Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 Lavrentyev Ave, Novosibirsk, 630090, Russia.
Novosibirsk State University, 1 Pirogova Street, Novosibirsk, 630090, Russia.
BMC Med Genet. 2020 Oct 22;21(Suppl 1):165. doi: 10.1186/s12881-020-01106-x.
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.
血红蛋白是由两条α链和两条β链组成的四聚体。球蛋白合成过程中的遗传异常是导致地中海贫血的根源，地中海贫血是全球最常见的单基因疾病之一。在人类中，除了α和β球蛋白外，胚胎 ζ-球蛋白和胎儿 γ-球蛋白也有表达。出生后，胎儿 Aγ-和 Gγ-球蛋白的表达立即停止，然后主要表达成人 β-球蛋白。已经表明，除了红细胞外，血红蛋白在包括啮齿动物大脑皮层、海马和小脑的神经元在内的非红细胞中广泛表达；在小鼠中，胚胎和成年脑神经元；以及人类、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，不同形式的贫血（血细胞数量和质量的变化）可能参与（或伴随）各种认知和精神障碍的发病机制，如阿尔茨海默病和帕金森病、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、低血容量和肺部疾病，从而导致脑缺氧和脑功能异常，这也可能导致认知缺陷。
在这项研究中，最初使用我们之前创建和发布的 SNP-TATA_Z-tester 搜索红细胞基因的未注释单核苷酸多态性（SNP），这是一种用于计算分析给定 SNP 的 Web 服务，用于估算其对 TATA 结合蛋白（TBP）与 TATA 和 TATA 样序列亲和力的影响。获得的预测结果最终通过电泳迁移率变动分析（EMSA）进行体外验证。
基于这些实验的体外结果和文献数据，我们研究了影响人类红细胞生成和认知能力的 TATA 盒 SNP。例如，TATA 盒中的取代（rs113180943）使 HbZ 启动子中 TBP-TATA 的亲和力降低 6.6 倍，从而可能破坏血红蛋白基因“切换”的阶段依赖性事件，并导致成红细胞增多症。因此，rs113180943 可能是与脑血流紊乱相关的严重血红蛋白病伴认知和/或精神障碍的合并症的候选标记物。
文献数据和实验及计算结果表明，在与常规健康志愿者相比，患有认知和/或精神障碍伴伴发红细胞生成疾病的患者队列中，也可以研究红细胞生成异常的潜在候选 SNP 标记物。研究确定的 SNP 标记物对血红蛋白病发展的调控机制以及相关认知缺陷的研究，不仅可以使医生及时采取适当措施治疗血红蛋白病，还可以制定预防认知和精神障碍的策略。
