Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions:: a novel disorder of mtDNA maintenance
Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions:: a novel disorder of mtDNA maintenance
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DOI：
10.1093/brain/awm272
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发表时间：
2008-02-01
期刊：
影响因子：
14.5
通讯作者：
Taylor, Robert W.
中科院分区：
文献类型：
--
作者：
Hudson, Gavin;Amati-Bonneau, Patrizia;Taylor, Robert W.
参与线粒体DNA（mtDNA）维持的核基因突变导致广泛的临床表型，这些表型与受累组织中多个mtDNA缺失的继发性积累相关。大多数常染色体显性进行性眼外肌麻痹（PEO）家族的基因编码三种特征明确的蛋白质之一- pol gamma，Twinkle或Ant 1突变。在这里，我们表明，杂合错义突变OPA 1导致多个线粒体DNA缺失骨骼肌和嵌合缺陷的细胞色素c氧化酶（考克斯）。该疾病在儿童时期表现为视力障碍和视神经萎缩，随后在成年后出现PEO、共济失调、耳聋和感觉运动神经病变。COX缺陷的骨骼肌纤维包含多个mtDNA缺失的超阈值水平，遗传连锁、测序和表达分析排除了POLG 1、PEO 1和编码Ant 1的基因SLC 25 A4作为原因。这表明OPA 1在mtDNA维持中的重要性，并暗示OPA 1与mtDNA继发性缺陷相关的疾病有关。
Mutations in nuclear genes involved in mitochondrial DNA ( mtDNA) maintenance cause a wide range of clinical phenotypes associated with the secondary accumulation of multiple mtDNA deletions in affected tissues. The majority of families with autosomal dominant progressive external ophthalmoplegia ( PEO) harbour mutations in genes encoding one of three well-characterized proteins - pol gamma, Twinkle or Ant 1. Here we show that a heterozygous mis-sense mutation in OPA1 leads to multiple mtDNA deletions in skeletal muscle and a mosaic defect of cytochrome c oxidase ( COX). The disorder presented with visual failure and optic atrophy in childhood, followed by PEO, ataxia, deafness and a sensory-motor neuropathy in adult life. COX-deficient skeletal muscle fibres contained supra-threshold levels of multiple mtDNA deletions, and genetic linkage, sequencing and expression analysis excluded POLG1, PEO1 and SLC25A4, the gene encoding Ant 1, as the cause. This demonstrates the importance of OPA1 in mtDNA maintenance, and implicates OPA1 in diseases associated with secondary defects of mtDNA.