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/

Constitutional mutations of the WT1 gene, encoding a zinc-finger trans cription factor involved in renal and gonadal development, are found i n most patients with Denys-Drash syndrome (DDS), or diffuse mesangial sclerosis (DMS) associated with pseudohermaphroditism and/or Wilms tum or (WT). Most mutations in DDS patients lie in exon 8 or exon 9, encod ing zinc finger 2 or zinc finger 3, respectively, with a hot spot (R39 4W) in exon 9. We analyzed a series of 24 patients, 10 with isolated D MS (IDMS), 10 with DDS, and 4 with urogenital abnormalities and/or WT. We report WT1 heterozygous mutations in 16 patients, 4 of whom presen ted with IDMS. One male and two female IDMS patients with WT1 mutation s underwent normal puberty. Two mutations associated with IDMS are dif ferent from those described in DDS patients. No WT1 mutations were det ected 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 germline mu tations, to compare the distribution and type of mutations, according to the different symptoms. This demonstrated (1) the association betwe en 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 phen otype; and (3) statistically significant evidence that mutations in ex ons 8 and 9 preferentially affect amino acids with different functions .