Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance
Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance
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DOI：
10.1093/hmg/ddn143
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发表时间：
2008-08-15
影响因子：
3.5
通讯作者：
Hirano, Michio
中科院分区：
文献类型：
--
作者：
Akman, Hasan O.;Dorado, Beatriz;Hirano, Michio
线粒体DNA（mtDNA）耗竭综合征（MDS）是一种常染色体隐性遗传疾病，其特征是受累组织中mtDNA拷贝数和呼吸链酶活性降低。线粒体DNA缺失与9个常染色体基因的突变有关，包括编码普遍存在的线粒体蛋白的胸苷激酶（TK2）。为了研究TK2缺乏症的发病机制，我们产生了携带H126N TK2突变的小鼠。纯合Tk 2突变（Tk 2（-/-））小鼠在10天后迅速出现进行性虚弱，并在2至3周之间死亡。Tk2（-/-）动物表现出Tk2缺陷、不平衡的dNTP池、mtDNA耗竭和含有mtDNA编码亚基的呼吸链酶缺陷，这些缺陷在中枢神经系统中最为突出。组织学检查显示脑脊髓病，脊髓前角有明显的空泡变化。H126N TK2小鼠是第一个人MDS的基因敲入动物模型，并证明组织中TK2缺陷的严重程度可能决定器官特异性表型。
Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA depletion has been associated with mutations in nine autosomal genes, including thymidine kinase (TK2), which encodes a ubiquitous mitochondrial protein. To study the pathogenesis of TK2-deficiency, we generated mice harboring an H126N Tk2 mutation. Homozygous Tk2 mutant (Tk2(-/-)) mice developed rapidly progressive weakness after age 10 days and died between ages 2 and 3 weeks. Tk2(-/-) animals showed Tk2 deficiency, unbalanced dNTP pools, mtDNA depletion and defects of respiratory chain enzymes containing mtDNA-encoded subunits that were most prominent in the central nervous system. Histopathology revealed an encephalomyelopathy with prominent vacuolar changes in the anterior horn of the spinal cord. The H126N TK2 mouse is the first knock-in animal model of human MDS and demonstrates that the severity of TK2 deficiency in tissues may determine the organ-specific phenotype.