PUBLICATION

Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

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.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.
ID
ZDB-PUB-201028-8
Date
2020
Source
The New England Journal of Medicine   383(27): 2628-2638 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Polyarteritis Nodosa/genetics
  • Mutation, Missense*
  • Exome/genetics
  • Age of Onset
  • Immunoblotting
  • Genotype
  • Myelodysplastic Syndromes/genetics
  • Genetic Diseases, X-Linked/genetics*
  • Aged
  • Ubiquitin-Activating Enzymes/genetics*
  • Autoimmune Diseases/genetics*
  • Aged, 80 and over
  • Syndrome
  • Middle Aged
  • Sweet Syndrome/genetics
  • Multiple Myeloma/genetics
  • Polychondritis, Relapsing/genetics
  • Cytokines/blood
  • Male
  • Giant Cell Arteritis/genetics
  • Inflammation/genetics*
  • Sequence Analysis, DNA
  • Humans
PubMed
33108101 Full text @ N. Engl. J. Med.
Citation
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.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. (2020) Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. The New England Journal of Medicine. 383(27):2628-2638.
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 We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 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.).
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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