A review of the genetic background in complicated WT1-related disorders

Abstract

AbstractThe Wilms tumor 1 (WT1) gene was first identified in 1990 as a strong candidate for conferring a predisposition to Wilms tumor. The WT1 protein has four zinc finger structures (DNA binding domain) at the C-terminus, which bind to transcriptional regulatory sequences on DNA, and acts as a transcription factor. WT1 is expressed during kidney development and regulates differentiation, and is also expressed in glomerular epithelial cells after birth to maintain the structure of podocytes. WT1-related disorders are a group of conditions associated with an aberrant or absent copy of the WT1 gene. This group of conditions encompasses a wide phenotypic spectrum that includes Denys–Drash syndrome (DDS), Frasier syndrome (FS), Wilms–aniridia–genitourinary–mental retardation syndrome, and isolated manifestations of nephropathy or Wilms tumor. The genotype–phenotype correlation is becoming clearer: patients with missense variants in DNA binding sites including C2H2 sites manifest DDS and develop early-onset and rapidly developing end-stage kidney disease. A deeper understanding of the genotype–phenotype correlation has also been obtained in DDS, but no such correlation has been observed in FS. The incidence of Wilms tumor is higher in patients with DDS and exon-truncating variants than in those with non-truncating variants. Here, we briefly describe the genetic background of this highly complicated WT1-related disorders.