{"doi":"10.1038/s41375-025-02775-4","title":"Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations","abstract":"VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe inflammatory and hematologic disease caused by somatic mutations in UBA1. Canonical pathogenic mutations at UBA1 p.Met41 (M41) lead to the loss of the cytoplasmic isoform (UBA1b), while non-canonical mutations outside of M41 (non-M41) result in reduced activity of both nuclear and cytoplasmic isoforms. Studies have reported clinical differences between canonical and non-canonical mutations, but these findings are constrained by small sample sizes and scarcity of genetic studies. In our study, we screened 29,000 individuals for UBA1 variants, referred for a broad range of hematologic diseases, and subjected to 62-gene panel sequencing, identifying 232 patients carrying likely disease-causing mutations. We identified decreased polyubiquitylation in all of the 18 UBA1 variants tested and found differences in H2A/B monoubiquitylation alteration between M41 and non-M41 mutations. Our findings confirm that patients harboring M41 mutations present at most with myelodysplastic neoplasms (MDS) and suggest that M41 mutations generally do not tolerate multiple co-mutations. In contrast, non-M41 mutations are more likely to appear with co-mutations and are detected in patients with hematologic neoplasms other than MDS. Our study establishes that M41 and non-M41 mutations exhibit distinct clinical and biological phenotypes, significantly enhancing UBA1 variant interpretation.","journal":"Leukemia","year":2025,"id":522194,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9658,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1394173,"name":"Amy K. Wang","orcid":null,"position":1,"is_corresponding":false},{"id":941877,"name":"Samuel J. Magaziner","orcid":"0000-0002-5345-217X","position":2,"is_corresponding":false},{"id":1394174,"name":"Sachiko P. Keane","orcid":null,"position":3,"is_corresponding":false},{"id":323648,"name":"Manja Meggendorfer","orcid":"0000-0002-9038-3265","position":4,"is_corresponding":false},{"id":615123,"name":"Wolfgang Kern","orcid":"0000-0002-6452-2874","position":5,"is_corresponding":false},{"id":623973,"name":"Claudia Haferlach","orcid":"0000-0002-6333-5049","position":6,"is_corresponding":false},{"id":323649,"name":"Torsten Haferlach","orcid":"0000-0003-0196-2837","position":7,"is_corresponding":false},{"id":218218,"name":"David B. Beck","orcid":"0000-0002-5884-6231","position":8,"is_corresponding":false},{"id":769382,"name":"Wencke Walter","orcid":"0000-0002-5083-9838","position":9,"is_corresponding":false},{"id":1393596,"name":"Maki Sakuma","orcid":"0000-0001-7579-6232","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:49:54.058858Z","pmid":"41068485","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":[]}