Effects on kidney disease, fertility and development in mice inheriting a protein-truncating Denys-Drash syndrome allele (Wt1(tmT396))

Denys- Drash syndrome (DDS) is caused by heterozygous mutations of the Wilms' tumour suppressor gene, WT1, characterised by earlyonset diffuse mesangial sclerosis often associated with male pseudohermaphroditism and/or Wilms' tumourigenesis. Previously, we reported that the Wt1(tmT396) allele induces DDS kidney disease in mice. In the present study heterozygotes (Wt1(tmT396/+)) were generated on inbred (129/Ola), crossbred (B6/129) and MF1 second backcross (MF1- N2) backgrounds.Whereas male heterozygotes on each background were fertile, inbred heterozygous females were infertile. Kidney disease (proteinuria and sclerosis) was not congenital and developed significantly earlier in inbred mice, although with variable onset. Disease onset in MF1- N2 stocks occurred later in Wt1(tmT396/+) mice than reported previously for Wt1(R394W/+) mice, and while no kidney disease has been reported in B6/129 Wt1(+/-) mice, B6/129 Wt1(tmT396/+) mice were affected. Offspring of both male and female B6/129 and MF1- N2 Wt1(tmT396/+) mice developed kidney disease, but its incidence was significantly higher in offspring of female heterozygotes. Wt1(tmT396/tmT396) embryos exhibited identical developmental abnormalities to those reported for Wt1(-/-) embryos. The results indicate that the Wt1(tmT396) allele does not predispose to Wilms' tumourigenesis or male pseudohermaphroditism, its effect on kidney disease and female fertility depends on genetic background, stochastic factors may affect disease onset, and disease transmission is subject to a partial parent- of-origin effect. Since the Wt1(tmT396) allele has no detectable intrinsic functional activity in vivo, and kidney disease progression is affected by the type of Wt1 mutation, the data support the view that DDS nephropathy results from a dominant- negative action rather than WT1 haploinsufficiency or gain- offunction.