组织非特异性碱性磷酸酶基因突变与低磷酸酶血症:2个新突变位点  

Identification of two novel mutations in the alkaline phospatase,live/bone/kidney gene in two Chinese families with hypophosphatasia

作　　者：邵冲[1,2] 郑慧[2] 傅文贞[2] 何进卫[2] 汪纯[2] 章振林[2] 

机构地区：[1]苏州大学医学部,苏州215000 [2]上海交通大学附属第六人民医院骨质疏松和骨病专科,上海200233

出　　处：《中华骨质疏松和骨矿盐疾病杂志》2014年第3期206-212,共7页Chinese Journal Of Osteoporosis And Bone Mineral Research

基　　金：国家自然科学基金(81070692;81170803;81370978;81270964;81200646);上海市卫生系统优秀学科带头人培养计划(XBR2011014);上海市科委重大科技专题攻关专项(10DZ1950100;11ZR1427300);上海市市级医院新兴前沿技术联合攻关项目(申康课题)(SHDC12013115)

摘　　要：目的：对2例低磷酸酶血症（HPP）患者及家系进行分析和基因突变检测，拓展国人HPP致病基因库，探讨HPP的致病机制。方法对HPP家系先证者和其父母进行生化指标[血常规、肝肾功能、碱性磷酸酶（ALP）、甲状旁腺素（PTH）、钙、磷等]和骨密度检测。同时对所有研究对象进行alkaline phospatase，live/bone/kidney（ALPL）基因全部12个外显子和外显子内含子交界区直接测序。结果来自家系1的先证者为36岁成年男性，身高131.0cm，体重35.0kg。X线提示多发性胸腰椎骨折和骨盆畸形，生化检测示血清ALP27U/L。测序发现ALPL基因6号外显子532位杂合突变（c.532T＞C），致ALPL成熟多肽中酪氨酸被组氨酸替代。该先证者母亲身高140.5cm，体重39.5kg，血清ALP30U/L，基因测序证明也是该杂合突变携带者。来自家系2的先证者5岁，其外祖父母为近亲结婚。该患儿身高100.0cm，体重18kg。血清ALP55U/L[低于同龄儿童正常范围（＜10岁）75～344U/L]，牙齿发育不良并脱落，有左股骨中下端骨折史。测序发现该患儿存在ALPL基因2个错义突变，其中9号外显子c.871G＞A突变。4号外显子269位突变（c.269A＞G）是一个新的错义突变，该突变导致成熟ALPL多肽中天冬氨酸被甘氨酸所替代。该患儿母亲亦是4号外显子c.269A＞G错义突变携带者，但其生化指标正常，无骨骼和牙齿异常。结论ALPL基因6号外显子c.532T＞C突变和4号外显子c.269A＞G突变是以往未曾报道过的新错义突变，为上述2例HPP患者致病基因。Objective We aimed to analyze the clinical manifestations to identify the disease-causing mutations in Chinese hypophosphatasia patients , and to realize the racial difference between diversified ethnic groups .Methods In family 1, a 35 year-old nonconsanguineous male was the proband with the severe clinical manifestation of hypophos -phatasia, his mother displayed mild clinical symptoms .In family 2, the proband was a 5-year-old boy, and his consan-guineous parents had no abnormal sign .All 12 exons and the exon-intron boundaries of the ALPL gene were amplified and directly sequenced in two probands from two unrelated Chinese families .The mutation sites were validated in other unaf-fected members of these two families and 200 healthy controls.Results In family 1, one novel missense mutation c.532T〉C which consisted of a heterozygous T 〉C transition at nucleotide 532 in exon 6 was detected in the proband and his mother.In family 2, the proband revealed two missense mutations in exon 4 and exon 9 respectively, the one in exon 4 was a novel mutation （c.269A〉G） which resulted in p.Asp90Gly in the mature ALPL polypeptide.Another mutation was c.871G〉A in exon 9, which had been already reported in 1998.His mother was a health carrier who harbored the same missense mutation in exon 4 without any clinical manifestations .Conclusion Our study showed that two novel mu-tations of the ALPL gene c.532T〉C in exon 6 and c.269A〉G in exon 4, taking responsibility for hypophosphatasia in Chinese patients .

关 键 词：低磷酸酶血症 组织非特异性碱性磷酸酶基因 突变 

分 类 号：R596[医药卫生—内科学]