Pulmonary dysplasia, Denys-Drash syndrome and Wilms tumor 1 gene mutation in twins

While a genetic basis for the association of developmental lung and kidney defects has been suspected, the involvement of specific genes in this process is under active investigation. We report such a possible genetic linkage present in identical twins with a mutant Wilms tumor (WT1) gene. Twin girls, born at 35 weeks gestation, manifested symptoms of congenital nephrotic syndrome, renal failure, and severe respiratory abnormalities refractory to assisted ventilation. Both died at 1 month of age. Renal biopsies and autopsy kidney tissue from both the girls revealed diffuse mesangial sclerosis (DMS). Autopsy lung tissue revealed pulmonary dysplasia and hypoplasia in both twins. The WT1 gene from renal tissue in both twins was analyzed for mutations using polymerase chain reaction (PCR) amplification and the single-strand conformation polymorphism (SSCP) technique. Both twins possessed an identical missense mutation in exon 8 of the WT1 gene, resulting in replacement of arginine by histidine at amino acid 366 (arg366his) in the WT1 protein. This mutation has previously been described in Denys-Drash syndrome. The WT1 gene plays a role in mesenchymal epithelial (ME) interactions in the developing urogenital system, and possibly has a similar role during lung morphogenesis. We propose that this WT1 gene mutation contributes to both DMS and developmental pulmonary abnormalities by altering ME interactions in both organs. Received: 13 June 2000 / Revised: 1 November 2000 / Accepted: 2 November 2000