后纵韧带骨化症患者基因变异及表型分析  

Genetic variants and phenotypic analysis in patients with ossification of the posterior longitudinal ligament

作　　者：陈欣[1,2,3] 张立 周非非[1,2,3] 赵衍斌 刁垠泽[1,2,3] 潘胜发 王少波 张凤山[1,2,3] 孙宇 CHEN Xin;ZHANG Li;ZHOU Feifei;ZHAO Yanbin;DIAO Yinze;PAN Shengfa;WANG Shaobo;ZHANG Fengshan;SUN Yu(Department of Orthopaedics,Peking University Third Hospital,Beijing 100191,China;Engineering Research Center of Bone and Joint Precision Medicine,Ministry of Education,Beijing 100191,China;Beijing Key Laboratory of Spinal Disease Research,Beijing 100191,China)

机构地区：[1]北京大学第三医院骨科,北京100191 [2]骨与关节精准医学工程研究中心,北京100191 [3]脊柱疾病研究北京市重点实验室,北京100191

出　　处：《中华骨与关节外科杂志》2024年第3期207-213,共7页Chinese Journal of Bone and Joint Surgery

基　　金：国家自然科学基金(81672121);北京市自然科学基金(7232210)。

摘　　要：目的:通过对后纵韧带骨化症(OPLL)患者进行全外显子组测序(WES),明确其可能的致病原因。方法:提取2017年1月至2019年12月收治的93例OPLL患者外周血基因组DNA,进行WES及生物信息学分析,筛查与OPLL相关的基因变异。结果:在2例OPLL患者中发现了ENPP1基因的2个错义变异,其中患者1携带1个c.T802C(p.Tyr268His)杂合变异,患者2携带1个c.T253C(p.Cys85Arg)杂合变异和1个c.T802C(p.Tyr268His)杂合变异。2个变异位点在不同物种中均具有高度保守性,多种蛋白预测软件均预测变异有害或可能有害,表型分析发现2例患者均发生了颈椎、胸椎OPLL及黄韧带骨化症。患者2血清磷水平在正常低限,血清碱性磷酸酶水平高于正常值。结论:ENPP1基因变异可能是OPLL患者的致病原因。该研究丰富了ENPP1基因变异谱,也为今后OPLL患者应用新的治疗方法提供了分子诊断依据。Objective:To identify potential pathogenic factors in patients with ossification of the posterior longitudinal ligament(OPLL)through whole exome sequencing(WES)Methods:Genomic DNA was extracted from the peripheral blood of 93 OPLL patients admitted from January 2017 to December 2019 for WES and bioinformatics analysis were performed to identify gene variants associated with OPLL.Results:Two missense variants in ENPP1 were identified in two OPLL patients.Case 1 carried a heterozygous variant c.T802C(p.Tyr268His),while Case 2 carried a heterozygous variant c.T253C(p.Cys85Arg)and a heterozygous variant c.T802C(p.Tyr268His).Both variant sites are highly conserved across different species.Several in silico tools predicted the two variants to be damaging or possibly damaging.Phenotypic analysis revealed that both patients had cervical and thoracic OPLL as well as thoracic ossification of ligamentum flavum.Case 2 had a serum phosphate level at the lower limit of normal,with a serum alkaline phosphatase level above the normal value.Conclusions:Variants of ENPP1 may contribute to the pathogenesis of OPLL in these two patients.This study enriches the spectrum of ENPP1 gene variants,and provides molecular diagnostic evidence for future application of novel therapeutic strategies in OPLL patients.

关 键 词：后纵韧带骨化症 全外显子组测序 基因变异 核苷酸焦磷酸酶/磷酸二酯酶1 

分 类 号：R681.5[医药卫生—骨科学]