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


METHODS
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.
Pediatric Nephrology, Dialysis and Transplant Unit, Department of Pediatrics, University of Padova, Via Giustiniani 3, 35128 Padova, Italy. elisabene@libero.it
Elisa
E
Benetti
Gianluca
G
Caridi
Cristina
C
Malaventura
Monica
M
Dagnino
Emanuela
E
Leonardi
Lina
L
Artifoni
Gian Marco
GM
Ghiggeri
Silvio C E
SC
Tosatto
Luisa
L
Murer
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D019943:Amino Acid Substitution; D001706:Biopsy; D019295:Computational Biology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons; D016162:Genes, Wilms Tumor; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007558:Italy; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D011507:Proteinuria / Q000235:genetics; D012307:Risk Factors; D013329:Structure-Activity Relationship; D025721:WT1 Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D025721:WT1 Proteins