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

Analysis of copy number variations in α-globin gene in the cases with combined increased levels of HbF with β thalassemia

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G地中海贫血的患者，首先采用Gap-PCR检测常见a一地中海贫血的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 a-globin gene, and analyze molecular mechanism of the impacts of fetal hemoglobin （HbF） levels for cx-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 a- thalassemia deletions were validated by Gap-PCR. Secondly, the largest deletions of the β-globin gene cluster were detected by multiplex ligation-dependent probe amplification （MLPA）. Result Among the 15 cases, there was i 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 a-globin gene cluster. Conclusion Additional α-globin gene can produce excessive a-chain, which can aggravate imbalance for a and β-chain, and cause clinical symptoms in patients with β-thalassemia. Yet, copy number loss or mutation in a-globin gene will cause a milder clinical phenotype.