Two Cases of Isolated Diffuse Mesangial Sclerosis with WT1 Mutations

Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Journal of Korean Medical Science (Impact Factor: 1.27). 03/2006; 21(1):160-4. DOI: 10.3346/jkms.2006.21.1.160
Source: PubMed


Here we report two cases of isolated diffuse mesangial sclerosis (IDMS) with early onset end-stage renal failure. These female patients did not show abnormalities of the gonads or external genitalia. Direct sequencing of WT1 PCR products from genomic DNA identified WT1 mutations in exons 8 (366 Arg>His) and 9 (396 Asp>Tyr). These mutations have been reported previously in association with Denys-Drash syndrome (DDS) with early onset renal failure. Therefore we suggest that, at least in part, IDMS is a variant of DDS and that investigations for the WT1 mutations should be performed in IDMS patients. In cases with identified WT1 mutations, the same attention to tumor development should be required as in DDS patients, and karyotyping and serial abdominal ultrasonograms to evaluate the gonads and kidney are warranted.

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Available from: Hae Il Cheong, Aug 12, 2014
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    ABSTRACT: The WT1 gene encodes a zinc finger transcription factor involved in kidney and gonadal development and, when mutated, in the occurrence of kidney tumor and glomerular diseases. Patients with Denys-Drash syndrome present with early nephrotic syndrome with diffuse mesangial sclerosis progressing rapidly to end-stage renal failure, male pseudohermaphroditism, and Wilms' tumor. Incomplete forms of the syndrome have been described. Germline WT1 missense mutations located in exons 8 or 9 coding for zinc fingers 2 or 3 have been detected in nearly all patients with Denys-Drash syndrome and in some patients with isolated diffuse mesangial sclerosis. Patients with Frasier syndrome present with normal female external genitalia, streak gonads, XY karyotype and progressive nephropathy with proteinuria and nephrotic syndrome with focal and segmental glomerular sclerosis progressing to end-stage renal disease in adolescence or young adulthood. They frequently develop gonadoblastoma. Germline intronic mutations leading to the loss of the +KTS isoforms have been observed in all patients with Frasier syndrome. The same mutations have been observed in genetically female patients with isolated FSGS. Transmission of the mutation is possible. Frasier mutations have also been reported in children with Denys-Drash syndrome.
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    ABSTRACT: Diffuse mesangial sclerosis (DMS) is a histologically distinct variant of nephrotic syndrome (NS) that is characterized by early onset and by progression to end-stage kidney disease (ESKD). Besides syndromic DMS, isolated (non-syndromic) DMS (IDMS) has been described. The etiology and pathogenesis of DMS is not understood. We recently identified by positional cloning recessive mutations in the gene PLCE1/NPHS3 as a novel cause of IDMS. We demonstrated a role of PLCE1 in glomerulogenesis. Mutations in two other genes WT1 and LAMB2 may also cause IDMS. We therefore determine in this study the relative frequency of mutations in PLCE1, WT1 or LAMB2 as the cause of IDMS in a worldwide cohort. We identified 40 children from 35 families with IDMS from a worldwide cohort of 1368 children with NS. All the subjects were analyzed for mutations in all exons of PLCE1 by multiplex capillary heteroduplex analysis and direct sequencing, by direct sequencing of exons 8 and 9 of WT1, and all the exons of LAMB2. The median (range) age at onset of NS was 11 (1-72) months. We detected truncating mutations in PLCE1 in 10/35 (28.6%) families and WT1 mutations in 3/35 (8.5%) families. We found no mutations in LAMB2. PLCE1 mutation is the most common cause of IDMS in this cohort. We previously reported that one child with truncating mutation in PLCE1 responded to cyclosporine therapy. If this observation is confirmed in a larger study, mutations in PLCE1 may serve as a biomarker for selecting patients with IDMS who may benefit from treatment.
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