PDF(Pubmed)
Abstract：
In 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.
摘要：
在这项研究中,研究了硫酸乙酰肝素(HS)糖胺聚糖链共聚聚合酶EXT1和EXT2中的杂合种系突变对人肾小球屏障功能和内皮糖萼的影响.硫酸乙酰肝素（HS）糖胺聚糖被认为对肾小球滤过屏障至关重要，包括肾小球内皮糖萼。动物研究表明，HS的丢失会导致糖萼变薄。此外，在人类的各种蛋白尿肾疾病中观察到肾小球HS表达降低。有EXT1突变的患者的病例报告表明，这可能导致特定的肾脏表型。这个病人患有多发性骨软骨瘤,由EXT1或EXT2基因的单等位基因种系突变引起的常染色体显性疾病。这些研究表明，HS确实对肾小球滤过屏障至关重要。然而,在各种动物模型中，HS的丢失不会导致蛋白尿。我们证明，与年龄匹配的对照组相比，多发性骨软骨瘤患者没有更多的微量白蛋白尿或糖萼特性改变（n=19）。对所有登记有骨软骨瘤和肾活检的荷兰患者的搜索（n=39）表明，EXT1或EXT2突变不一定导致特定的肾小球形态表型变化。总之,这项研究表明，人类HS主链延伸酶EXT1和EXT2的杂合突变不会导致（微量）白蛋白尿，特定的肾脏表型或内皮糖萼的变化，增加了对EXT1和EXT2基因在病理生理学中作用的不断增长的认识。
