Jamsai Duangporn, Zaibak Faten, Vadolas Jim, Voullaire Lucille, Fowler Kerry J, Gazeas Sophie, Peters Heidi, Fucharoen Suthat, Williamson Robert, Ioannou Panayiotis A
Cell and Gene Therapy Research Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
Genomics. 2006 Sep;88(3):309-15. doi: 10.1016/j.ygeno.2006.03.009. Epub 2006 May 2.
Hemoglobin E (HbE) is caused by a G-->A mutation at codon 26 of the beta-globin gene, which substitutes Glu-->Lys. This mutation gives rise to functional but unstable hemoglobin and activates a cryptic splice site causing mild anemia. HbE reaches a carrier frequency of 60-80% in some Southeast Asian populations. HbE causes serious disease when co-inherited with a beta-thalassemia mutation. In this study, we report the creation and evaluation of humanized transgenic mice containing the beta(E) mutation in the context of the human beta-globin locus. Developmental expression of the human beta(E) locus transgene partially complements the hematological abnormalities in heterozygous knockout mice ((mu)beta(th-3/+)) and rescues the embryonic lethality of homozygous knockout mice ((mu)beta(th-3/th-3)). The phenotype of rescued mice was dependent on the transgene copy number. This mouse model displays hematological abnormalities similar to HbE/beta-thalassemia patients and represent an ideal in vivo model system for pathophysiological studies and evaluation of novel therapies.
血红蛋白E（HbE）是由β-珠蛋白基因第26密码子处的G→A突变引起的，该突变使谷氨酸（Glu）被赖氨酸（Lys）取代。这种突变产生了有功能但不稳定的血红蛋白，并激活了一个隐蔽的剪接位点，导致轻度贫血。在一些东南亚人群中，HbE的携带频率达到60%-80%。当与β-地中海贫血突变共同遗传时，HbE会导致严重疾病。在本研究中，我们报告了在人β-珠蛋白基因座背景下含有β（E）突变的人源化转基因小鼠的创建和评估。人β（E）基因座转基因的发育表达部分弥补了杂合敲除小鼠（（μ）β（th-3/+））的血液学异常，并挽救了纯合敲除小鼠（（μ）β（th-3/th-3））的胚胎致死性。获救小鼠的表型取决于转基因拷贝数。该小鼠模型表现出与HbE/β-地中海贫血患者相似的血液学异常，是病理生理学研究和新疗法评估的理想体内模型系统。
