隐性致病性AARS1变异表现出可变的功能丧失和显性负效应。

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-27 DOI:10.1242/dmm.052006
Molly E Kuo, Kira E Jonatzke, Maclaine Parish, Anthony Antonellis
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引用次数: 0

摘要

Alanyl-tRNA合成酶1 (AARS1)与多系统隐性表型和晚发性显性神经病有关;到目前为止,还没有单一的变异与显性和隐性疾病相关,这引发了关于两种遗传模式之间共享机制的问题。与隐性疾病相关的AARS1变异体导致功能丧失或等位基因的次形,这在一定程度上已通过酵母互补试验得到证实。然而,致病等位基因尚未在并排研究中进行评估。在这里,我们采用人源化酵母模型来评估在隐性疾病中报道的所有AARS1错义变异的功能后果。大多数变异表现出不同的功能丧失效应,从不生长到显著减少生长。这些数据认为酵母是测试AARS1变异影响的可靠模型;然而,我们的数据表明,该模型容易产生假阴性结果,并且不能为基因型-表型研究提供信息。接下来,我们测试了与无生长相关的错义变异的显性负效应。有趣的是,K81T和E99G AARS1同时表现出功能丧失和显性负作用,这表明某些AARS1变异可能导致显性和隐性疾病表型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects.

Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects.

Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects.

Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects.

Alanyl-tRNA synthetase 1 (AARS1) has been implicated in multi-system recessive phenotypes and in later-onset dominant neuropathy; to date, no single variant has been associated with both dominant and recessive diseases, raising questions about shared mechanisms between the two inheritance patterns. AARS1 variants associated with recessive disease result in loss-of-function or hypomorphic alleles, and this has been demonstrated, in part, via yeast complementation assays. However, pathogenic alleles have not been assessed in a side-by-side study. Here, we employed a humanized yeast model to evaluate the functional consequences of all AARS1 missense variants reported in recessive disease. The majority of variants showed variable loss-of-function effects, ranging from no growth to significantly reduced growth. These data deem yeast a reliable model to test the effects of AARS1 variants; however, our data also indicate that this model is prone to false-negative results and is not informative for genotype-phenotype studies. We next tested missense variants associated with no growth for dominant-negative effects. Interestingly, K81T and E99G AARS1 demonstrated both loss-of-function and dominant-negative effects, indicating that certain AARS1 variants can cause both dominant and recessive disease phenotypes.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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