UBA1 – VEXAS syndrome

UBA1 encodes the ubiquitin-activating enzyme E1, a key initiator of ubiquitin-mediated protein homeostasis. Somatic mutations in UBA1 affecting the methionine-41 start codon cause VEXAS syndrome, an adult-onset autoinflammatory disorder characterized by systemic inflammation and hematologic abnormalities. VEXAS syndrome often presents in late-adult males with features overlapping relapsing polychondritis, Sweet’s syndrome, and hematologic disorders such as myelodysplastic syndrome and multiple myeloma. Pathognomonic cytoplasmic vacuoles in myeloid and erythroid precursors are a hallmark finding on bone marrow biopsy. The disease results from clonal somatic UBA1 variants in hematopoietic stem cells, leading to impaired translation of the cytoplasmic UBA1b isoform and reduced ubiquitylation. Diagnosis requires identification of somatic UBA1 variants in peripheral blood or bone marrow cells.

Assessment of clinical validity by ClinGen criteria yields a Strong gene–disease relationship (PMID:33108101). More than 25 unrelated adult male patients harboring somatic UBA1 p.Met41Leu, p.Met41Val, or p.Met41Thr variants have been described (PMID:33108101; PMID:34489099). Presentation includes refractory fever, chondritis, neutrophilic dermatosis, pulmonary infiltrates, and cytopenias, with characteristic myeloid vacuolization. Multi-center studies confirm the consistency of phenotype across distinct cohorts. Functional concordance has been demonstrated across in vitro and zebrafish models reproducing UBA1b deficiency. The somatic nature of the variants precludes traditional familial segregation, but clonal hematopoiesis has been demonstrated by deep sequencing analyses.

UBA1 variants in VEXAS syndrome are acquired somatic mutations restricted to hematopoietic lineages, with no evidence of germline transmission. The inheritance is best described as somatic, X-linked mosaicism. Case series have identified 25 probands with missense mutations at codon 41, predominantly c.122T>C (p.Met41Thr), c.121A>G (p.Met41Val), or c.121A>T (p.Met41Leu) (PMID:33108101; PMID:34489099). The variant spectrum is limited to start-codon missense changes, with no truncating, splice, or structural variants reported to date. Mosaic variant allele fractions range from 35% to 75% in myeloid cells, correlating with disease severity. One recurrent c.122T>C (p.Met41Thr) variant has been reported across multiple unrelated patients (PMID:35757758).

In vitro studies demonstrate that p.Met41 variants abolish translation of the UBA1b cytoplasmic isoform, leading to reduced global ubiquitylation in patient-derived cells (PMID:33108101; PMID:35793467). CRISPR-mediated knockout of the cytoplasmic UBA1 isoform in zebrafish recapitulates hallmark inflammatory features seen in patients, including elevated interleukin-1β and neutrophil-driven inflammation (PMID:33108101). Further mechanistic assays reveal that the p.Met41Val variant yields less UBA1b translation compared to p.Met41Leu or p.Met41Thr, correlating with poorer survival outcomes. Electron microscopy of myeloid cells from affected patients shows endolysosomal vacuoles, consistent with disrupted ubiquitin pathways (PMID:38091008). These concordant functional studies support a ClinGen Moderate tier for experimental evidence.

Clinically, VEXAS syndrome presents with systemic inflammation manifesting as recurrent fever (HP:0001945), chondritis of the pinna (HP:0200047), inflammatory arthritis (HP:0001369), pulmonary infiltrates, and neutrophilic dermatoses. Hematologic abnormalities include macrocytic anemia (HP:0001972), thrombocytopenia, and vacuolated myeloid precursors. Relapsing polychondritis and Sweet’s syndrome–like lesions are frequent, and patients may develop venous thrombosis. Over 30% of patients exhibit hematologic neoplasms such as myelodysplastic syndrome or plasma cell dyscrasias. The average age at diagnosis is 67–74 years, predominantly affecting males. Treatment is largely supportive, with high-dose glucocorticoids providing transient relief, and emerging use of JAK inhibitors, IL-6 blockade, and azacitidine.

No studies have refuted the association between UBA1 somatic mutations and VEXAS syndrome. Alternative inflammatory and hematologic diagnoses often overlap but are distinguished by the presence of vacuoles in hematopoietic precursors and UBA1 mutational status. Rare reports of non-Met41 UBA1 variants expand the genetic landscape but support the core mechanism of UBA1b deficiency. There are no case reports of VEXAS-like disease without UBA1 mutation, and no recurrent inconsistencies have been reported to date.

The integration of robust genetic and functional data confirms that UBA1 somatic missense mutations at codon 41 are causative for VEXAS syndrome. The ClinGen Strong gene–disease association, supported by multi-cohort genetic studies and mechanistic in vivo and in vitro work, underpins diagnostic decision-making and therapeutic targeting. While current treatments focus on immunosuppressive strategies and hematopoietic stem cell transplantation, ongoing research into UBA1-targeted therapies may yield curative approaches. Routine screening for UBA1 variants in adult males with unexplained autoinflammatory and hematologic manifestations is recommended. Key Take-home: UBA1 somatic p.Met41 variants drive VEXAS syndrome via loss of cytoplasmic UBA1b translation, establishing a strong mechanistic and clinical association critical for diagnosis and management.

References

• The New England Journal of Medicine | 2020 | Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease PMID:33108101
• Blood | 2022 | Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis PMID:35793467
• Mayo Clinic Proceedings | 2021 | Clinical Heterogeneity of the VEXAS Syndrome: A Case Series PMID:34489099

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