Molly E Kuo, Kira E Jonatzke, Maclaine Parish, Anthony Antonellis
{"title":"隐性致病性AARS1变异表现出可变的功能丧失和显性负效应。","authors":"Molly E Kuo, Kira E Jonatzke, Maclaine Parish, Anthony Antonellis","doi":"10.1242/dmm.052006","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233060/pdf/","citationCount":"0","resultStr":"{\"title\":\"Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects.\",\"authors\":\"Molly E Kuo, Kira E Jonatzke, Maclaine Parish, Anthony Antonellis\",\"doi\":\"10.1242/dmm.052006\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":11144,\"journal\":{\"name\":\"Disease Models & Mechanisms\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233060/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Disease Models & Mechanisms\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1242/dmm.052006\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Disease Models & Mechanisms","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1242/dmm.052006","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/27 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
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.
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.