A Cysteinyl-tRNA Synthetase Mutation Causes Novel Autosomal-Dominant Inheritance of a Parkinsonism/Spinocerebellar-Ataxia Complex
Han‑Kui Liu1,7 · Hong‑Lin Hao2 · Hui You2 · Feng Feng2,4 · Xiu‑Hong Qi3 · Xiao‑Yan Huang1 · Bo Hou4 · Chang‑Geng Tian1 · Han Wang2 · Huan‑Ming Yang1 · Jian Wang1 · Rui Wu5 · Hui Fang6 · Jiang‑Ning Zhou3,8 · Jian‑Guo Zhang1,7 · Zhen‑Xin Zhang21 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 Afliated Hospital of Anhui Medical University, Hefei 230022, China
Abstract
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 tRNACys 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.
Keywords
Parkinsonism; Spinocerebellar ataxia; CARS gene
