Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.

Pars Plana Vitrectomy Combined With Either Secondary Scleral-Fixated or Anterior Chamber Intraocular Lens Implantation.

PURPOSE: To compare visual outcomes among eyes that underwent pars plana vitrectomy (PPV) in combination with either anterior chamber intraocular lens implantation (ACIOL) or scleral suturing of posterior chamber lens (PCIOL). DESIGN: Retrospective comparative case series. METHODS: All eyes presented with aphakia or luxated or subluxated posterior chamber intraocular lens (IOL) following complicated cataract surgery, trauma, or spontaneous dislocation. Eyes involving visually significant macular pathology, past retinal detachment, follow-up of less than 6 months, and surgeries requiring the removal of an ACIOL were excluded. The main outcomes measured were final best-corrected visual acuity (BCVA) and surgical complication rates. RESULTS: Fifty-seven eyes met inclusion criteria; median follow-up was 13.2 months. Initial median BCVA for ACIOL patients was logMAR 1.301 (Snellen equivalent 20/400, range 20/20 to light perception); final median BCVA was logMAR 0.477 (Snellen equivalent 20/60, range 20/20 to light perception, P < .001). Initial median BCVA for PCIOL patients was logMAR 1.239 (Snellen equivalent 20/347, range 20/60 to light perception); final median BCVA was logMAR 0.301 (Snellen equivalent 20/40, range 20/20 to hand motions, P < .001). The change in BCVA between the 2 groups over the course of the study was similar (P > .05). More epiretinal membrane (ERM) formations occurred postoperatively in the ACIOL group (P = .011). Other complication rates were similar between both groups. CONCLUSIONS: PPV with secondary IOL placement is safe and effective, resulting in improved visual outcomes regardless of the technique used. Patients undergoing ACIOL placement have a higher incidence of ERM formation.