HbF增高合并β地中海贫血患者的α-珠蛋白基因拷贝数变异分析

摘要

目的 阐述α珠蛋白基因拷贝数丢失与增加对胎儿血红蛋白(fetal hemoglobin,HbF)水平的影响.方法 收集15例HbF增高合并β地中海贫血的患者,首先采用Gap-PCR检测常见α-地中海贫血的3种缺失型,之后应用多重探针连接扩增技术对α-珠蛋白基因簇行片段缺失与重复分析.结果 15例患者中,检出-SEA缺失杂合子3例,-α3.7缺失杂合子1例,-α4.2缺失纯合子1例,-α3.7与-SEA双重缺失杂合子1例,α珠蛋白基因簇大片段重复1例,类α-珠蛋白基因杂合缺失1例,7例样本未见α拷贝数的丢失与增加.结论 α拷贝数的增多会生成过多的α链,加重α与β链的不平衡性,同时过量的α链与γ链组成过多的HbF,导致HbF水平的升高;α拷贝数的减少会修正α与β链比例的失衡,减轻β0/β0或β0/β+的贫血症状,这类病例归为中间型β地中海贫血,一般具有较高的HbF水平.%Objective To detect copy number changes of α-globin gene,and analyze molecular mechanism of the impacts of fetal hemoglobin (HbF) levels for α-globin gene copy numbers loss or increase.Methods A total of 15 cases with combined increased levels of fetal hemoglobin with β thalassemia were collected.Firstly,three common α-thalassemia deletions were validated by Gap-PCR.Secondly,the largest deletions of the ββ-globin gene cluster were detected by multiplex ligation-dependent probe amplification (MLPA).Result Among the 15 cases,there was 1 case with duplication of the α-globin gene cluster,3 cases of SEA heterozygote deletion of the α-globin gene,1 cases of alpha 3.7 deletion heterozygote of the α-globin gene,1 case of alpha 4.2 deletion homozygote of the α-globin gene,1 case of deletion homozygote in the like α-globin gene.A compound heterozygous for SEA and alpha 3.7 of the α-globin gene was also detected.However,7 cases showed no copy numbers loss and increase of the the α-globin gene cluster.Conclusion Additional α-globin gene can produce excessive α-chain,which can aggravate imbalance for α and β-chain,and cause clinical symptoms in patients with ββ-thalassemia.Yet,copy number loss or mutation in α-globin gene will cause a milder clinical phenotype.