4 Mutations in the heparan sulfate backbone elongating enzymes EXT1 and EXT2 have no major effect on endothelial glycocalyx and the glomerular filtration barrier 67 Background Te effect of heterozygous germline mutations in EXT1 or EXT2 on the glomerular filtration barrier, with special attention to the endothelial glycocalyx, is investigated in this study. We hypothesized that patients with a mutation in EXT1 or EXT2 have a perturbed endothelial glycocalyx and glomerular basement membrane that results in changes in renal morphology and altered glomerular permeability. Therefore, we performed a cross-sectional observational study in a cohort of patients with EXT1 and EXT2 mutations to investigate endothelial glycocalyx health and the glomerular barrier function in humans. In addition, we identified a historic cohort of renal biopsy or autopsy tissue from patients with osteochondromas in which we examined whether a specific renal morphological phenotype is present. HS is made up of repeating disaccharide units of N-acetyl glucosamine and glucuronic acid, covalently attached to a core protein, such as syndecans and glypicans.(9) Biosynthesis of HS comprises three steps: chain initiation, chain elongation, (requiring the EXT1 and EXT2 co-polymerase)and chain modification. Depending on the modification state of HS, various sulfate groups are attached to the chain and thus infer negative charge, anti-coagulatory properties, and the capability to bind various cytokines and chemokines (52). HS has been studied extensively in the glomerular filtration barrier (GFB).(7, 8) The GFB consists of fenestrated endothelial cells covered by glycocalyx, the glomerular basement membrane, and specialized visceral epithelial cells (podocytes) with interdigitating foot processes. There has a been a longstanding discussion on whether HS is essential to glomerular permeability (53). Glomeruli of patients with lupus nephritis, membranous glomerulonephritis, minimal change disease, and diabetic nephropathy showed a decreased staining of heparan sulfate.(22) Degradation of HS in the glycocalyx by heparanase increases glomerular permeability to albumin, results in increased accessibility to autoantibodies, and loss of HS was observed in various proteinuric renal diseases (22, 29, 37). On the other hand, a genetic HS deficiency has been shown not to result in significant proteinuria in various experimental animal models. (23, 25, 27, 54, 55) Gleadle et al. reported on a patient with a monoallelic germline mutation in an HS polymerizing gene, EXT1, that presented with a nephrotic syndrome. Histology from a renal biopsy of this patient showed specific changes on EM of fibrillar deposition in the GBM and mesangium (56). Based on this case, the renal disease ‘glomerulopathy of hereditary multiple exostoses’ is recognised as a separate disease entity (57). EXT1 or EXT2 loss of function mutations result in the autosomal dominant disease multiple
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