Identification of Constitutional WT1 Mutations, in Patients with Isolated Diffuse Mesangial Sclerosis, and Analysis of Genotype/Phenotype Correlations by Use of a Computerized Mutation Database

Abstract

Constitutional mutations of the WT1 gene, encoding a zinc-finger transcription factor involved in renal and gonadal development, are found in most patients with Denys-Drash syndrome (DDS), or diffuse mesangial sclerosis (DMS) associated with pseudohermaphroditism and/or Wilms tumor (WT). Most mutations in DDS patients lie in exon 8 or exon 9, encoding zinc finger 2 or zinc finger 3, respectively, with a hot spot (R394W) in exon 9. We analyzed a series of 24 patients, 10 with isolated DMS (IDMS), 10 with DDS, and 4 with urogenital abnormalities and/or WT. We report WT1 heterozygous mutations in 16 patients, 4 of whom presented with IDMS. One male and two female IDMS patients with WT1 mutations underwent normal puberty. Two mutations associated with IDMS are different from those described in DDS patients. No WT1 mutations were detected in the six other IDMS patients, suggesting genetic heterogeneity of this disease. We analyzed genotype/phenotype correlations, on the basis of the constitution of a WT1 mutation database of 84 germ-line mutations, to compare the distribution and type of mutations, according to the different symptoms. This demonstrated (1) the association between mutations in exons 8 and 9 and DMS; (2) among patients with DMS, a higher frequency of exon 8 mutations among 46, XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and (3) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions.

Gonadal Tumor in Frasier Syndrome: A Review and Classification

“…Eight cases of type 3 Frasier syndrome have been reported (10,13,14,(31)(32)(33)(34)(35)(36). Few type 3 Frasier syndrome cases are diagnosed because patients exhibit normal secondary sexual characteristics by the XX chromosome and suffer from renal failure without gonadal impairment.…”

Genetic Basis of Congenital and Infantile Nephrotic Syndromes

“…1 Mutations were detected in 17 individuals (56.7% overall; 93.3% and 20.0% of patients with congenital and infantile nephrotic syndrome, respectively), in the WT1 (n ϭ 8), NPHS1 (n ϭ 6), LAMB2 (n ϭ 2), and NPHS2 (n ϭ 1) genes; no polymorphisms were detected in the PLCE1 gene [2][3][4][5] (Table 1). The frequency of mutations in patients with congenital nephrotic syndrome was similar to those of 2 large studies of European 7 (84.8%) and multiethnic 8 (81.3%) cohorts.…”

Congenital Nephrotic Syndrome

“…Mutations in WT1 may cause several types of developmental syndromes (Denys-Drash, Frasier, and WAGR syndromes) manifesting in childhood [20][21][22]. WT1 mutations can also cause an isolated kidney disease, with NS appearing in the first 3 months of life [17,23]. They account for a few percent of CNS cases.…”