Mutations in the heparan sulfate backbone elongating enzymes EXT1 and EXT2 have no major effect on endothelial glycocalyx and the glomerular filtration barrier
-
Published:2022-02-01
Issue:2
Volume:297
Page:397-405
-
ISSN:1617-4615
-
Container-title:Molecular Genetics and Genomics
-
language:en
-
Short-container-title:Mol Genet Genomics
Author:
Khalil RamziORCID, Boels Margien G. S., Bezuijen A., Boers J. E., de Bruin P. C., van Dijk M. A. A. M., Drillenburg P., Hamel A. F., Hazelbag H. M., Jonges G. N., Kibbelaar R. E., Lam K. H., van der Linden H., van Marsdijk J., Meijer C., Nagtegaal I. D., Oudejans J. J., Roelofs J. J. T. H., Rozendaal L., Sastrowijoto S. H., Smits M. M., Stavast J., van den Berg Bernard M.ORCID, Bruijn Jan A., Rabelink Ton J.ORCID, Hogendoorn Pancras C. W.ORCID, Baelde Hans J.ORCID,
Abstract
AbstractIn this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial glycocalyx in humans is investigated. Heparan sulfate (HS) glycosaminoglycans are deemed essential to the glomerular filtration barrier, including the glomerular endothelial glycocalyx. Animal studies have shown that loss of HS results in a thinner glycocalyx. Also, decreased glomerular HS expression is observed in various proteinuric renal diseases in humans. A case report of a patient with an EXT1 mutation indicated that this could result in a specific renal phenotype. This patient suffered from multiple osteochondromas, an autosomal dominant disease caused by mono-allelic germline mutations in the EXT1 or EXT2 gene. These studies imply that HS is indeed essential to the glomerular filtration barrier. However, loss of HS did not lead to proteinuria in various animal models. We demonstrate that multiple osteochondroma patients do not have more microalbuminuria or altered glycocalyx properties compared to age-matched controls (n = 19). A search for all Dutch patients registered with both osteochondroma and kidney biopsy (n = 39) showed that an EXT1 or EXT2 mutation does not necessarily lead to specific glomerular morphological phenotypic changes. In conclusion, this study shows that a heterozygous mutation in the HS backbone elongating enzymes EXT1 and EXT2 in humans does not result in (micro)albuminuria, a specific renal phenotype or changes to the endothelial glycocalyx, adding to the growing knowledge on the role of EXT1 and EXT2 genes in pathophysiology.
Publisher
Springer Science and Business Media LLC
Subject
Genetics,Molecular Biology,General Medicine
Reference34 articles.
1. Anower EKMF, Matsumoto K, Habuchi H, Morita H, Yokochi T, Shimizu K, Kimata K (2013) Glycosaminoglycans in the blood of hereditary multiple exostoses patients: Half reduction of heparan sulfate to chondroitin sulfate ratio and the possible diagnostic application. Glycobiology 23(7):865–876 2. Bovee JV (2008) Multiple osteochondromas. Orphanet J Rare Dis 3:3 3. Bovee JV, Hogendoorn PC (2002) Multiple osteochondromas. In: Fletcher CDM, Unni KK, Mertens F (eds) World Health Organization classification of tumours: pathology and genetics tumours of soft tissue and bone. IARC Publications, Lyon, pp 360–362 4. Bovee JV, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PC (1999) EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet 65(3):689–698 5. Chen S, Wassenhove-McCarthy DJ, Yamaguchi Y, Holzman LB, van Kuppevelt TH, Jenniskens GJ, Wijnhoven TJ, Woods AC, McCarthy KJ (2008) Loss of heparan sulfate glycosaminoglycan assembly in podocytes does not lead to proteinuria. Kidney Int 74(3):289–299
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|