{"doi":"10.1093/hmg/ddad054","title":"A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations","abstract":"Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that ligate tRNA molecules to cognate amino acids. Heterozygosity for missense variants or small in-frame deletions in six ARS genes causes dominant axonal peripheral neuropathy. These pathogenic variants reduce enzyme activity without significantly decreasing protein levels and reside in genes encoding homo-dimeric enzymes. These observations raise the possibility that neuropathy-associated ARS variants exert a dominant-negative effect, reducing overall ARS activity below a threshold required for peripheral nerve function. To test such variants for dominant-negative properties, we developed a humanized yeast assay to co-express pathogenic human alanyl-tRNA synthetase (AARS1) mutations with wild-type human AARS1. We show that multiple loss-of-function AARS1 mutations impair yeast growth through an interaction with wild-type AARS1, but that reducing this interaction rescues yeast growth. This suggests that neuropathy-associated AARS1 variants exert a dominant-negative effect, which supports a common, loss-of-function mechanism for ARS-mediated dominant peripheral neuropathy.","journal":"Human Molecular Genetics","year":2023,"id":344169,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1083092,"name":"Sheila Marte","orcid":null,"position":1,"is_corresponding":false},{"id":763466,"name":"T.J. Smith","orcid":"0000-0001-8444-6808","position":2,"is_corresponding":false},{"id":288163,"name":"Shawna Feely","orcid":"0000-0003-1689-1963","position":3,"is_corresponding":false},{"id":486795,"name":"Marina Kennerson","orcid":"0000-0003-3332-5074","position":4,"is_corresponding":false},{"id":291673,"name":"Garth A. Nicholson","orcid":"0000-0001-9694-066X","position":5,"is_corresponding":false},{"id":1083093,"name":"Mike E Shy","orcid":null,"position":6,"is_corresponding":false},{"id":304098,"name":"Kristin S. Koutmou","orcid":"0000-0002-7763-9262","position":7,"is_corresponding":false},{"id":88785,"name":"Anthony Antonellis","orcid":"0000-0002-5820-3156","position":8,"is_corresponding":false},{"id":1082547,"name":"Rebecca Meyer‐Schuman","orcid":"0000-0002-2004-3505","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T01:11:30.951510Z","pmid":"37010095","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}