X-连锁低血磷性佝偻病(XLHR)是儿童常见的致畸/致残性遗传病，由PHEX基因突变所致。申请者前期对28例XLHR患儿进行了PHEX基因型分析，发现10种新突变。本研究将进一步扩大收集XLHR病例，对其进行PHEX基因外显子及其邻近序列、启动子区序列进行测序以明确我国XLHR病人基因变异特征，并对XLHR的临床表型与基因突变类型进行关联研究。PHEX基因错义和无义突变是致XLHR的两大突变类型。本研究将对已检测到的PHEX基因错义突变进行功能研究，将错义突变进行内质网滞留型和酶活缺失型分类，进而探讨化学分子伴侣类药物Orkambi和4-PBA对内质网滞留型突变蛋白的纠正作用；同时研究促通读药物NB54、NB84、PTC124是否能够抑制PHEX基因无义突变的作用，促进完整PHEX蛋白合成、恢复内肽酶活性，为XLHR病人的治疗提供新思路。

The X-linked hypophosphatemic rickets (XLHR) is a common metabolic bone disease caused by mutations in the PHEX gene. We have carried PHEX genotype analysis in 28 children with XLHR and discovered 10 novel PHEX mutations. This study will continue to collect XLHR cases. Sequencing analysis of all the exons and their adjacent sequence and promoter region will be performed to clarify the gene variation of XLHR patients in China. Genotype- phenotype correlation study will be carried on the basis of genotype results. Missense and nonsense mutations are the two major types of mutations caused XLHR in PHEX gene. In this study, we will take function analysis of the detected missense mutations and classify them into endoplasmic reticulum retention and enzyme activity defective types. We next want to discuss the corrective effect of chemical chaperones drugs Orkambi and 4-PBA on endoplasmic reticulum retention mutant protein in vitro and vivo. In recent years，read-through drugs are playing increasing prominent roles in the researches related to genetic diseases caused by nonsense mutations．We will study whether the read-through drugs NB54, NB84, PTC124 can inhibit the role of PHEX gene nonsense mutation; promote complete PHEX protein synthesis; recovery of endopeptidase activity. Our study will provide a new experimental basis for the clinical treatment of XLHR.