Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency.
Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency.
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DOI：
10.15252/emmm.201404092
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发表时间：
2014-08
影响因子：
11.1
通讯作者：
Hirano M
中科院分区：
文献类型：
--
作者：
Garone C;Garcia-Diaz B;Emmanuele V;Lopez LC;Tadesse S;Akman HO;Tanji K;Quinzii CM;Hirano M
胸苷激酶2基因（TK 2）中的常染色体隐性突变会导致TK 2酶活性丧失导致线粒体DNA耗竭、多处缺失或两者兼而有之，从而导致脱氧核苷酸三磷酸（dNTP）池失衡。为了绕过Tk 2缺陷，我们从出生后第4天开始对Tk 2 H126 N（Tk 2 −/−）基因敲入小鼠模型给予脱氧胞苷和脱氧胸苷一磷酸（dCMP+dTMP），此时突变小鼠表型正常，但生化受到影响。对13日龄Tk 2 −/−小鼠进行的评估表明，在突变动物中，这些化合物提高了dTTP浓度，增加了mtDNA水平，改善了线粒体呼吸链酶的缺陷，并显着延长了它们的寿命（治疗34天，未治疗13天）。dCMP+dTMP各400 mg/kg/天的第二次试验显示出更大的表型和生化改善。总之，dCMP/dTMP补充是Tk 2缺乏症的第一种有效药物治疗。遗传学，基因治疗和遗传疾病;代谢
Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion, multiple deletions, or both due to loss of TK2 enzyme activity and ensuing unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, we administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2 H126N (Tk2−/−) knock-in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Assessment of 13-day-old Tk2−/− mice treated with dCMP+dTMP 200 mg/kg/day each (Tk2−/−200dCMP/dTMP) demonstrated that in mutant animals, the compounds raise dTTP concentrations, increase levels of mtDNA, ameliorate defects of mitochondrial respiratory chain enzymes, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency. Subject Categories Genetics, Gene Therapy & Genetic Disease; Metabolism
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影响因子：
3.5
作者：
Lopez, Luis C.;Akman, Hasan O.;Hirano, Michio
通讯作者：
Hirano, Michio
影响因子：
30.8
作者：
Bourdon, Alice;Minai, Limor;Rotig, Agnes
通讯作者：
Rotig, Agnes
DOI：
10.1007/978-1-61779-504-6_9
发表时间：
2012-01-01
期刊：
MITOCHONDRIAL DISORDERS: BIOCHEMICAL AND MOLECULAR ANALYSIS
影响因子：
--
作者：
Marti, Ramon;Dorado, Beatriz;Hirano, Michio
通讯作者：
Hirano, Michio
影响因子：
30.8
作者：
Saada, A;Shaag, A;Elpeleg, O
通讯作者：
Elpeleg, O
影响因子：
3.5
作者：
Bulst, Stefanie;Abicht, Angela;Horvath, Rita
通讯作者：
Horvath, Rita