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Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.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.We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The geneUsing 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.).

Triggering Receptor Expressed on Myeloid cells (TREM) family receptors modulate responses of a variety of leukocytes. We found that TREM-like 4 (TREML4) mRNA is elevated in the peripheral blood of patients with advanced coronary artery calcification (CAC) and that a single nucleotide polymorphism (SNP), rs2803496, tracks with the level of TREML4 mRNA in these patients. In an effort to elucidate the mechanism through which TREML4 in peripheral blood could affect CAC, we began by determining what cells express it. Monocytes and lymphocytes of donors with this SNP expressed very low levels of TREML4 mRNA whereas their neutrophils (PMNs) were strongly positive. Consistent with its association with CAC, we found variation in the levels of TREML4 mRNA in PMNs that correlated rs2803496, and a second SNP rs2803495. Unlike murine Treml4, which has the typical TREM family structure, human TREML4 has a noncanonical leader, lacks a portion of the transmembrane domain (TM) and has no cytoplasmic tail. Characterization of the Treml4 cDNA suggests that this truncated TM domain is sufficient to anchor the protein in the plasma membrane but that the TREML4 native leader sequence is ineffective. Lastly, immunostaining of human atherosclerotic plaques shows TREML4 in macrophage-rich regions, as well as on the endothelium. Together our findings suggest that TREML4 may play an important role in atherosclerosis and CAC but that it is unlikely to function as a typical, DAP12-coupled TREM.