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Nephrol Dial Transplant (1995) 10: 2205-2211
© 1995 European Renal Association-European Dialysis and Transplant Association

research-article

Aberrant proteoglycan composition of the glomerular basement membrane in a patient with Denys-Drash syndrome

L. P. W. J. van den Heuvel1,2,, P. J. Westenend2, J. van den Born3, K. J. M. Assmann2, N. Knoers4 and L. A. H. Monnens1

1Department of Paediatrics, University of Nijmegen Nijmegen, The Netherlands 2Department of Pathology, University of Nijmegen Nijmegen, The Netherlands 3Department of Nephrology, University of Nijmegen Nijmegen, The Netherlands 4Department of Human Genetics, University of Nijmegen Nijmegen, The Netherlands

Correspondence and offprint requests to: Correspondence and offprint requests to: Dr L. P. van den Heuvel, Department of Paediatrics, University of Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

BACKGROUND: To ascertain whether changes in proteo-glycans are involved in the pathogenesis of the nephrotic syndrome in Denys—Drash syndrome (DDS), we analysed the glycosaminoglycan (GAG) content and composition of the glomerular basement membrane (GBM) in one child with this disorder and in children of comparable age who had died from unrelated disorders.

METHODS: The diagnosis of DDS was confirmed by the presence of a previously described mutation in the WT1 gene (a tumour suppressor gene). The GAG content and composition of the GBM and tubular basement membrane (TBM), both in the Denys-Drash patient as well as age-matched control infants, was analysed by biochemical studies and indirect immuno-fiuorescence studies. Finally we investigated the urinary GAG excretion of the Drash patient.

RESULTS: The biochemical studies revealed that the total GAG content in the GBM as well as TBM was comparable in the Drash patient and the control group. However, the GAG composition of the GBM of the patient was clearly different, with relatively more chondroitin sulphate. The urinary GAG content (expressed as mg GAG/mmol creatinine) was elevated in the Denys—Drash patient due to an increased heparan sulphate (HS(GAG)) excretion. Indirect immunofluo-rescence (IF) studies for the core protein of human GBM heparan sulphate proteoglycan (HSPG) showed a similar linear staining of all renal basement membranes in the patient and the controls. A monoclonal antibody directed against the HS chain of HSPG (MoAb 403) displayed a strong GBM and a weak TBM staining of normal kidneys. Kidney tissue from the Drash patient displayed a reduced staining of the GBM with MoAb 403. IF studies for chondroitin sulphate proteoglycan (CSPG) showed increased staining of the mesangium and glomerular capillary loops in the Denys—Drash patient which is in agreement with the biochemical studies. No discernible differences in distribution or quality of staining with antibodies against collagen type IV and laminin were observed.

CONCLUSIONS: These biochemical and immunohisto-chemical results indicate that in our patient the proteoglycan composition of the GBM is altered. This alteration may play a role in the pathogenesis of proteinuria in this syndrome.

Keywords: chondroitin sulphate proteoglycan; Denys—Drash syndrome; glomerular basement membrane; Wilms' tumour gene


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