Jamsai Duangporn, Zaibak Faten, Khongnium Wantana, Vadolas Jim, Voullaire Lucille, Fowler Kerry J, Gazeas Sophie, Fucharoen Suthat, Williamson Robert, Ioannou Panayiotis A
CAGT Research Group, The Murdoch Children's Research Institute, Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Flemington Road, Melbourne, VIC 3052, Australia.
Genomics. 2005 Apr;85(4):453-61. doi: 10.1016/j.ygeno.2004.11.016.
Accurate animal models that recapitulate the phenotype and genotype of patients with beta-thalassemia would enable the development of a range of possible therapeutic approaches. Here we report the generation of a mouse model carrying the codons 41-42 (-TTCT) beta-thalassemia mutation in the intact human beta-globin locus. This mutation accounts for approximately 40% of beta-thalassemia mutations in southern China and Thailand. We demonstrate a low level of production of gamma-globins from the mutant locus in day 18 embryos, as well as production of mutant human beta-globin mRNA. However, in contrast to transgenic mice carrying the normal human beta-globin locus, 4-bp deletion mice fail to show any phenotypic complementation of the knockout mutation of both murine beta-globin genes. Our studies suggest that this is a valuable model for gene correction in hemopoietic stem cells and for studying the effects of HbF inducers in vivo in a "humanized" thalassemic environment.
能够重现β地中海贫血患者表型和基因型的精确动物模型，将有助于开发一系列可能的治疗方法。在此，我们报告了在完整的人类β珠蛋白基因座中携带41-42密码子（-TTCT）β地中海贫血突变的小鼠模型的构建。该突变在中国南方和泰国约占β地中海贫血突变的40%。我们证明，在第18天的胚胎中，突变基因座产生的γ珠蛋白水平较低，同时也产生了突变的人类β珠蛋白mRNA。然而，与携带正常人β珠蛋白基因座的转基因小鼠不同，4碱基缺失小鼠未能显示出对两个小鼠β珠蛋白基因敲除突变的任何表型互补。我们的研究表明，这是一个用于造血干细胞基因校正以及在“人源化”地中海贫血环境中体内研究HbF诱导剂作用的有价值模型。
