Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia
Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia
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中国 X 连锁低磷血症患者大型队列的临床和遗传分析
DOI：
10.1016/j.bone.2019.01.021
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发表时间：
2019-04-01
期刊：
影响因子：
4.1
通讯作者：
Xia, Weibo
中科院分区：
文献类型：
--
作者：
Zhang, Cong;Zhao, Zhen;Xia, Weibo
X连锁低磷血症（XLH）是由PHEX基因功能缺失突变引起的。鉴于最近XLH的新疗法的可用性，对最近在北京协和医院评价的261例XLH中国患者进行了回顾性分析。采用临床、生物化学、放射学研究以及遗传分析，包括点突变的桑格测序和检测大缺失/重复的多重连接依赖性探针扩增（MLPA）。基于M13家族成员Neprilysin（NEP）的结构，构建了PHEX的三维模型，在预测的结构上定位错义突变和无义突变，以可视化这两种类型变体的相对位置。对261例XLH患者进行了基因分析，发现166个PHEX突变。166个突变中有111个未报告。在该群组中鉴定出四个突变“热点”（P534 L、G579 R、R747 X、c.1645 + 1G> A）。错义突变，而不是无义突变，聚集在两个假定的叶的PHEX蛋白，这表明这些是功能重要的区域的分子。完整FGF 23的循环水平显著升高（中位水平101.9 pg/mL;参考范围16.1-42.2 pg/mL）。在假定截短型和非截短型PHEX突变的患者之间没有发现显著的性别差异，也没有发现表型差异。然而，具有N末端PHEX突变的患者具有更早的发病年龄，（P = 0.015）和较高的iFGF 23水平（P = 0.045）。这些数据提供了迄今为止中国报告的最大XLH患者队列的综合特征，这将有助于评估这种疾病的新兴疗法在该种族群体中的适用性。
X-linked Hypophosphatemia (XLH) is caused by loss of function mutations in the PHEX gene. Given the recent availability of a new therapy for XLH, a retrospective analysis of the most recent 261 Chinese patients with XLH evaluated at Peking Union Medical College Hospital was conducted. Clinical, biochemical, radiographic studies, as well as genetic analyses, including Sanger sequencing for point mutations and Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large deletions/duplications were employed. Based on the structure of Neprilysin (NEP), a member of M13 family that includes PHEX, a three-dimensional (3D) model of PHEX was constructed, missense and nonsense mutations were positioned on the predicted structure to visualize relative positions of these two types of variants. Sex differences and genotype-phenotype correlations were also undertaken.Genetic analyses identified 166 PHEX mutations in 261 XLH patients. One hundred and eleven of the 166 mutations were unreported. Four mutational 'hot-spots' were identified in this cohort (P534L, G579R, R747X, c.1645 + 1 G > A). Missense mutations, but not nonsense mutations, clustered in the two putative lobes of the PHEX protein, suggesting these are functionally important regions of the molecule. Circulating levels of intact FGF23 were significantly elevated (median level 101.9 pg/mL; reference range 16.1-42.2 pg/mL). No significant sex differences, as well as no phenotypic differences were identified between patients with putative truncating and non-truncating PHEX mutations. However, patients with N-terminal PHEX mutations had an earlier age of onset of disease (P = 0.015) and higher iFGF23 levels (P = 0.045) as compared to those with C-terminal mutations.These data provide a comprehensive characterization of the largest cohort of patients with XLH reported to date from China, which will help in evaluating the applicability of emerging therapies for this disease in this ethnic group.