Greaves D R, Fraser P, Vidal M A, Hedges M J, Ropers D, Luzzatto L, Grosveld F
Laboratory of Gene Structure and Expression, National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.
Nature. 1990 Jan 11;343(6254):183-5. doi: 10.1038/343183a0.
A single base-pair mutation (beta s) in codon 6 of the human beta-globin gene, causing a single amino-acid substitution, is the cause of sickle cell anaemia. The mutant haemoglobin molecule, HbS, polymerizes when deoxygenated and causes deformation of the erythrocytes to a characteristic 'sickled' shape. Sickling of cells in small vessels causes painful crises and other life-threatening complications. Although the molecular basis for sickle cell anaemia has been known for 30 years, no definitive treatment is available. An animal model of sickle cell anaemia would not only allow a detailed analysis of the factors that initiate erythrocyte sickling in vivo and of the pathophysiology of the disease, but would also permit the development of novel approaches to the treatment of the disease. By using the dominant control region sequences from the human beta-globin locus, together with human alpha- and beta s-globin genes, we have obtained three transgenic mice with HbS levels ranging from 10 to 80% of total haemoglobin in their red cells. As observed in homozygous and heterozygous Hbs patients, the erythrocytes of this mouse sickle readily on deoxygenation. Irreversibly sickled cells, which are characteristic of sickle-cell patients homozygous for beta s, are also observed in the peripheral blood of the mouse with high levels of HbS.
人类β-珠蛋白基因第6密码子处的单个碱基对突变（βs）导致单个氨基酸替换，是镰状细胞贫血的病因。突变的血红蛋白分子HbS在脱氧时会聚合，并导致红细胞变形为特征性的“镰状”形状。小血管中细胞的镰变会引发疼痛危机和其他危及生命的并发症。尽管镰状细胞贫血的分子基础已为人所知30年，但尚无确切的治疗方法。镰状细胞贫血的动物模型不仅可以详细分析体内引发红细胞镰变的因素以及该疾病的病理生理学，还可以开发治疗该疾病的新方法。通过使用人类β-珠蛋白基因座的显性控制区序列，以及人类α-和βs-珠蛋白基因，我们获得了三只转基因小鼠，其红细胞中HbS水平占总血红蛋白的10%至80%。正如在纯合和杂合Hbs患者中观察到的那样，这种小鼠的红细胞在脱氧时很容易发生镰变。在HbS水平较高的小鼠外周血中也观察到了不可逆镰状细胞，这是βs纯合镰状细胞患者的特征。
