一种与β39地中海贫血珠蛋白基因及高胎儿血红蛋白生成相关的Aγ-珠蛋白G→A基因多态性。
An Aγ-globin G->A gene polymorphism associated with β39 thalassemia globin gene and high fetal hemoglobin production.
作者信息
Breveglieri Giulia, Bianchi Nicoletta, Cosenza Lucia Carmela, Gamberini Maria Rita, Chiavilli Francesco, Zuccato Cristina, Montagner Giulia, Borgatti Monica, Lampronti Ilaria, Finotti Alessia, Gambari Roberto
机构信息
Department of Life Sciences and Biotechnology, Ferrara University, Via Fossato di Mortara 74, 44121, Ferrara, Italy.
Biotechnology Center, Ferrara University, Ferrara, Italy.
出版信息
BMC Med Genet. 2017 Aug 29;18(1):93. doi: 10.1186/s12881-017-0450-3.
BACKGROUND
Increase of the expression of γ-globin gene and high production of fetal hemoglobin (HbF) in β-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF-associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify β-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea).
METHODS
Aγ-globin gene sequencing was performed on genomic DNA isolated from a total of 75 β-thalassemia patients, including 31 β39/β39, 33 β39/βIVSI-110, 9 βIVSI-110/βIVSI-110, one βIVSI-1/βIVSI-6 and one β39/βIVSI-6.
RESULTS
The results show that the rs368698783 polymorphism is present in β-thalassemia patients in the 5'UTR sequence (+25) of the Aγ-globin gene, known to affect the LYAR (human homologue of mouse Ly-1 antibody reactive clone) binding site 5'-GGTTAT-3'. This Aγ(+25 G->A) polymorphism is associated with the Gγ-globin-XmnI polymorphism and both are linked with the β39-globin gene, but not with the βIVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the Aγ(+25 G->A) and Gγ-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from β39/β39 thalassemia patients.
CONCLUSIONS
As a potential explanation of our findings, we hypothesize that in β-thalassemia the Gγ-globin-XmnI/Aγ-globin-(G->A) genotype is frequently under genetic linkage with β-thalassemia mutations, but not with the β-thalassemia mutation here studied (i.e. βIVSI-110) and that this genetic combination has been selected within the population of β-thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the Aγ-globin gene associated in β39 thalassemia patients with high HbF in erythroid precursor cells.
背景
β地中海贫血患者中γ珠蛋白基因表达增加及胎儿血红蛋白（HbF）高产量与病情较轻甚至无症状相关，这一观点已被广泛接受。为了根据首次输血预期、每年输血需求、对HbF诱导剂（研究最多的是羟基脲）的反应对β地中海贫血患者进行分层，寻找与HbF相关的多态性（如XmnI、BCL11A和MYB多态性）最近受到了极大关注。
方法
对从总共75例β地中海贫血患者中分离的基因组DNA进行Aγ珠蛋白基因测序，其中包括31例β39/β39、33例β39/βIVSI-110、9例βIVSI-110/βIVSI-110、1例βIVSI-1/βIVSI-6和1例β39/βIVSI-6。
结果
结果显示，rs368698783多态性存在于β地中海贫血患者Aγ珠蛋白基因的5'UTR序列（+25）中，已知该序列会影响LYAR（小鼠Ly-1抗体反应性克隆的人类同源物）结合位点5'-GGTTAT-3'。这种Aγ（+25 G->A）多态性与Gγ珠蛋白-XmnI多态性相关，且两者均与β39珠蛋白基因连锁，但与βIVSI-110珠蛋白基因无关。与该突变改变LYAR结合活性的预期一致，我们发现Aγ（+25 G->A）和Gγ珠蛋白-XmnI多态性与从β39/β39地中海贫血患者分离的红系前体细胞中的高HbF相关。
结论
作为对我们研究结果的一种潜在解释，我们假设在β地中海贫血中，Gγ珠蛋白-XmnI/Aγ珠蛋白-（G->A）基因型经常与β地中海贫血突变处于遗传连锁状态，但与此处研究的β地中海贫血突变（即βIVSI-110）无关，并且由于与高HbF的功能关联，这种遗传组合在β地中海贫血患者群体中被选择。在此，我们描述了β39地中海贫血患者中与红系前体细胞高HbF相关的Aγ珠蛋白基因rs368698783（+25 G->A）多态性的特征。
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