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.
Neurosci Bull. 2024 Oct;40(10):1489-1501. doi: 10.1007/s12264-024-01231-0. Epub 2024 Jun 13.
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 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.
本研究旨在鉴定一个 90 人的家系中可能的致病基因，该家系具有多种神经退行性疾病表型的罕见组合，这些表型尚未被已知的神经退行性疾病所描绘。我们对患者进行了体格检查和神经系统检查，采用国际评分量表评估共济失调、帕金森病和认知功能的体征，以及 7 个序列的脑磁共振成像扫描。我们通过全基因组测序和连锁分析，寻找异常重复扩展位点、已知脊髓小脑共济失调相关基因的致病变异以及新的罕见突变的共分离。通过桑格测序验证了 CARS 基因中罕见的共分离错义突变，并用分光光度法测定了突变 CARS 的氨酰化活性。该家系呈现了新的迟发性核心特征，包括 9 名受累者的小脑共济失调、帕金森病和锥体束征。脑磁共振成像显示小脑/脑桥萎缩、脑桥中线线性高信号、双侧基底节和小脑齿状核 rCBF 减少，以及小脑齿状核、基底节、中脑红核和黑质低信号，均提示神经退行性变。全基因组测序鉴定了 CARS 基因中的一个新的致病性杂合突变（E795V），同时，在致病基因中未发现已知的重复扩展或点突变。值得注意的是，与野生型相比，该 CARS 突变导致 L-半胱氨酸的 tRNA 氨酰化活性在蛋白质合成中降低了 20%。所有携带杂合突变 CARS（E795V）的家系成员均具有相同的帕金森病和脊髓小脑共济失调的临床表现和神经病理学改变。这些发现确定了帕金森病-脊髓小脑共济失调的新发病机制，并为其遗传结构提供了新的认识。
