Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease.

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.).

Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy.

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder characterized by seemingly unprovoked recurrent episodes of fever and serosal, synovial, or cutaneous inflammation. FMF is caused by recessively inherited mutations in MEFV, which encodes pyrin, and most of the mutations are present in the C-terminal end of the protein encoding B30.2 domain. The FMF carrier frequencies are extremely high in several eastern Mediterranean populations. Pyrin is expressed in granulocytes, monocytes, dendritic cells, and synovial fibroblasts. Pyrin regulates caspase-1 activation and consequently interleukin-1beta production through the interactions of its N-terminal PYRIN domain and C-terminal B30.2 domain with an adaptor protein, apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC) and caspase-1 respectively. Pyrin is cleaved by caspase-1 and the cleaved N-terminal fragment translocates to nucleus and enhances ASC-independent nuclear factor (NF)-kappaB activation through interactions with p65 NF-kappaB and IkappaB-alpha. In addition to the regulatory role of pyrin for caspase-1, the cleavage of pyrin provides an important clue not only in understanding the molecular pathogenesis of FMF but also in developing new therapeutic targets for FMF.