北京协和医院张振馨和华大基因张国捷合作，近期取得重要工作进展。他们研究提出，胱氨酰-tRNA合成酶突变导致帕金森病/小脑共济失调症复合体的新型常染色体显性遗传。相关研究成果2024年6月13日在线发表于《神经科学通报》杂志上。

据介绍，这一研究旨在确定一个90人家族中可能的致病基因，该家族具有多种神经退行性疾病表型的罕见组合，而已知的神经退行性病变尚未描述这种表型。

研究人员用国际评定量表进行了身体和神经检查，以评估共济失调、帕金森病和认知功能的症状，并用七个序列进行了脑磁共振成像扫描。研究人员通过全基因组测序和连锁分析，寻找异常重复扩增基因座的共分离、已知脊髓小脑共济失调相关基因的致病性变异和新的罕见突变。通过Sanger测序验证了CARS基因中一个罕见的共分离错义突变，并通过分光光度法测定了突变CARS的氨基酰化活性。该谱系在所有9名受影响成员中都表现出新的晚发核心特征，包括小脑共济失调、帕金森病和锥体细胞体征。

脑磁共振成像显示小脑/桥脑萎缩，桥中线线性高信号，双侧基底节和小脑齿状核rCBF降低，小脑齿状核、基底节、中脑红核和黑质低强度，均提示神经退行性变。全基因组测序在CARS基因中发现了一种新的致病性杂合突变（E795V），同时在致病基因中没有显示出已知的重复扩增或点突变。值得注意的是，与野生型相比，这种CARS突变导致蛋白质合成中用L-半胱氨酸充电tRNA^Cys的氨基酰化活性降低20%。所有携带杂合突变CARS（E795V）的家庭成员都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变化。

总之，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见解。

附：英文原文

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

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

Issue&Volume: 2024-06-13

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.

DOI: 10.1007/s12264-024-01231-0

Source: https://link.springer.com/article/10.1007/s12264-024-01231-0