Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

By D. Beck, M. Ferrada, K. Sikora, A. Ombrello, Jason C. Collins, W. Pei, Nicholas Balanda, Daron L Ross, Daniela Ospina Cardona, Zhijie Wu and 52 more. New England Journal of Medicine, 2020

871 citations recorded by the source corpus.

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.)

Subfields: Hematology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/f602230d11e7e89ef5177c6d790c551cbe4c99f1

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In Hematology

1. J. Apperley
2. Andreas Hochhaus
3. H. Kantarjian
4. Brian J. Druker

In Rheumatology

1. Andreas Hochhaus
2. H. Kantarjian
3. Brian J. Druker

Citations in the corpus

• The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms (2022, background): “More specific emerging associations, such as those characterizing the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic UBA1 mutations) syndrome [7], represent manifestations of the interplay between inflammation and CH/ myeloid neoplasia that are being gradually uncovered.”
• Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee (2022, background): “Somatic/mosaic disease-causing mutations in TLR8 [58] and UBA1 [97] have also been identified, even though the pathogenic alleles were detected in only 5–30% of most blood cells (TLR8) [58] or 50–85% of myeloid cells but not in lymphocytes of fibroblasts (UBA1) [97].”