Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling
Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling
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DOI：
10.1016/j.bone.2021.116135
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发表时间：
2021-08-14
期刊：
影响因子：
4.1
通讯作者：
Kubota, Takuo
中科院分区：
文献类型：
--
作者：
Ishihara, Yasuki;Ohata, Yasuhisa;Kubota, Takuo
X-连锁低磷血症性佝偻病（XLH）是一种遗传性佝偻病，由磷酸盐调节内肽酶同源物X-连锁（PHEX）基因的失活变体引起，其导致成纤维细胞生长因子23（FGF 23）过量产生。PHEX损伤导致FGF 23过度产生的机制尚不清楚。由于对日本XLH的基因型-表型相关性知之甚少，我们总结了现有的临床和遗传数据，并使用三维（3D）结构建模分析了基因型-表型关系，以阐明XLH的病理生理学。我们回顾性分析了来自28个携带任何已知或新的PHEX变异的无关家系的39例日本XLH患者的临床特征，并进行了遗传分析。为了预测突变体PHEX的三维结构变化，我们构建了每个突变体的假定三维模型，并通过基因型-表型相关分析评估了结构改变的影响。遗传分析发现了23个PHEX变体，其中包括8个新变体。它们与高i-FGF 23水平、低磷酸盐血症、磷酸盐尿、高碱性磷酸酶水平和身材矮小有关。当比较截短和非截短变体时，没有观察到基因剂量效应或基因型-表型相关性。然而，PHEX中锌结合位点和空腔的保守性对i-FGF 23水平的升高有影响。通过使用三维建模的基因型-表型关系分析，我们表明PHEX中锌结合位点和空腔在其功能中起关键作用。这些发现为研究PHEX的功能和XLH的发病机制提供了新的遗传学线索。
X-linked hypophosphatemic rickets (XLH) is an inheritable type of rickets caused by inactivating variants in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene, which results in the overproduction of fibroblast growth factor 23 (FGF23). The mechanism by which PHEX impairment leads to FGF23 overproduction is unknown. Because little is known regarding the genotype-phenotype correlation in Japanese XLH, we summarized the available clinical and genetic data and analyzed the genotype-phenotype relationships using 3-dimensional (3D) structure modeling to clarify the XLH pathophysiology.We retrospectively reviewed the clinical features and performed genetic analysis of 39 Japanese patients with XLH from 28 unrelated pedigrees carrying any known or novel PHEX variant. To predict changes in the 3D structure of mutant PHEX, we constructed a putative 3D model of each mutant and evaluated the effect of structural alteration by genotype-phenotype correlation analysis.Genetic analysis revealed 23 PHEX variants, including eight novel variants. They were associated with high i-FGF23 levels, hypophosphatemia, phosphaturia, high alkaline phosphatase levels, and short stature. No gene dosage effect or genotype-phenotype correlation was observed when truncating and non-truncating variants were compared. However, the conservation of the zinc-binding site and cavity in PHEX had an impact on the elevation of i-FGF23 levels.Via genotype-phenotype relationship analysis using 3D modeling, we showed that the zinc-binding site and cavity in PHEX can play a critical role in its function. These findings provide new genetic clues for investigating the function of PHEX and the pathogenesis of XLH.