一名近端占主导地位的运动神经病患者的一种错义、功能丧失的YARS1变体。

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Cold Spring Harbor Molecular Case Studies Pub Date : 2022-12-28 Print Date: 2022-12-01 DOI:10.1101/mcs.a006246
Megan E Forrest, Alayne P Meyer, Stephanie M Laureano Figueroa, Anthony Antonellis
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引用次数: 0

摘要

氨酰基tRNA合成酶(ARSs)是在蛋白质合成中发挥关键作用的必需酶:用同源氨基酸为tRNA分子充电。编码细胞质二聚体ARS的五个基因(AARS1、GARS1、HARS1、WARS1和YARS1)变体的杂合性与常染色体显性神经表型有关,包括轴索性Charcot-Marie Tooth病(CMT)。YARS1催化结构域中的错义变体先前与C型显性中间体CMT(DI-CMTC)连接。在这里,我们报道了一名患者,其具有未知意义的错义变体,预测会修饰YARS1的反密码子结合结构域中的残基308(p.Asp308Tyr)。有趣的是,p.Asp308.Tyr与近端显性运动神经病有关,而在致病性YARS1变体的患者中尚未报道。我们证明,当在YARS1和酵母直系同源物TYS1中建模时,该等位基因在酵母互补测定中引起功能丧失效应;该变体的结构建模进一步支持功能损失效应。总之,这项研究提出了某些YARS1变体导致近端突出运动神经病变的可能性,并表明具有这种表型的患者应筛查YARS1的遗传病变。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A missense, loss-of-function <i>YARS1</i> variant in a patient with proximal-predominant motor neuropathy.

A missense, loss-of-function YARS1 variant in a patient with proximal-predominant motor neuropathy.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes with a critical role in protein synthesis: charging tRNA molecules with cognate amino acids. Heterozygosity for variants in five genes (AARS1, GARS1, HARS1, WARS1, and YARS1) encoding cytoplasmic, dimeric ARSs have been associated with autosomal dominant neurological phenotypes, including axonal Charcot-Marie-Tooth disease (CMT). Missense variants in the catalytic domain of YARS1 were previously linked to dominant intermediate CMT type C (DI-CMTC). Here, we report a patient with a missense variant of unknown significance predicted to modify residue 308 in the anticodon binding domain of YARS1 (p.Asp308Tyr). Interestingly, p.Asp308Tyr is associated with proximal-predominant motor neuropathy, which has not been reported in patients with pathogenic YARS1 variants. We demonstrate that this allele causes a loss-of-function effect in yeast complementation assays when modeled in YARS1 and the yeast ortholog TYS1; structural modeling of this variant further supports a loss-of-function effect. Taken together, this study raises the possibility that certain YARS1 variants cause proximal-prominent motor neuropathy and indicates that patients with this phenotype should be screened for genetic lesions in YARS1.

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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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