Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease

A study partially funded by NIH examined differences in ubiquitin-related genes, which play a role in autoinflammatory disease and may characterize previously unknown conditions. The research involved 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. Severe inflammatory syndrome is known to develop in late adulthood in this population, often with deadly consequences. Investigators isolated peripheral-blood exome sequence data in the 25 patients, most of whom satisfied clinical definitions for an inflammatory syndrome or a hematologic condition or both, subsequently detecting mutations in more than one-half of the hematopoietic stem cells. Mutations affecting p.Met41 triggered loss of the canonical cytoplasmic isoform of UBA1 which, as demonstrated with an in vivo model using zebrafish, promoted systemic inflammation. The researchers also discovered that mutant peripheral-blood cells showed reduced ubiquitylation and activated innate immune pathways. The study allowed the team to identify VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, a disorder that connects what otherwise appear to be unrelated adult-onset inflammatory syndromes.