Adult-onset inflammatory diseases are often a result of underlying and overlapping clinical features. Studies have shown that mutations in the ubiquitin-related genes previously implicated in anti-inflammatory disorders might lead to new disorders. This study aims to investigate the association between somatic mutations in UBA1 and the severe adult-onset of autoinflammatory disorders.

This study included 25 men with deleterious mutations in ubiquitin-related genes, as confirmed by peripheral-blood exome sequence data analysis. The researchers also performed immunoblotting, immunohistochemical testing, Sanger sequencing, transcriptome & cytokine profiling, and flow cytometry. The primary outcome of the study was the onset of inflammatory syndromes.

Of the 25 patients, most of them met the criteria for an inflammatory syndrome or a hematologic condition (or both). The findings suggested that there were mutations in more than half the hematopoietic stem cells but not in lymphocytes and fibroblasts. Mutations that affected p.Met41 – the E1 enzyme that initiates ubiquitylation – led to the loss of canonical cytoplasmic isoform of the UBA1 gene. The findings also indicated that the mutant peripheral blood cells showed activated innate immune pathways and reduced ubiquitylation.

The research concluded that utilizing a genotype-driven approach is useful in identifying disorders that could lead to adult-onset inflammatory syndromes.

Ref: https://www.nejm.org/doi/full/10.1056/NEJMoa2026834