Somatic Mutations in a Single Residue of UBA1 Cause VEXAS, a Severe Adult-Onset Rheumatic Disease Presenting as Relapsing Polychondritis, Polyarteritis Nodosa, or Giant Cell Arteritis

David Beck¹, Marcela Ferrada², Keith Sikora³, Amanda Ombrello⁴, Daniela Ospina Cardona⁵, Nicholas Balanda⁶, Wuhong Pei⁶, Jason Collins⁶, Robert Colbert⁷, Mariana Kaplan⁸, Massimo Gadina⁹, Sinisa Savic¹⁰, Helen Lachmann¹¹, Kyle Retterer¹², Shawn Burgess¹³, William Gahl⁶, Achim Werner⁶, Ivona Aksentijevich¹⁴, Neal S. Young⁶, Katherine R. Calvo⁶, Peter C. Grayson¹⁵ and Daniel Kastner¹⁶, ¹National Human Genome Research Institute, Bethesda, ²Systemic Autoimmunity Branch, Vasculitis Translational Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ³National Institutes of Health Clinical Center, Bethesda, MD, ⁴National Human Genome Research Institute/National Institutes of Health, Bethesda, MD, ⁵National Institute of Health, Bethesda, ⁶National Institutes of Health, Bethesda, ⁷Pediatric Clinical Trials Unit and Office of Clinical Director, NIAMS, NIH, Bethesda, MD, ⁸National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, ⁹National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, ¹⁰University of Leeds, England, United Kingdom, ¹¹National Amyloidosis CenterRoyal Free Campus, Rowland Hill St, London, United Kingdom, ¹²GeneDX, Gaithersburg, ¹³National Institutes of Health, Bethesda, MD, ¹⁴National Human Genome Research Institute, Bethesda, MD, ¹⁵Systemic Autoimmunity Branch, National Institutes of Health, NIAMS, Bethesda, MD, ¹⁶National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD

Meeting: ACR Convergence 2020

Keywords: Autoinflammatory diseases, genetics, giant cell arteritis, innate immunity, Vasculitis

Session Information

Date: Monday, November 9, 2020

Title: Genetics, Genomics & Proteomics (1953–1957)

Session Type: Abstract Session

Session Time: 12:00PM-12:50PM

Background/Purpose: Identifying the causes of adult-onset rheumatic diseases remains a challenge, and limits diagnosis, prognosis, and targeted treatment. We hypothesized that mutations in genes regulating the post-translational modification ubiquitin, previously implicated in two autoinflammatory diseases, may define new rheumatic disorders.

Methods: We analyzed peripheral blood exome sequence data from 2,560 individuals with inflammation-related diagnoses for deleterious mutations in >800 ubiquitin-related genes. After discovering three patients with novel UBA1 mutations, we identified additional cases based on clinical similarities. Sanger sequencing, digital droplet PCR, immunoblotting, immunohistochemistry, flow cytometry, and transcriptome/cytokine profiling were performed. CRISPR/Cas9 knockout zebrafish provided an in vivo model to assess UBA1 gene function.

Results: Twenty-eight adult males were identified with somatic mutations at methionine 41 in UBA1, an X-linked gene, encoding the major E1 enzyme that initiates ubiquitylation. Methionine 41 is highly conserved in UBA1, and these somatic mutations were not observed in exome sequences from over 80,000 healthy controls. Among affected individuals, mutations were found in more than half of hematopoietic stem cells, exclusively in peripheral blood myeloid cells, and not in lymphocytes or fibroblasts. Patients developed an often-fatal, treatment-refractory inflammatory syndrome in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursors cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Patients fulfilled clinical criteria for inflammatory (relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, giant cell arteritis) and hematologic (myelodysplastic syndrome or multiple myeloma) conditions. Mutations at p.Met41 resulted in loss of the cytoplasmic isoform of UBA1 and decreased ubiquitylation and, unexpectedly, the expression of a novel, catalytically inactive, toxic isoform, in mutant, but not wildtype, lineages. Mutant peripheral blood cells exhibited activated innate immune pathways and evidence for unfolded protein response (UPR). Knockout of the zebrafish UBA1 cytoplasmic isoform homologue caused systemic inflammation.

Conclusion: By querying exomes for mutations in ubiquitylation genes, we have defined a novel disorder, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, which connects seemingly unrelated adult-onset inflammatory syndromes and establishes a precedent for a new molecular taxonomy of rheumatic diseases. Our work also reveals somatic mutations as an underrecognized cause of adult-onset rheumatic diseases.

Disclosure: D. Beck, None; M. Ferrada, None; K. Sikora, None; A. Ombrello, None; D. Ospina Cardona, None; N. Balanda, None; W. Pei, None; J. Collins, None; R. Colbert, Eli Lilly and Company, 2, Eli Lilly and Company, 9; M. Kaplan, None; M. Gadina, None; S. Savic, Novartis, 5, 8, SOBI, 2, 5, 8; H. Lachmann, None; K. Retterer, Opko Health Inc, 1, 3; S. Burgess, None; W. Gahl, None; A. Werner, None; I. Aksentijevich, None; N. Young, None; K. Calvo, None; P. Grayson, None; D. Kastner, None.

To cite this abstract in AMA style:

Beck D, Ferrada M, Sikora K, Ombrello A, Ospina Cardona D, Balanda N, Pei W, Collins J, Colbert R, Kaplan M, Gadina M, Savic S, Lachmann H, Retterer K, Burgess S, Gahl W, Werner A, Aksentijevich I, Young N, Calvo K, Grayson P, Kastner D. Somatic Mutations in a Single Residue of UBA1 Cause VEXAS, a Severe Adult-Onset Rheumatic Disease Presenting as Relapsing Polychondritis, Polyarteritis Nodosa, or Giant Cell Arteritis [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/somatic-mutations-in-a-single-residue-of-uba1-cause-vexas-a-severe-adult-onset-rheumatic-disease-presenting-as-relapsing-polychondritis-polyarteritis-nodosa-or-giant-cell-arteritis/. Accessed .

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