The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease
Abstract
BACKGROUND: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS: lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
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“Singh et al. reported that autoreactive B cell clones from patients with Sjogren's syndrome-associated cryoglobulinemic vasculitis harboured mutations in genes recurrently mutated in B cell lymphomas, despite the absence of malignancy at the time of analysis 192 .”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [192]
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International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma
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Metadata
- Authors
- Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Ospina Cardona, D., Wu, Z., Patel, B., Manthiram, K., Groarke, E. M., Gutierrez-Rodrigues, F., Hoffmann, P., Rosenzweig, S., Nakabo, S., Dillon, L. W., Hourigan, C. S., Tsai, W. L., Gupta, S., Carmona-Rivera, C., Asmar, A. J., Xu, L., Oda, H., Goodspeed, W., Barron, K. S., Nehrebecky, M., Jones, A., Laird, R. S., Deuitch, N., Rowczenio, D., Rominger, E., Wells, K. V., Lee, C.-C. R., Wang, W., Trick, M., Mullikin, J., Wigerblad, G., Brooks, S., Dell’Orso, S., Deng, Z., Chae, J. J., Dulau-Florea, A., Malicdan, M. C. V., Novacic, D., Colbert, R. A., Kaplan, M. J., Gadina, M., Savic, S., Lachmann, H. J., Abu-Asab, M., Solomon, B. D., Retterer, K., Gahl, W. A., Burgess, S. M., Aksentijevich, I., Young, N. S., Calvo, K. R., Werner, A., Kastner, D. L., & Grayson, P. C.
- Affiliations
- From the National Human Genome Research Institute (D.B.B., A.K.O., W.P., N.B., D.L.R., D.O.C., K.M., P.H., S.R., L.X., H.O., M.N., A.J., R.S.L., N.D., J.J.C., M.C.V.M., D.N., B.D.S., W.A.G., S.M.B., I.A., D.L.K.), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (M.A.F., K.A.S., S.N., W.L.T., S.G., C.C.-R., W.G., E.R., K.V.W., G.W., S.B., S.D., Z.D., R.A.C., M.J.K., M.G., P.C.G.), the National Institute of Dental and Craniofacial Research (J.C.C., A.J.A., A.W.), the Undiagnosed Diseases Program, Common Fund, Office of the Director (N.B., D.L.R., M.C.V.M., D.N., W.A.G.), the Hematology Branch, National Heart, Lung, and Blood Institute (Z.W., B.P., E.M.G., F.G.-R., L.W.D., C.S.H., N.S.Y.), the National Institute of Allergy and Infectious Diseases (K.S.B.), the Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (C.-C.R.L.), the National Institutes of Health (NIH) Intramural Sequencing Center, National Human Genome Research Institute (J.M.), the Department o...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-12-31
- Volume
- 383
- Issue
- 27
- Pages
- 2628-2638
- ISSN
- 0028-4793
- 1533-4406
- PMC
- PMC7847551
- Cited by
- 1,206
- References
- 44
- Language
- en
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- Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Ospina Cardona, D., Wu, Z., Patel, B., Manthiram, K., Groarke, E. M., Gutierrez-Rodrigues, F., Hoffmann, P., Rosenzweig, S., Nakabo, S., Dillon, L. W., Hourigan, C. S., . . . Grayson, P. C. (2020). Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. New England Journal of Medicine. https://doi.org/10.1056/nejmoa2026834
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