Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion
Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion
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DOI：
10.1038/ng2040
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发表时间：
2007-06-01
期刊：
影响因子：
30.8
通讯作者：
Rotig, Agnes
中科院分区：
文献类型：
--
作者：
Bourdon, Alice;Minai, Limor;Rotig, Agnes
线粒体DNA耗竭综合征(MDS；MIM 251880)是以线粒体DNA拷贝数减少为特征的氧化磷酸化紊乱的普遍原因。迄今已知的疾病机制改变了线粒体DNA复制(Polg(参考文献))。1)或线粒体脱氧核糖核苷5‘-三磷酸(DNTPs)对线粒体DNA合成的挽救途径(DGUOK(Ref.2)，TK2(参考文献3)和SUCLA2(参4))。最后一个基因，MPV17(参考文献5)，没有已知的功能。然而，大多数案件仍未得到解释。通过对4个无关家系的7例线粒体DNA严重缺失(肌肉中残留1-2%的线粒体DNA)的研究，我们发现了编码胞浆P53诱导的核糖核苷酸还原酶小亚基的RRM2B基因的无义、错义和剪接点突变和框内缺失。因此，在Rrm2b(-/-)小鼠的不同组织中发现了严重的mtDNA缺失。在人类和小鼠中，由p53R2改变引发的mtDNA耗竭意味着p53R2在mtDNA合成的dNTP供应中起着至关重要的作用。
Mitochondrial DNA (mtDNA) depletion syndrome (MDS; MIM 251880) is a prevalent cause of oxidative phosphorylation disorders characterized by a reduction in mtDNA copy number. The hitherto recognized disease mechanisms alter either mtDNA replication (POLG (ref. 1)) or the salvage pathway of mitochondrial deoxyribonucleosides 5'- triphosphates (dNTPs) for mtDNA synthesis (DGUOK (ref. 2), TK2 (ref. 3) and SUCLA2 (ref. 4)). A last gene, MPV17 ( ref. 5), has no known function. Yet the majority of cases remain unexplained. Studying seven cases of profound mtDNA depletion (1-2% residual mtDNA in muscle) in four unrelated families, we have found nonsense, missense and splice-site mutations and in-frame deletions of the RRM2B gene, encoding the cytosolic p53-inducible ribonucleotide reductase small subunit. Accordingly, severe mtDNA depletion was found in various tissues of the Rrm2b(-/-) mouse. The mtDNA depletion triggered by p53R2 alterations in both human and mouse implies that p53R2 has a crucial role in dNTP supply for mtDNA synthesis.