Novel somatic mutations in UBA1 as a cause of VEXAS syndrome

Abstract

Somatic mutations at methionine 41 (Met41) in UBA1, encoding the major E1 enzyme responsible for initiating ubiquitylation, were recently identified as the cause of a novel autoinflammatory disease, named VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). We sought to determine the prevalence of UBA1 mutations in a UK cohort of patients matching the VEXAS clinical phenotype. We identified 10 new patients with somatic mutations in UBA1, but only 8 had altered p.Met41. A novel variant, c.167C>T; p.Ser56Phe was identified, which was present in myeloid, and not lymphoid lineages and led to preferential loss of the catalytic activity of cytoplasmic UBA1. An additional novel variant, c.118-1G>C was identified at the splice acceptor site of exon 3 leading to altered splicing in vitro. Bone marrow biopsies from two patients with a Met41 substitution and the novel splice site variant were consistent with previously reported features of VEXAS. The bone marrow of the patient with the p.Ser56Phe variant was less similar, likely driven by a distinct but overlapping disease mechanism. Our study therefore confirms somatic p.Met41 substitutions in UBA1 as a major cause of VEXAS syndrome and identifies two new disease causing mutations.

Vacuoles in neutrophil precursors in VEXAS syndrome: diagnostic performances and threshold

“…The previously described somatic mutations in UBA1 (NM_003334.3) were screened by Sanger sequencing to confirm the diagnosis. 1,9 The polymerase chain reaction (PCR) primers used were forward 5 0 -AAAGCCGGGTTC-TAACTGCT and reverse 5 0 -CAGGACACTGGATGTCTGGA.…”

“…7,8 Furthermore, blinatumomab has been used to good effect in adults with MPAL and CD19-positive AML as a bridge to transplant or consolidation chemotherapy/donor lymphocyte infusion. [9][10][11] Here, we report on blinatumomab as an effective bridge to transplant in three paediatric patients with MPAL, including one that arose as a consequence of ALL therapy. All three patients had separate populations of different lineages immunophenotypically as opposed to a single clone with coexpression of lymphoid and myeloid markers (shown along with other patient characteristics in Table I).…”

Successful allogeneic hematopoietic stem cell transplantation in patients with VEXAS syndrome: a 2-center experience

“…This results in decreased ubiquitylation and activation of innate immune pathways, elevated serum cytokine levels and severe inflammatory effects 1 . Other mutations affecting the acceptor-splice site of exon 3 or the serine 56 have also been rarely described 4,5 . The identification of VEXAS syndrome is of particular interest for clinical practice as it provides a strong diagnostic marker, giving the opportunity to design specific treatment strategies in such patients, whose inflammatory symptoms are usually refractory to most therapies 4 .…”

Thrombosis in VEXAS syndrome

“…VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome [1] is described as a late-onset autoinflammatory syndrome exhibiting a spectrum of systemic inflammatory manifestations as well as significant haematologic abnormalities such as macrocytic anaemia, marrow dysplasia, vacuolisation in myeloid cells [2] and thrombosis. Several published case series [1,[3][4][5][6][7][8][9][10] have observed a high prevalence of venous thromboembolism (VTE) in patients with VEXAS syndrome of between 10% and 56%, with a significant mortality rate (27%-50%). We report a case of VEXAS syndrome complicated by unprovoked venous thromboembolism, followed by a rapid review of available literature.…”