The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency
The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency
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DOI：
10.1074/jbc.m210490200
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发表时间：
2003-03-14
影响因子：
4.8
通讯作者：
Karaplis, AC
中科院分区：
文献类型：
--
作者：
Bai, XY;Miao, DS;Karaplis, AC
成纤维细胞生长因子23（FGF 23）的错义突变是常染色体显性遗传性低磷血症性佝偻病（ADHR）的原因。突变（R176 Q、R179 W和R179 Q）替换枯草杆菌蛋白酶样前蛋白转化酶（SPC）切割位点（RXXR基序）内的Arg残基，导致FGF 23的蛋白酶抗性。本研究的目的是在体内检查R176 Q突变型FGF 23形式的生物学效力，并表征引起这种疾病的表型呈现的稳态机制的改变。为此，使用荷瘤裸鼠系统在完整动物中过表达野生型和R176 Q突变型FGF 23。在可比较的循环水平下，与野生型FGF 23相比，突变形式在诱导低磷酸盐血症、降低循环中1，25-二羟基维生素D-3（1，25（OH）（2）D-3）浓度以及引起佝偻病和骨软化方面更有效。钙稳态参数也发生改变，导致继发性甲状旁腺功能亢进和甲状旁腺增生。然而，甲状旁腺激素循环水平的升高并不能通过增加25（OH）D-3- 1 α-羟化酶（Cyp 40）的肾脏表达来促进其合成，并通过减少25（OH）D-3-24-羟化酶（Cyp 24）的表达来防止其分解代谢，从而使降低的1，25（OH）（2）D-3水平恢复正常。这些发现提供了直接的体内证据，即ADHR激酶的错义突变是保留和增加蛋白质生物学效力的功能获得性突变。此外，他们第一次确定了FGF 23在肾脏水平上解离甲状旁腺激素对矿物质通量和维生素D代谢的作用中的潜在作用。
Missense mutations in fibroblast growth factor 23 (FGF23) are the cause of autosomal dominant hypophosphatemic rickets (ADHR). The mutations (R176Q, R179W, and R179Q) replace Arg residues within a subtilisin-like proprotein convertase (SPC) cleavage site (RXXR motif), leading to protease resistance of FGF23. The goals of this study were to examine in vivo the biological potency of the R176Q mutant FGF23 form and to characterize alterations in homeostatic mechanisms that give rise to the phenotypic presentation of this disorder. For this, wild type and R176Q mutant FGF23 were overexpressed in the intact animals using a tumor-bearing nude mouse system. At comparable circulating levels, the mutant form was more potent in inducing hypophosphatemia, in decreasing circulating concentrations of 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), and in causing rickets and osteomalacia in these animals compared with wild type FGF23. Parameters of calcium homeostasis were also altered, leading to secondary hyperparathyroidism and parathyroid gland hyperplasia. However, the raised circulating levels of parathyroid hormone were ineffective in normalizing the reduced 1,25(OH)(2)D-3, levels by increasing renal expression of 25(OH)D-3-1alpha-hydroxylase (Cyp40) to promote its synthesis and by decreasing that of 25(OH)D-3-24-hydroxylase (Cyp24) to prevent its catabolism. The findings provide direct in vivo evidence that missense mutations from ADHR kindreds are gain-of-function mutations that retain and increase the protein's biological potency. Moreover, for the first time, they define a potential role for FGF23 in dissociating parathyroid hormone actions on mineral fluxes and on vitamin D metabolism at the level of the kidney.