with RCS, incl uding a large Brazilian kindred in whom a new PAX2 mutation was identified. In a total of 29 patients, renal hypoplasia was the most common congenital renal abnormality. To determine the direct effects of PAX2 mutations on ki dney development fetal kidneys of mice carrying a Pax2(1Neu) mutation were examined. At E15, heterozygous mutant kidneys were similar to 60% of the si ze of wild-type littermates, and the number of nephrons was strikingly redu ced. Heterozygous 1Neu mice showed increased apoptotic cell death during fe tal kidney development, but the increased apoptosis was not associated with random stochastic inactivation of Pax2 expression in mutant kidneys; Pax2 was shown to be biallelically expressed during kidney development. These fi ndings support the notion that heterozygous mutations of PAX2 are associate d with increased apoptosis and reduced branching of the ureteric bud, due t o reduced PAX2 dosage during a critical window in kidney development.