A novel WT1 gene mutation in a three-generation family with progressive isolated focal segmental glomerulosclerosis

Elisa Benetti, Gianluca Caridi, Cristina Malaventura, Monica Dagnino, Emanuela Leonardi, Lina Artifoni, Gian Marco Ghiggeri, Silvio C E Tosatto, Luisa Murer

Research output: Contribution to journalArticlepeer-review


Background and objectives: Wilms tumor-suppressor gene-1 (WT1) plays a key role in kidney development and function. WT1 mutations usually occur in exons 8 and 9 and are associated with Denys-Drash, or in intron 9 and are associated with Frasier syndrome. However, overlapping clinical and molecular features have been reported. Few familial cases have been described, with intrafamilial variability. Sporadic cases of WT1 mutations in isolated diffuse mesangial sclerosis or focal segmental glomerulosclerosis have also been reported. Design, setting, participants, & measurements: Molecular analysis of WT1 exons 8 and 9 was carried out in five members on three generations of a family with late-onset isolated proteinuria. The effect of the detected amino acid substitution on WT1 protein's structure was studied by bioinformatics tools. Results: Three family members reached end-stage renal disease in full adulthood. None had genital abnormalities or Wilms tumor. Histologic analysis in two subjects revealed focal segmental glomerulosclerosis. The novel sequence variant c. 1208G > A in WT1 exon 9 was identified in all of the affected members of the family. Conclusions: The lack of Wilms tumor or other related phenotypes suggests the expansion of WT1 gene analysis in patients with focal segmental glomerulosclerosis, regardless of age or presence of typical Denys-Drash or Frasier syndrome clinical features. Structural analysis of the mutated protein revealed that the mutation hampers zinc finger-DNA interactions, impairing target gene transcription. This finding opens up new issues about WT1 function in the maintenance of the complex gene network that regulates normal podocyte function. copyright

Original languageEnglish
Pages (from-to)698-702
Number of pages5
JournalClinical Journal of the American Society of Nephrology
Issue number4
Publication statusPublished - Apr 1 2010

ASJC Scopus subject areas

  • Nephrology
  • Transplantation
  • Epidemiology
  • Critical Care and Intensive Care Medicine


Dive into the research topics of 'A novel WT1 gene mutation in a three-generation family with progressive isolated focal segmental glomerulosclerosis'. Together they form a unique fingerprint.

Cite this