A novel mouse model for ataxia-telangiectasia with a N-terminal mutation displays a behavioral defect and a low incidence of lymphoma but no increased oxidative burden
A novel mouse model for ataxia-telangiectasia with a N-terminal mutation displays a behavioral defect and a low incidence of lymphoma but no increased oxidative burden
复制标题
DOI：
10.1093/hmg/ddv342
复制
发表时间：
2015-11-15
影响因子：
3.5
通讯作者：
Mayer-Proeschel, Margot
中科院分区：
文献类型：
--
作者：
Campbell, Andrew;Krupp, Brittany;Mayer-Proeschel, Margot
共济失调毛细血管扩张症是一种罕见的由ATM基因突变引起的多系统疾病。在潜在的基因突变和临床表型中存在显著的异质性。许多小鼠模型已经在该基因的远端区域产生了突变，最近的一项研究表明，在其中一个模型的大脑中存在残留的ATM蛋白。这些小鼠重现了许多在人类身上看到的A-T的特征，除了明显的神经变性。为了研究n端突变如何影响疾病表型，我们建立了一个诱导型Atm突变小鼠模型（Atm(tm1Mmpl/tm1Mmpl)，简称A-T [M]），预测只表达Atm的前62个氨基酸。来自A-T [M]突变小鼠的细胞表现出细胞增殖减少和DNA损伤反应改变，但令人惊讶的是，没有显示出氧化失衡的证据。对A-T [M]动物的检查显示与A-T一致的免疫表型改变。与携带c端Atm突变的小鼠不成比例地发生胸腺淋巴瘤相反，a -t [M]小鼠发生淋巴瘤的比率与人类a -t患者相似。A-T [M]小脑的形态学分析显示，与其他A-T模型相似，没有实质性的细胞缺陷，尽管小鼠表现出与小脑功能障碍一致的行为缺陷。总的来说，这些结果表明，Atm蛋白的丢失并不一定与先前提出的氧化表型相关，并且Atm蛋白的丢失并不足以诱导小鼠小脑变性。
Ataxia-telangiectasia (A-T) is a rare multi-system disorder caused by mutations in the ATM gene. Significant heterogeneity exists in the underlying genetic mutations and clinical phenotypes. A number of mouse models have been generated that harbor mutations in the distal region of the gene, and a recent study suggests the presence of residual ATM protein in the brain of one such model. These mice recapitulate many of the characteristics of A-T seen in humans, with the notable exception of neurodegeneration. In order to study how an N-terminal mutation affects the disease phenotype, we generated an inducible Atm mutant mouse model (Atm(tm1Mmpl/tm1Mmpl), referred to as A-T [M]) predicted to express only the first 62 amino acids of Atm. Cells derived from A-T [M] mutant mice exhibited reduced cellular proliferation and an altered DNA damage response, but surprisingly, showed no evidence of an oxidative imbalance. Examination of the A-T [M] animals revealed an altered immunophenotype consistent with A-T. In contrast to mice harboring C-terminal Atm mutations that disproportionately develop thymic lymphomas, A-T [M] mice developed lymphoma at a similar rate as human A-T patients. Morphological analyses of A-T [M] cerebella revealed no substantial cellular defects, similar to other models of A-T, although mice display behavioral defects consistent with cerebellar dysfunction. Overall, these results suggest that loss of Atm is not necessarily associated with an oxidized phenotype as has been previously proposed and that loss of ATM protein is not sufficient to induce cerebellar degeneration in mice.