Hematology, Hospital Clínico San Carlos, Madrid, Spain
Hematology, Hospital Clínico San Carlos, Madrid, Spain.
J Clin Pathol. 2020 Jan;73(1):14-16. doi: 10.1136/jclinpath-2019-206004. Epub 2019 Aug 21.
Untranslated regions (UTRs) play an important role in post-transcriptional regulation of gene expression, including by modulating messenger RNA (mRNA) transport out of the nucleus, translation efficiency, subcellular localisation and stability. Any mutation in this region could alter the stability of mRNA and thereby affect protein synthesis. We analysed if a mutation located in the α complex protected region of the α1 globin gene could cause non-deletional α-thalassaemia by affecting post-transcriptional stability (mRNA stability).
A total of 14 patients without anaemia, normal or slight microcytosis and hypochromia (medium concentration haemoglobin [MCH] <27 pg) were studied. Haemoglobin subtypes were screened using capillary zone electrophoresis and ion-exchange high-performance liquid chromatography (VARIANT II β-Thalassaemia Short Program). The most common α-globin mutations were identified by multiplex PCR (Alpha-Globin StripAssay kit) and the molecular characterisation by automatic sequencing of alpha globin genes.
All of them shown a novel transversion mutation in nt 778 (C>A), which is located in the 3' UTR in the α complex protected region [HBA1: c.*+46C>A].
This mutation is in the αRNAmin binding site, so a single nucleotide substitution in this region can decrease mRNA stability by potentially compromising the binding of α-complex protein to αRNAmin, favouring the decay of α-globin mRNA via erythroid cell-enriched endoribonuclease cleavage. In this case, it is a non-deletional α-thalassaemia. However, in silico and empirical studies predicted that it could be a silent polymorphism. Functional studies should be carried out to confirm whether it is a pathological mutation or a silent polymorphism.
非翻译区（UTR）在基因表达的转录后调控中发挥重要作用，包括调节信使 RNA（mRNA）从核内输出、翻译效率、亚细胞定位和稳定性。该区域的任何突变都可能改变 mRNA 的稳定性，从而影响蛋白质合成。我们分析了位于α珠蛋白基因α1 复合体保护区域的一个突变是否可以通过影响转录后稳定性（mRNA 稳定性）导致非缺失型α-地中海贫血。
共研究了 14 名无贫血、正常或轻度小细胞低色素（中浓度血红蛋白 [MCH] <27 pg）的患者。使用毛细管区带电泳和离子交换高效液相色谱（VARIANT II β-地中海贫血短程序）筛选血红蛋白亚型。通过多重 PCR（Alpha-Globin StripAssay 试剂盒）鉴定最常见的α-珠蛋白突变，并通过α-珠蛋白基因自动测序进行分子特征分析。
他们均显示出 nt778（C>A）的新型颠换突变，位于α复合体保护区域的 3'UTR 中[HBA1：c.*+46C>A]。
该突变位于αRNAmin 结合位点，因此该区域的单个核苷酸取代可能通过潜在损害α 复合体蛋白与αRNAmin 的结合来降低 mRNA 稳定性，从而通过红细胞丰富的内切核酸酶切割促进α-珠蛋白 mRNA 的降解。在这种情况下，它是非缺失型α-地中海贫血。然而，基于计算机预测和经验研究表明，它可能是一种沉默多态性。应进行功能研究以确认其是否为病理性突变或沉默多态性。
