Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
Cold Spring Harb Mol Case Stud. 2022 Dec 28;8(7). doi: 10.1101/mcs.a006246. Print 2022 Dec.
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 (, , , , and ) 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 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 (p.Asp308Tyr). Interestingly, p.Asp308Tyr is associated with proximal-predominant motor neuropathy, which has not been reported in patients with pathogenic variants. We demonstrate that this allele causes a loss-of-function effect in yeast complementation assays when modeled in and the yeast ortholog ; structural modeling of this variant further supports a loss-of-function effect. Taken together, this study raises the possibility that certain variants cause proximal-prominent motor neuropathy and indicates that patients with this phenotype should be screened for genetic lesions in .
氨酰-tRNA 合成酶（ARSs）是蛋白质合成中必不可少的关键酶：将 tRNA 分子与对应的氨基酸结合。编码细胞质二聚体 ARS 的五个基因（,,,, 和 ）中的变体杂合性与常染色体显性神经表型有关，包括轴索性夏科-马里-图病（CMT）。催化结构域中的错义变体 先前与显性中间型 CMT 型 C（DI-CMTC）有关。在这里，我们报告了一名患者，其 中的一个意义不明的错义变体，预测会改变反密码子结合域中残基 308（p.Asp308Tyr）。有趣的是，p.Asp308Tyr 与近端为主的运动神经病有关，而在致病性 变体患者中尚未报道过。我们证明，当在 和酵母同源物 中建模时，该等位基因在酵母互补测定中会导致功能丧失效应；对该变体的结构建模进一步支持了功能丧失效应。总之，这项研究提出了某些 变体可能导致近端突出运动神经病的可能性，并表明具有这种表型的患者应筛查 中的遗传病变。
