Srinoun Kanitta, Svasti Saovaros, Chumworathayee Worrakavee, Vadolas Jim, Vattanaviboon Phantip, Fucharoen Suthat, Winichagoon Pranee
Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Salaya, Phuttamonthon 4 Rd., Phuttamonthon, Nakornpathom, Thailand.
Haematologica. 2009 Sep;94(9):1211-9. doi: 10.3324/haematol.2009.005827. Epub 2009 Jul 16.
beta-thalassemia occurs from the imbalanced globin chain synthesis due to the absence or inadequate beta-globin chain production. The excessive unbound alpha-globin chains precipitate in erythroid precursors and mature red blood cells leading to ineffective erythropoiesis and hemolysis.
In vitro globin chain synthesis in reticulocytes from different types of thalassemic mice was performed. The effect of imbalanced globin chain synthesis was assessed from changes of red blood cell properties including increased numbers of red blood cells vesicles and apoptotic red blood cells, increased reactive oxygen species and decreased red blood cell survival.
The alpha/beta-globin chain ratio in beta(IVSII-654)-thalassemic mice, 1.26+/-0.03, was significantly higher than that of wild type mice, 0.96+/-0.05. The thalassemic mice show abnormal hematologic data and defective red blood cell properties. These values were improved significantly in doubly heterozygous thalassemic mice harboring 4 copies of human beta(E)-globin transgene, with a more balanced globin chain synthesis, 0.92+/-0.05. Moreover, transgenic mice harboring 8 extra copies of the human beta(E)-globin transgene showed inversely imbalanced alpha/beta-globin synthesis ratio, 0.83+/-0.01, that resulted in a mild beta-thalassemia phenotype due to the excessive beta-globin chains. The degree of ineffective erythropoiesis also correlated with the degree of imbalanced globin chain synthesis. Bone marrow and splenic erythroid precursor cells of beta(IVSII-654)-thalassemic mice showed increased phosphatidylserine exposure in basophilic and polychromatophilic stages, which was restored to the normal level in doubly heterozygous mice.
Imbalanced alpha/beta-globin chain as a consequence of either reduction or enhancement of beta-globin chain synthesis can cause abnormal red blood cell properties in mouse models.
β地中海贫血是由于β珠蛋白链生成缺失或不足导致珠蛋白链合成失衡所致。过量未结合的α珠蛋白链在红系前体细胞和成熟红细胞中沉淀，导致无效造血和溶血。
对不同类型地中海贫血小鼠的网织红细胞进行体外珠蛋白链合成实验。通过红细胞特性的变化评估珠蛋白链合成失衡的影响，这些特性包括红细胞囊泡数量增加、凋亡红细胞增多、活性氧增加以及红细胞存活期缩短。
β（IVSII - 654）地中海贫血小鼠的α/β珠蛋白链比值为1.26±0.03，显著高于野生型小鼠的0.96±0.05。地中海贫血小鼠呈现异常血液学数据和有缺陷的红细胞特性。在携带4个人β（E）珠蛋白转基因拷贝的双杂合地中海贫血小鼠中，这些数值显著改善，珠蛋白链合成更为平衡，比值为0.92±0.05。此外，携带8个额外人β（E）珠蛋白转基因拷贝的转基因小鼠显示α/β珠蛋白合成比值反向失衡，为0.83±0.01，由于β珠蛋白链过量导致轻度β地中海贫血表型。无效造血程度也与珠蛋白链合成失衡程度相关。β（IVSII - 654）地中海贫血小鼠的骨髓和脾脏红系前体细胞在嗜碱性和多染性阶段显示磷脂酰丝氨酸暴露增加，在双杂合小鼠中恢复到正常水平。
β珠蛋白链合成减少或增加导致的α/β珠蛋白链失衡可在小鼠模型中引起异常红细胞特性。
