MOUSE MODEL OF HUMAN BETA(0) THALASSEMIA - TARGETED DELETION OF THE MOUSE BETA(MAJ)-GLOBIN AND BETA(MIN)-GLOBIN GENES IN EMBRYONIC STEM CELLS
MOUSE MODEL OF HUMAN BETA(0) THALASSEMIA - TARGETED DELETION OF THE MOUSE BETA(MAJ)-GLOBIN AND BETA(MIN)-GLOBIN GENES IN EMBRYONIC STEM CELLS
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DOI：
10.1073/pnas.92.20.9259
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发表时间：
1995-09-26
影响因子：
11.1
通讯作者：
TOWNES, TM
中科院分区：
文献类型：
--
作者：
CIAVATTA, DJ;RYAN, TM;TOWNES, TM
β（0）-地中海贫血是一种遗传性疾病，其特征在于缺乏源自受影响等位基因的β-珠蛋白多肽。这种缺陷的分子基础是成人β-珠蛋白结构基因或控制β-珠蛋白基因表达的顺式调节元件的突变。这种疾病的小鼠模型将使治疗方案的测试，旨在纠正缺陷，在这里，我们报告了一个16 kb的缺失，包括成人β样珠蛋白基因，β（maj）和β（maj），在小鼠胚胎干细胞。来自靶细胞的杂合子动物严重贫血，血红蛋白水平显著降低，红细胞形态异常，脾肿大，网织红细胞计数显著增加，纯合子动物在子宫内死亡;然而，杂合小鼠是可育的，并将缺失的等位基因传递给后代，贫血表型在来自交配β（0）-地中海贫血动物与表达高水平人血红蛋白A的转基因小鼠，β（0）-地中海贫血小鼠可用于测试β（0）-地中海贫血的基因疗法。地中海贫血，并且可以与表达高水平的人血红蛋白HbS的转基因小鼠一起繁殖，以产生镰状细胞病的改进的小鼠模型。
beta(0)-Thalassemia is an inherited disorder characterized by the absence of beta-globin polypeptides derived from the affected allele, The molecular basis for this deficiency is a mutation of the adult beta-globin structural gene or cis regulatory elements that control beta-globin gene expression. A mouse model of this disease would enable the testing of therapeutic regimens designed to correct the defect, Here we report a 16-kb deletion that includes both adult beta-like globin genes, beta(maj) and beta(maj), in mouse embryonic stem cells. Heterozygous animals derived from the targeted cells are severely anemic with dramatically reduced hemoglobin levels, abnormal red cell morphology, splenomegaly, and markedly increased reticulocyte counts, Homozygous animals die in utero; however, heterozygous mice are fertile and transmit the deleted allele to progeny, The anemic phenotype is completely rescued in progeny derived from mating beta(0)-thalassemic animals with transgenic mice expressing high levels of human hemoglobin A, The beta(0)-thalassemic mice can be used to test genetic therapies for beta(0)-thalassemia and can be bred with transgenic mice expressing high levels of human hemoglobin HbS to produce an improved mouse model of sickle cell disease.