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Unannotated single nucleotide polymorphisms in the TATA box of erythropoiesis genes show in vitro positive involvements in cognitive and mental disorders
BMC Medical Genetics Pub Date : 2020-10-22 , DOI: 10.1186/s12881-020-01106-x
Mikhail Ponomarenko , Ekaterina Sharypova , Irina Drachkova , Irina Chadaeva , Olga Arkova , Olga Podkolodnaya , Petr Ponomarenko , Nikolay Kolchanov , Ludmila Savinkova

Hemoglobin is a tetramer consisting of two α-chains and two β-chains of globin. Hereditary aberrations in the synthesis of one of the globin chains are at the root of thalassemia, one of the most prevalent monogenic diseases worldwide. In humans, in addition to α- and β-globins, embryonic zeta-globin and fetal γ-globin are expressed. Immediately after birth, the expression of fetal Aγ- and Gγ-globin ceases, and then adult β-globin is mostly expressed. It has been shown that in addition to erythroid cells, hemoglobin is widely expressed in nonerythroid cells including neurons of the cortex, hippocampus, and cerebellum in rodents; embryonic and adult brain neurons in mice; and mesencephalic dopaminergic brain cells in humans, mice, and rats. Lately, there is growing evidence that different forms of anemia (changes in the number and quality of blood cells) may be involved in (or may accompany) the pathogenesis of various cognitive and mental disorders, such as Alzheimer’s and Parkinson’s diseases, depression of various severity levels, bipolar disorders, and schizophrenia. Higher hemoglobin concentrations in the blood may lead to hyperviscosity, hypovolemia, and lung diseases, which may cause brain hypoxia and anomalies of brain function, which may also result in cognitive deficits. In this study, a search for unannotated single-nucleotide polymorphisms (SNPs) of erythroid genes was initially performed using our previously created and published SNP-TATA_Z-tester, which is a Web service for computational analysis of a given SNP for in silico estimation of its influence on the affinity of TATA-binding protein (TBP) for TATA and TATA-like sequences. The obtained predictions were finally verified in vitro by an electrophoretic mobility shift assay (EMSA). On the basis of these experimental in vitro results and literature data, we studied TATA box SNPs influencing both human erythropoiesis and cognitive abilities. For instance, TBP–TATA affinity in the HbZ promoter decreases 6.6-fold as a result of a substitution in the TATA box (rs113180943), thereby possibly disrupting stage-dependent events of “switching” of hemoglobin genes and thus causing erythroblastosis. Therefore, rs113180943 may be a candidate marker of severe hemoglobinopathies with comorbid cognitive and mental disorders associated with cerebral blood flow disturbances. The literature data and experimental and computations results suggest that the uncovered candidate SNP markers of erythropoiesis anomalies may also be studied in cohorts of patients with cognitive and/or mental disorders with comorbid erythropoiesis diseases in comparison to conventionally healthy volunteers. Research into the regulatory mechanisms by which the identified SNP markers contribute to the development of hemoglobinopathies and of the associated cognitive deficits will allow physicians not only to take timely and adequate measures against hemoglobinopathies but also to implement strategies preventing cognitive and mental disorders.

中文翻译:

TATA盒红细胞生成基因框中未注释的单核苷酸多态性显示了认知和精神障碍的体外正相关

血红蛋白是由球蛋白的两条α链和两条β链组成的四聚体。珠蛋白链之一的合成中的遗传畸变是地中海贫血的根源,地中海贫血是全球最普遍的单基因疾病之一。在人类中,除了α-和β-珠蛋白外,还表达了胚胎的ζ-珠蛋白和胎儿的γ-珠蛋白。出生后立即停止胎儿Aγ-和Gγ-球蛋白的表达,然后主要表达成人β-球蛋白。研究表明,除红系细胞外,血红蛋白在啮齿类动物的非红系细胞中广泛表达,包括皮质,海马和小脑的神经元。小鼠的胚胎和成年脑神经元;和人类,小鼠和大鼠的中脑多巴胺能脑细胞。最近,越来越多的证据表明,各种形式的贫血(血细胞数量和质量的变化)可能参与(或可能伴随)各种认知和精神疾病的发病机制,例如阿尔茨海默氏病和帕金森氏病,各种严重程度的抑郁症,双相情感障碍和精神分裂症。血液中较高的血红蛋白浓度可能导致高粘度,血容量不足和肺部疾病,这可能会导致脑缺氧和脑功能异常,也可能导致认知缺陷。在这项研究中,最初是使用我们先前创建和发布的SNP-TATA_Z-tester对红细胞基因的未注释单核苷酸多态性(SNP)进行搜索,这是一个用于对给定SNP进行计算分析的网络服务,用于通过计算机方式估算其对TATA结合蛋白(TBP)对TATA和TATA样序列的亲和力的影响。最后通过电泳迁移率变动分析(EMSA)在体外验证了获得的预测。根据这些体外实验结果和文献数据,我们研究了影响人红细胞生成和认知能力的TATA盒SNP。例如,由于在TATA盒中的取代,HbZ启动子中的TBP-TATA亲和力降低了6.6倍(rs113180943),从而可能破坏血红蛋白基因“转换”的阶段依赖性事件,从而导致成红细胞增多。因此,rs113180943可能是严重血红蛋白病伴有与脑血流障碍相关的合并性认知和精神疾病的候选标记。文献数据以及实验和计算结果表明,与传统上健康的志愿者相比,患有认知和/或精神障碍合并性红细胞生成病患者的队列中也可能研究未发现的红细胞生成异常的候选SNP标记。对确定的SNP标记有助于血红蛋白病和相关的认知缺陷发展的调控机制的研究将使医生不仅能够及时采取适当的措施来对抗血红蛋白病,而且还可以实施预防认知和精神疾病的策略。文献数据以及实验和计算结果表明,与传统上健康的志愿者相比,患有认知和/或精神障碍合并性红细胞生成病患者的队列中也可能研究未发现的红细胞生成异常的候选SNP标记。对确定的SNP标记有助于血红蛋白病和相关的认知缺陷发展的调控机制的研究将使医生不仅能够及时采取适当的措施来对抗血红蛋白病,而且还可以实施预防认知和精神疾病的策略。文献数据以及实验和计算结果表明,与传统上健康的志愿者相比,患有认知和/或精神障碍合并性红细胞生成病患者的队列中也可能研究未发现的红细胞生成异常的候选SNP标记。对确定的SNP标记有助于血红蛋白病和相关的认知缺陷发展的调控机制的研究将使医生不仅能够及时采取适当的措施来对抗血红蛋白病,而且还可以实施预防认知和精神疾病的策略。
更新日期:2020-10-26
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