由CHCHD2突变和线粒体功能障碍引起的早发性帕金森病。
Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunction.
作者信息
Lee Richard G, Sedghi Maryam, Salari Mehri, Shearwood Anne-Marie J, Stentenbach Maike, Kariminejad Ariana, Goullee Hayley, Rackham Oliver, Laing Nigel G, Tajsharghi Homa, Filipovska Aleksandra
机构信息
Centre for Medical Research (R.G.L., A.-M.J.S., M. Stentenbach, H.G., O.R., N.G.L., H.T., A.F.), University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia; Department of Genetics (M. Sedghi), University of Isfahan, Isfahan; Functional Neurosurgery Research Center (M. Salari), Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Kariminejad-Najmabadi Pathology and Genetics Center (A.K.), Tehran, Iran; School of Molecular Sciences (O.R., A.F.), The University of Western Australia, Crawley; Department of Diagnostic Genomics (N.G.L.), PathWest, QEII Medical Centre, Nedlands, Western Australia, Australia; and Division Biomedicine and Public Health (H.T.), School of Health and Education, University of Skovde, Sweden.
出版信息
Neurol Genet. 2018 Oct 5;4(5):e276. doi: 10.1212/NXG.0000000000000276. eCollection 2018 Oct.
OBJECTIVE
Our goal was to identify the gene(s) associated with an early-onset form of Parkinson disease (PD) and the molecular defects associated with this mutation.
METHODS
We combined whole-exome sequencing and functional genomics to identify the genes associated with early-onset PD. We used fluorescence microscopy, cell, and mitochondrial biology measurements to identify the molecular defects resulting from the identified mutation.
RESULTS
Here, we report an association of a homozygous variant in , encoding coiled-coil-helix-coiled-coil-helix domain containing protein 2, a mitochondrial protein of unknown function, with an early-onset form of PD in a 26-year-old Caucasian woman. The mutation in PD patient fibroblasts causes fragmentation of the mitochondrial reticular morphology and results in reduced oxidative phosphorylation at complex I and complex IV. Although patient cells could maintain a proton motive force, reactive oxygen species production was increased, which correlated with an increased metabolic rate.
CONCLUSIONS
Our findings implicate in the pathogenesis of recessive early-onset PD, expanding the repertoire of mitochondrial proteins that play a direct role in this disease.
目的
我们的目标是鉴定与早发型帕金森病（PD）相关的基因以及与该突变相关的分子缺陷。
方法
我们结合全外显子组测序和功能基因组学来鉴定与早发型PD相关的基因。我们使用荧光显微镜、细胞和线粒体生物学测量来鉴定由所鉴定的突变导致的分子缺陷。
结果
在此，我们报告了在一名26岁的白种女性中，编码含卷曲螺旋 - 螺旋 - 卷曲螺旋 - 螺旋结构域蛋白2（一种功能未知的线粒体蛋白）的基因中的纯合变异与早发型PD相关。PD患者成纤维细胞中的该突变导致线粒体网状形态破碎，并导致复合体I和复合体IV处的氧化磷酸化减少。尽管患者细胞能够维持质子动力势，但活性氧的产生增加，这与代谢率增加相关。
结论
我们的发现表明该基因参与隐性早发型PD的发病机制，扩展了在该疾病中起直接作用的线粒体蛋白种类。
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