A Cysteinyl-tRNA Synthetase Mutation Causes Novel Autosomal-Dominant Inheritance of a Parkinsonism/Spinocerebellar-Ataxia Complex  

作　　者：Han-Kui Liu Hong-Lin Hao Hui You Feng Feng Xiu-Hong Qi Xiao-Yan Huang Bo Hou Chang-Geng Tian Han Wang Huan-Ming Yang Jian Wang Rui Wu Hui Fang Jiang-Ning Zhou Jian-Guo Zhang Zhen-Xin Zhang 

机构地区：[1]BGI Genomics and BGI Research,Shenzhen 518083,China [2]Department of Neurology,Clinical Epidemiology Unit,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Beijing 100730,China [3]Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230026,China [4]Department of Radiology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Beijing 100730,China [5]Department of Pathology,Beijing Key Laboratory of Biomarker Research and Transformation for Neurodegenerative Diseases,Peking University Third Hospital,School of Basic Medical Sciences,Peking University Health Science Center,Beijing 100191,China [6]Anhui Provincial Children's Hospital,Children's Hospital of Fudan University,Hefei 230051,China [7]Hebei Industrial Technology Research Institute of Genomics in Maternal and Child Health,Clin Lab,BGI Genomics,Shijiazhuang 050011,China [8]Institute of Brain Science,The First Affliated Hospital of Anhui Medical University,Hefei 230022,China

出　　处：《Neuroscience Bulletin》2024年第10期1489-1501,共13页神经科学通报（英文版）

基　　金：supported by the NIH-NIA Research Project (R21AG036454);the National Key R&D Program of China (2016YFC0901500);CAMS Innovation Fund for Medical Sciences (2016-12M-1-004);the National Key R&D Program of China (2016YFC1305900);the National Natural Science Foundation of China (3203004);the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB02030001);Shenzhen Municipal of Government of China (JCYJ20170412153248372 and JCYJ20180507183615145).

摘　　要：This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes,which has not been depicted by the known neurodegenerative disease.We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia,Parkinsonism,and cognitive function,as well as brain magnetic resonance imaging scans with seven sequences.We searched for co-segregations of abnormal repeat-expansion loci,pathogenic variants in known spinocerebellar ataxiarelated genes,and novel rare mutations via whole-genome sequencing and linkage analysis.A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay.This pedigree presented novel late-onset core characteristics including cerebellar ataxia,Parkinsonism,and pyramidal signs in all nine affected members.Brain magnetic resonance imaging showed cerebellar/pons atrophy,pontine-midline linear hyperintensity,decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus,and hypo-intensities of the cerebellar dentate nuclei,basal ganglia,mesencephalic red nuclei,and substantia nigra,all of which suggested neurodegeneration.Whole-genome sequencing identified a novel pathogenic heterozygous mutation(E795V)in the CARS gene,meanwhile,exhibited none of the known repeat-expansions or point mutations in pathogenic genes.Remarkably,this CARS mutation causes a 20%decrease in aminoacylation activity to charge tRNA^(Cys) with L-cysteine in protein synthesis compared with that of the wild type.All family members carrying a heterozygous mutation CARS(E795V)had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia.These findings identify novel pathogenesis of Parkinsonismspinocerebellar ataxia and provide insights into its genetic architecture.

关 键 词：PARKINSONISM Spinocerebellar ataxia CARS gene 

分 类 号：R742.5[医药卫生—神经病学与精神病学]