Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations

Abstract

We investigated 17 children with nephrotic syndrome (NS) of early onset (14 aged < 1 year) and rapid progression to end-stage renal disease for the presence of mutations in the Wilms' tumor suppressor gene WT1 on chromosome 11. In eight children (7 genotypic males) an association with Wilms' tumor and/or ambiguous genitalia (Denys-Drash syndrome) was observed. In these eight and two additional female patients with NS only constitutional missense mutations in the WT1 gene were detected; four children presented the so-called hot spot mutation in exon 9 (R394N) and six had different mutations in exons 8 and 9 (4 not previously described). Renal biopsy showed diffuse mesangial sclerosis in eight and focal segmental sclerosis in two cases. End-stage renal disease was reached either concomitantly or within four months after onset of NS in seven of ten patients. A unilateral Wilms' tumor was found before or concomitant with NS in four children (3 males, 1 female). From the seven genotypic males with WT1 mutations, five presented ambiguous genitalia and two a female phenotype. No mutation of the WT1 gene was found in seven other children with isolated congenital or infantile NS with or without DMS who appeared to have a slower progression than the first group. It is proposed that patients with early onset, rapidly progressive NS and diffuse mesangial or focal segmental sclerosis should be tested for WT1 mutations to identify those at risk for developing Wilms' tumor.

Transcriptional Regulation by the Wilms Tumor Protein, Wt1, Suggests a Role of the Metalloproteinase Adamts16 in Murine Genitourinary Development

“…Subsequent in vitro organ culture experiments and transgenic animal studies proved a requirement of Wt1 not only for the early inductive events but also during the later phases of kidney formation (i.e. the differentiation and maturation of the glomeruli) (46) and for the integrity of mature kidneys (47)(48)(49). Interestingly, recent disruption of the Adamts16 gene in Dahl Salt-sensitive rats caused splitting and thickening of glomerular capillaries in addition to a significant reduction of arterial blood pressure (50).…”

Inherited Podocytopathies

“…Denys-Drash syndrome (DDS) is a related disorder characterized by diffuse mesangial sclerosis on renal biopsy, genitourinary tumors, and pseudohermaphroditism. A different spectrum of mutations is associated with DDS, most commonly in exon 9 of the WT1 gene (55,62).…”

Nephrotic Syndrome: Past, Present and Future

“…При синдроме Дениса-Драша также молеку-лярно-генетически был обследован 1 пациент и опре-делена мутация в 9-м экзоне гена WT1. У всех наблю-даемых больных, как это отмечается и в литературе [28], при использовании иммуносупрессивной тера-пии наблюдалось ухудшение состояния. Проведен-ная трансплантация почек двум больным на стадии терминальной хронической почечной недостаточно-сти не сопровождалась рецидивом нефротического синдрома, что также характерно для генетически де-терминированной патологии.…”