国人COL1A1和COL1A2突变致成骨不全家系内表型不一  

Variable phenotypes of intrafamiliar of osteogenesis imperfecta in Chinese patients with COL1A1 and COL1A2 mutations

作　　者：张浩[1] 汪纯[1] 岳华[1] 顾洁梅[1] 胡伟伟[1] 何进卫[1] 傅文贞[1] 魏占英[1] 章振林[1] ZHANG Hao;WANG Chun;YUE Hua;GU Jie-mei;HU Wei-wei;HE Jin-wei;FU Wen-zhen;WEI Zhan-ying;ZHANG Zhen-lin(Department of Osteoporosis and Bone Diseases,Metabolic Bone Diseases and Genetic Research Unit,Shanghai Key Clinical Center for Metabolic Disease,Shanghai Jiao Tong University Affiliated Sixth People s Hospital,Shanghai,200233,China)

机构地区：[1]上海交通大学附属第六人民医院骨质疏松和骨病专科骨代谢病与遗传研究室,上海200233

出　　处：《中华骨质疏松和骨矿盐疾病杂志》2018年第6期532-539,共8页Chinese Journal Of Osteoporosis And Bone Mineral Research

基　　金：科技部973重大研究项目(2014CB942903);国家自然科学基金(81570794;81370978;30800387;8127096);上海市自然科学基金(14ZR1431900;14JC1405000);重庆市基础与前沿研究计划项目(CSTC2013jcyj C00009)

摘　　要：目的观察123个汉族成骨不全(osteogenesis imperfecta,OI)家系中存在表型不一的家系比率,并探讨导致同一突变不同表型的潜在机制。方法分析123个汉族OI家系(包括以往研究的117个家系)中存在表型不一的家系比率。用单核苷酸多态性(single nucleotide polymorphism,SNP) SNa Pshot分型技术检测21个家系先证者及其表型不一家系成员的血液和口腔黏膜的脱氧核糖核酸(deoxyribonucleic acid,DNA)中COL1A1和COL1A2基因21个SNP位点的分型,从而检查体细胞样本的嵌合率。同时检测2个存在COL1A2基因同一突变(c. 1009G>A)家系的甲基化程度差异。结果在123个OI家系中,21个(17. 1%)家系存在表型不一,仅1例先证者的父亲显示体细胞基因镶嵌,其血液中有43. 1%突变等位基因,口腔上皮细胞有39. 6%的突变等位基因。在2个存在COL1A2基因同一突变(c. 1009G>A)的家系中,2例先证者的甲基化程度均高于其母亲。结论国人OI家系内COL1A1和COL1A2基因同一突变发生不同表型的比率为17%。在这21个表型不一的家系中只有1例(4. 8%)先证者的父亲存在体细胞镶嵌。甲基化程度可能与表型严重程度有关。在遗传咨询时,对先证者无临床表型的家属进行致病基因的突变检测是十分必要的。Objective To observe the percentage of variable phenotypes of all 123 Chinese osteogenesis imperfecta （OI） families of Han nationality and to explore the underlying mechanisms which cause variable phenotypes with the same mutations. Methods We explored variable phenotypes in 123 Chinese OI families （including 117 in our previous studies）. We used SNP SNaPshot typing technology to carry on 21 SNP loci typing on DNA samples from both blood and oral mucosas of the probands and their relatives with variable expressions to examine somatic mosaic for the COL1A1 and COL1A2 mutations and the fitting rate. We also examined the degree of methylation of the same mutation （c.1009G〉A） of COL1A2 gene in two families. Results Among the 123 OI families, 21 （17.1%） families displayed variable expression of OI. Only 1 proband s father showed mosaicism whose mutant allele was presented in 43.1% of his blood and 39.6% of his epithelial cell. Degree of methylation was higher in both probands who had same mutation （c.1009G〉A） than their mothers. Conclusions We found 17.1% of the Chinese OI families with either COL1A1 or COL1A2 mutations showed intrafamiliar variable phenotypes. Only 1 of the 21 families （4.8%） was found to be mosaic. Degree of methylation might contribute to the variable manifestations of the same mutations of OI. These suggest that it is necessary to carry out mutation detection of pathogenic genes in family members without clinical symptoms.

关 键 词：成骨不全 COL1A1 COL1A2 突变 不同表型 

分 类 号：R681[医药卫生—骨科学]