Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

Abstract

BACKGROUNDAdult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODSWe 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-Cas9edited zebrafish were used as an in vivo model to assess gene function. RESULTSWe 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. CONCLUSIONSUsing 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.

VEXAS syndrome in myelodysplastic syndrome with autoimmune disorder

“…In addition, a medical history that may cause copper deficiency, such as total parenteral hyperalimentation, is suggestive to diagnosis. In contrast, in VEXAS syndrome, numerous round vacuoles consisting of lipid droplets and disordered cellular organelles occur in myeloid and erythroid precursors [1,2,14].…”

“…To the Editor, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly-described adult-onset inflammatory syndrome characterized by fevers, cytopenias, vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary infiltrates, nose and ear chondritis and vasculitis. The syndrome is associated with somatic mutations affecting methionine-41 (p.Met41) in UBA1, an X-chromosome gene encoding ubiquitin-like modifier-activating enzyme 1 [1]. Among the initial 25 patients reported with VEXAS syndrome, 6 met the World Health Organization (WHO) diagnostic criteria for myelodysplastic syndromes (MDS).…”

The Immunopathology of Giant Cell Arteritis Across Disease Spectra

“…However, recently published data suggests myeloid activation may be even further upstream, as early as the bone marrow, given the prominent left shift seen by CyToF in patients with untreated GCA (80). Supporting this, GCA can occur as a paraneoplastic phenomenon to myelodysplastic/ myeloproliferative neoplasms as well as in the recently described somatic, myeloid-activating autoinflammatory condition VEXAS (173,174). Upon breach of vascular immunoprivilege, preactivated monocytes and CD4 + T cells mutually enter the vessel and cooperate to destroy it.…”

L’Homme Gelé (渐冻人) et le déficit en cristalline αB

“…On en veut pour preuve la description toute récente de formes congénitales de cristallinopathie αB à transmission dominante [22]. Cet adage vaut aussi pour des maladies beaucoup plus fréquentes comme l'illustre parfaitement, et dans un autre domaine, des mutations somatiques du gène UBA1 dans des pathologies inflammatoires de l'adulte [23]. A contrario, il faut se garder de sur-interpréter des résultats de NGS en validant trop facilement la pathogénicité de certains variants de séquence, ces derniers pouvant être des simples polymorphismes.…”