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          Labs @ NIAMS
          NIAMS Scientific Advances
          Level of UBA1 Production Inside the Cell Contributes to VEXAS Syndrome








NIAMS Advances


Level of UBA1 Production Inside the Cell Contributes to VEXAS Syndrome September 29, 2022
                                CLINICAL
        Peter Grayson, M.D., M.Sc.
                                          |
              Vasculitis Translational Research Program
                                          |
              NIAMS IRP
        DescriptionVEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory Somatic) syndrome is caused by mutations in the UBA1 gene and is associated with a high mortality rate. VEXAS patients, primarily adult males aged 50 or older, exhibit episodes of fever, anemia, and abnormal inflammation of the joints, skin, nose, or blood vessels. This study identified several clinical factors associated with survival outcome in people with VEXAS. While the presence of ear chondritis is associated with increased survival, the specific genetic variation (UBA1 p. Met41Val) and transfusion dependency are independently associated with mortality. The finding reveals how reduced production of UBA1 protein isoform results in poor prognosis for VEXAS patients. This study indicates that genetic profiling of VEXAS patients may significantly improve patient care.

What is exciting about this article?The discovery of VEXAS syndrome demonstrates that genetic mutations acquired later in life can cause adult-onset inflammatory diseases. This study reveals that in addition to being an important diagnostic tool, molecular genotyping of patients also serves as a biomarker of disease severity in VEXAS syndrome. A better understanding of how UBA1 protein expression level affects disease severity might offer the potential for targeted therapeutics for this life-threatening condition.

How does this fit into the larger NIAMS portfolio?VEXAS syndrome is a newly defined disease that was discovered by a group of investigators within NIAMS and across NIH. This report demonstrates that molecular phenotyping of VEXAS patients may improve clinical care by identifying those who would benefit from early and/or aggressive treatment.

Grant supportAR041204
        Research Areas:
            Autoimmunity
      Clinical Research
      Computational Biology
      Epidemiology
      Genetics and Genomics
      Immunology
                                        Reference:
            Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.

    Ferrada MA, Savic S, Cardona DO, Collins JC, Alessi H, Gutierrez-Rodrigues F, Kumar DBU, Wilson L, Goodspeed W, Topilow JS, Paik JJ, Poulter JA, Kermani TA, Koster MJ, Warrington KJ, Cargo C, Tattersall RS, Duncan CJA, Cantor A, Hoffmann P, Payne EM, Bonnekoh H, Krause K, Cowen EW, Calvo KR, Patel BA, Ombrello AK, Kastner DL, Young NS, Werner A, Grayson PC, Beck DB
        

                    Blood.
        
                    2022 Sep 29;
        
                    140(13).
        
                    doi: 10.1182/blood.2022016985
                            PMID: 35793467
        Research reported in this publication was supported by the Intramural Research Program of the NIHʼs National Institute of Arthritis and Musculoskeletal and Skin Diseases.
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