Vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory illness with overlapping hematologic symptoms, is caused by somatic mutations in UBA1. High mortality and great clinical variability are hallmarks of VEXAS syndrome. In VEXAS, researchers looked for independent predictors of survival, as well as the molecular underpinnings of these predictors.
The start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b) is at p.Met41 (p.Met41Leu/Thr/Val), which was present in 83 cases. Most patients with an undifferentiated inflammatory condition had the genotype p.Met41Val. According to multivariate analysis, transfusion dependency and the p.Met41Val variation were both independently related to lower mortality, but ear chondritis was shown to be associated with enhanced survival. In addition, they showed that the p.Met41Val variation promotes less UBA1b translation than the p.Met41Leu or p.Met41Thr variants, explaining the reduced survival mechanically.
Furthermore, they demonstrated that none of the other 6 potential single-nucleotide variations inside the codon create more UBA1b than these 3 canonical VEXAS variants. Last but not least, they presented a patient who was clinically diagnosed with VEXAS syndrome and who had two unique UBA1 mutations that occurred in cis on the same allele. In a reporter test, one mutant (c.121 A>T; p.Met41Leu) significantly decreased UBA1b translation, while coexpression with a second mutation (c.119 G>C; p.Gly40Ala) restored UBA1b levels to those of canonical mutations.
They concluded that control of residual UBA1b translation was essential to the etiology of VEXAS syndrome and affected the prognosis of the condition.