Mutations in the
Wilms' tumor suppressor gene (WT1) are linked with
Denys-Drash syndrome (DDS), a rare childhood disease characterized by
diffuse mesangial sclerosis and
renal failure of early onset, XY
pseudohermaphroditism, and high risk of
Wilms' tumor. KTS (
lysine-
threonine-
serine) splice site mutations in WT1 intron 9 have been described in patients with
Frasier syndrome, another rare syndrome defined by focal and
segmental glomerulosclerosis (FSGS), XY
pseudohermaphroditism, and frequent occurrence of
gonadoblastoma. Cases of
Frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the
nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of
diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had
proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228+5 G-->A) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 +KTS/-KTS
isoforms in the index case's father and one index case's maternal uncle showed a normal +KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in
Frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for
Frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.