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.).
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.).
Authors: Hanna L M Koskela; Samuli Eldfors; Pekka Ellonen; Arjan J van Adrichem; Heikki Kuusanmäki; Emma I Andersson; Sonja Lagström; Michael J Clemente; Thomas Olson; Sari E Jalkanen; Muntasir Mamun Majumder; Henrikki Almusa; Henrik Edgren; Maija Lepistö; Pirkko Mattila; Kathryn Guinta; Pirjo Koistinen; Taru Kuittinen; Kati Penttinen; Alun Parsons; Jonathan Knowles; Janna Saarela; Krister Wennerberg; Olli Kallioniemi; Kimmo Porkka; Thomas P Loughran; Caroline A Heckman; Jaroslaw P Maciejewski; Satu Mustjoki Journal: N Engl J Med Date: 2012-05-17 Impact factor: 91.245
Authors: Tracy A Briggs; Gillian I Rice; Sarah Daly; Jill Urquhart; Hannah Gornall; Brigitte Bader-Meunier; Kannan Baskar; Shankar Baskar; Veronique Baudouin; Michael W Beresford; Graeme C M Black; Rebecca J Dearman; Francis de Zegher; Emily S Foster; Camille Francès; Alison R Hayman; Emma Hilton; Chantal Job-Deslandre; Muralidhar L Kulkarni; Martine Le Merrer; Agnes Linglart; Simon C Lovell; Kathrin Maurer; Lucile Musset; Vincent Navarro; Capucine Picard; Anne Puel; Frederic Rieux-Laucat; Chaim M Roifman; Sabine Scholl-Bürgi; Nigel Smith; Marcin Szynkiewicz; Alice Wiedeman; Carine Wouters; Leo A H Zeef; Jean-Laurent Casanova; Keith B Elkon; Anthony Janckila; Pierre Lebon; Yanick J Crow Journal: Nat Genet Date: 2011-01-09 Impact factor: 38.330
Authors: Simon A Forbes; David Beare; Harry Boutselakis; Sally Bamford; Nidhi Bindal; John Tate; Charlotte G Cole; Sari Ward; Elisabeth Dawson; Laura Ponting; Raymund Stefancsik; Bhavana Harsha; Chai Yin Kok; Mingming Jia; Harry Jubb; Zbyslaw Sondka; Sam Thompson; Tisham De; Peter J Campbell Journal: Nucleic Acids Res Date: 2016-11-28 Impact factor: 16.971