OPA1 mutations induce mitochondrial DNA instability and optic atrophy plus phenotypes
OPA1 mutations induce mitochondrial DNA instability and optic atrophy plus phenotypes
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DOI：
10.1093/brain/awm298
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发表时间：
2008-02-01
期刊：
影响因子：
14.5
通讯作者：
Carelli, Valerio
中科院分区：
文献类型：
--
作者：
Amati-Bonneau, Patrizia;Valentino, Maria Lucia;Carelli, Valerio
OPA1是一种参与线粒体融合、嵴组织和细胞凋亡控制的动力蛋白相关GT3，其突变与作为常染色体显性遗传性状（DOA）传播的非综合征性视神经病变有关。我们在这里报告了来自六个独立家庭的八名患者，表明OPA 1基因的突变也可能导致与感音神经性耳聋、共济失调、轴突感觉运动多发性神经病、慢性进行性眼外肌麻痹和线粒体肌病相关的综合征形式的DOA。细胞色素c氧化酶阴性和破碎的红纤维。最值得注意的是，我们证明，这些患者的骨骼肌中都有线粒体DNA（mtDNA）的多重缺失，从而揭示了OPA1蛋白在mtDNA稳定性中未被认识到的作用。与这些DOA plus表型相关的5个OPA1突变均为影响高度保守氨基酸位置的错义点突变，并且排除了先前已知诱导mtDNA多重缺失的核基因，如POLG 1、PEO 1（Twinkle）和SLC 25 A4（ANT 1）。我们的研究结果表明，某些OPA1突变发挥了显性负效应，负责多系统疾病，密切相关的经典线粒体细胞病变，涉及mtDNA的不稳定性的机制。
Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA plus phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability.