A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect
A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect
复制标题
DOI：
10.1016/j.ygeno.2007.05.012
复制
发表时间：
2007-09-01
期刊：
影响因子：
4.4
通讯作者：
Slaugenhaupt, Susan A.
中科院分区：
文献类型：
--
作者：
Hims, Matthew M.;Shetty, Ranjit S.;Slaugenhaupt, Susan A.
家族性自主神经障碍(FD)是一种严重的遗传性感觉和自主神经病变，所有FD患者都存在IKBKAP基因的剪接突变。FD剪接突变导致IKBKAP rnRNA中可变的、组织特异性的外显子20跳过，从而导致IKAP蛋白水平降低。FD治疗方法的发展将需要合适的小鼠模型进行临床前研究。在这项研究中，我们报告了一个携带完整的人类IKBKAP基因座的小鼠模型的产生和特征，该基因带有FD IVS20+6T->；C剪接突变。我们发现突变的IKBKAP转基因在这个模型中以组织特异性的方式错误拼接，复制了在FD患者组织中看到的模式。这种人源化小鼠的创建是开发复杂的FD表型模型的第一步。这些转基因小鼠是测试针对错接缺陷的治疗剂有效性的理想模型系统。最后，这些小鼠将允许对组织特异性剪接进行直接研究，并识别在复杂基因表达中发挥作用的调节因子。(C)2007 Elsevier Inc.保留所有权利。
Familial dysautonomia (FD) is a severe hereditary sensory and autonomic neuropathy, and all patients with FD have a splice mutation in the IKBKAP gene. The FD splice mutation results in variable, tissue-specific skipping of exon 20 in IKBKAP rnRNA, which leads to reduced IKAP protein levels. The development of therapies for FD will require suitable mouse models for preclinical studies. In this study, we report the generation and characterization of a mouse model carrying the complete human IKBKAP locus with the FD IVS20+6T -> C splice mutation. We show that the mutant IKBKAP transgene is misspliced in this model in a tissue-specific manner that replicates the pattern seen in FD patient tissues. Creation of this humanized mouse is the first step toward development of a complex phenotypic model of FD. These transgenic mice are an ideal model system for testing the effectiveness of therapeutic agents that target the missplicing defect. Last, these mice will permit direct studies of tissue-specific splicing and the identification of regulatory factors that play a role in complex gene expression. (c) 2007 Elsevier Inc. All rights reserved.