Clinical and Molecular Characterization of Patients with Heterozygous Mutations in Wilms Tumor Suppressor Gene 1

Abstract

Background and objectives The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT.Design, setting, participants & measurements Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012.Results Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P,0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR,.8]; P,0.001) and splice site mutations (12.3 [IQR,.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations.Conclusions Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.

Truncating <b><i>Wilms Tumor Suppressor Gene 1</i></b> Mutation in an XX Female with Adult-Onset Focal Segmental Glomerulosclerosis and Streak Ovaries: A Case Report

“…These data are supported by studies on wt1 heterozygous mice indicating that wt1 -heterozygosity predisposes the development of proteinuria and increased plasma levels of urea and creatinine leading to glomerular sclerosis later in life [12]. Lehnhardt et al [5] recently reported from a cohort of 53 patients that constitutional heterozygous WT1 mutations neither cause the full syndromal picture of DDS or FS nor a NS in all patients. Our patient was diagnosed with proteinuria in early adulthood, and her renal function is not impaired at 38 years, which is an unusual manifestation of a WT1 -associated nephropathy.…”

“…The WT1 mutation c.1372C>T (p.Arg458*) found in our patient results in truncation of the protein. This mutation has already been described as disease causing by others [5,6,8,9,10] and arginine at this position is highly conserved in evolution, which makes the pathogenicity of the mutation very likely.…”

“…Recent publications evaluating genotype-phenotype correlations of WT1 mutations describe that in most cases truncating mutations in the hot spot exons 8 and 9 are associated with proteinuria diagnosed in later childhood, an increased risk of developing early bilateral nephroblastoma (Wilms tumor), and renal failure; male patients have a disorder in sex development (46,XY DSD) [5,6,11]. These data are supported by studies on wt1 heterozygous mice indicating that wt1 -heterozygosity predisposes the development of proteinuria and increased plasma levels of urea and creatinine leading to glomerular sclerosis later in life [12].…”

“…Up to now, only little is known about its role in the development of the female reproductive system. A small number of XX females with a WT1 mutation and abnormal development of uterus or ovaries are reported [5,6]. Usually complete gonadal dysgenesis is assumed in association with streak ovaries.…”

“…Furthermore, heterozygous mutations in WT1 are present in syndromal NS, known as Denys-Drash syndrome (DDS), and Frasier syndrome (FS) in which childhood-onset steroid-resistant NS is associated with renal failure, gonadal dysgenesis in XY males, and Wilms tumor (DDS) [2,3] or gonadoblastoma (FS) [4]. In recent reports analyzing genotype-phenotype correlations of patients with missense and truncating mutations and intronic KTS (lysine-threonine-serine) splice site mutations in WT1 [5,6], patients rarely showed the full picture of DDS and FS. FSGS is found in patients with exon and intron mutations in WT1 .…”