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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

Beck, David B., Ferrada, Marcela A., Sikora, Keith A., Ombrello, Amanda K., Collins, Jason C., Pei, Wuhong, Balanda, Nicholas, Ross, Daron L., Ospina Cardona, Daniela, Wu, Zhijie, Patel, Bhavisha, Manthiram, Kalpana, Groarke, Emma M., Gutierrez-Rodrigues, Fernanda, Hoffmann, Patrycja, Rosenzweig, Sofia, Nakabo, Shuichiro, Dillon, Laura W., Hourigan, Christopher S., Tsai, Wanxia L., Gupta, Sarthak, Carmona-Rivera, Carmelo, Asmar, Anthony J., Xu, Lisha, Oda, Hirotsugu, Goodspeed, Wendy, Barron, Karyl S., Nehrebecky, Michele, Jones, Anne, Laird, Ryan S., Deuitch, Natalie, Rowczenio, Dorota, Rominger, Emily, Wells, Kristina V., Lee, Chyi-Chia R., Wang, Weixin, Trick, Megan, Mullikin, James, Wigerblad, Gustaf, Brooks, Stephen, Dell’Orso, Stefania, Deng, Zuoming, Chae, Jae J., Dulau-Florea, Alina, Malicdan, May C.V., Novacic, Danica, Colbert, Robert A., Kaplan, Mariana J., Gadina, Massimo, Savic, Sinisa, Lachmann, Helen J., Abu-Asab, Mones, Solomon, Benjamin D., Retterer, Kyle, Gahl, William A., Burgess, Shawn M., Aksentijevich, Ivona, Young, Neal S., Calvo, Katherine R., Werner, Achim, Kastner, Daniel L., Grayson, Peter C.·2020·New England Journal of Medicine
DOI 10.1056/nejmoa2026834PMC PMC7847551
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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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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
DOI
10.1056/nejmoa2026834
PMC
PMC7847551
Cited by
1,206
References
44
Language
en

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