Hyperostosis-hyperphosphatemia syndrome:: A congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23
Hyperostosis-hyperphosphatemia syndrome:: A congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23
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DOI：
10.1359/jbmr.061105
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发表时间：
2007-02-01
影响因子：
6.2
通讯作者：
Fukumoto, Seiji
中科院分区：
文献类型：
--
作者：
Frishberg, Yaacov;Ito, Nobuaki;Fukumoto, Seiji
前言：骨质疏松症-高磷血症综合征(HHS)是一种常染色体隐性遗传性疾病，表现为严重的高磷血症伴发作性骨痛，放射学表现为皮质骨质增生症和骨膜反应。持续性高磷血症不能被甲状旁腺素或1，25-二羟基维生素D抵消，这是由于成纤维细胞生长因子23活性增加所致的低磷血症状态的镜像。材料和方法：我们描述了两名HHS儿童，他们被发现是编码粘蛋白O-糖基化相关肽(ppGaNTase-T3)的GALNT3突变的纯合子。用双抗体夹心法和免疫印迹法检测FGF23水平。采用基质辅助激光解吸电离飞行时间质谱仪分析FGF23蛋白。结果：两例患者均有较低水平的全长FGF23表达，失活片段数量明显增多。具有生物活性的FGF23有三个O-连接的糖链。只有一个或两个O-连接的多糖的FGF23被加工成无活性的片段。通过RNA干扰降低GALNT3基因的表达可促进FGF23的加工。结论：HHS的主要缺陷是GALNT3基因突变导致FGF23糖基化障碍，导致FGF23加工增强。FGF23的这些变化消除了它的磷尿酸效应，并导致严重的持续性高磷血症。本研究提供了第一例发现的粘蛋白O-糖基化缺陷的致病机制。
Introduction: Hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive entity manifesting as severe hyperphosphatemia associated with episodic bone pain and radiological findings of cortical hyperostosis and periosteal reaction. Persistent hyperphosphatemia is not counterbalanced by PTH or 1,25-dihydroxyvitamin D, posing a mirror image of hypophosphatemic states attributed to increased fibroblast growth factor (FGF)23 activity.Materials and Methods: We describe two children with HHS who were found to be homozygous for a mutation in GALNT3 encoding a peptide involved in mucin-type O-glycosylation (ppGaNTase-T3). FGF23 levels were evaluated by two ELISAs and Western blotting. FGF23 protein was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Effect of silencing GALNT3 was evaluated using siRNA in cells transfected with expression vector for FGF23.Results: Both patients had low levels of the full-length FGF23 with markedly augmented amounts of the inactive fragments. Biologically active FGF23 has three O-linked glycans. FGF23 with only one or two O-linked glycans is processed into inactive fragments. Decreasing the expression of the GALNT3 gene by RNA interference resulted in enhanced processing of FGF23.Conclusions: The primary defect in HHS is impairment of glycosylation of FGF23 resulting from mutations in GALNT3 and leading to augmented processing of FGF23. These changes in FGF23 abolish its phosphaturic effect and lead to severe persistent hyperphosphatemia. This study provides the pathogenetic mechanism of the first mucin-type O-glycosylation defect identified.