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

Autor: Liu HK; BGI Genomics and BGI Research, Shenzhen, 518083, China.; Hebei Industrial Technology Research Institute of Genomics in Maternal and Child Health, Clin Lab, BGI Genomics, Shijiazhuang, 050011, China., Hao HL; Department of Neurology, Clinical Epidemiology Unit, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China., You H; Department of Neurology, Clinical Epidemiology Unit, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China., Feng F; Department of Neurology, Clinical Epidemiology Unit, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.; Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China., Qi XH; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China., Huang XY; BGI Genomics and BGI Research, Shenzhen, 518083, China., Hou B; Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China., Tian CG; BGI Genomics and BGI Research, Shenzhen, 518083, China., Wang H; Department of Neurology, Clinical Epidemiology Unit, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China., Yang HM; BGI Genomics and BGI Research, Shenzhen, 518083, China., Wang J; BGI Genomics and BGI Research, Shenzhen, 518083, China., Wu R; 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., Fang H; Anhui Provincial Children's Hospital, Children's Hospital of Fudan University, Hefei, 230051, China., Zhou JN; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.; Institute of Brain Science, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China., Zhang JG; BGI Genomics and BGI Research, Shenzhen, 518083, China. zhangjg@genomics.cn.; Hebei Industrial Technology Research Institute of Genomics in Maternal and Child Health, Clin Lab, BGI Genomics, Shijiazhuang, 050011, China. zhangjg@genomics.cn., Zhang ZX; Department of Neurology, Clinical Epidemiology Unit, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China. wuzhangzhenxin@163.com.
Jazyk: angličtina
Zdroj: Neuroscience bulletin [Neurosci Bull] 2024 Oct; Vol. 40 (10), pp. 1489-1501. Date of Electronic Publication: 2024 Jun 13.
DOI: 10.1007/s12264-024-01231-0
Abstrakt: 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 ataxia-related 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 Parkinsonism-spinocerebellar ataxia and provide insights into its genetic architecture.
(© 2024. The Author(s).)
Databáze: MEDLINE
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