1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France.
Brain. 2014 Aug;137(Pt 8):2329-45. doi: 10.1093/brain/awu138. Epub 2014 Jun 16.
Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.
线粒体 DNA 不稳定性疾病导致了广泛的临床表现，其中肌萎缩侧索硬化症样症状和额颞叶痴呆极为罕见。我们报告了一个大型家族，其发病年龄较晚，包括运动神经元病、类似额颞叶痴呆的认知能力下降、小脑共济失调和肌病。所有患者的肌肉活检均显示破碎红纤维和细胞色素 c 氧化酶阴性纤维，伴有联合呼吸链缺陷和复合物 V 异常组装。骨骼肌中发现的多种线粒体 DNA 缺失表明存在线粒体 DNA 不稳定性疾病。患者成纤维细胞表现出呼吸链缺陷、线粒体超微结构改变和线粒体网络碎片化。有趣的是，表达基质靶向光活化 GFP 表明患者成纤维细胞中线粒体融合并未受到抑制。通过全外显子组测序，我们在编码卷曲螺旋螺旋卷曲螺旋蛋白的 CHCHD10 基因中发现了一个错义突变（c.176C>T;p.Ser59Leu），其功能未知。我们表明 CHCHD10 是一种位于线粒体间空间的线粒体蛋白，在嵴连接处富集。在 HeLa 细胞中过度表达 CHCHD10 突变等位基因会导致线粒体网络碎片化和超微结构主要异常，包括嵴的缺失、紊乱和扩张。在一个线粒体疾病中观察到额颞叶痴呆-肌萎缩侧索硬化症表型，促使我们在 21 个经病理学证实的额颞叶痴呆-肌萎缩侧索硬化症家族的队列中分析 CHCHD10。我们在其中一个家族中发现了相同的错义 p.Ser59Leu 突变。这项工作开辟了一个新的领域，通过表明线粒体疾病可能是这些表型的起源之一，来探索额颞叶痴呆-肌萎缩侧索硬化症临床谱的发病机制。
