OBJECTIVE: Somatic mutations in UBA1 have recently been causally linked to a severe adult-onset inflammatory condition referred to as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Ubiquitin-activating enzyme E1 (UBA-1) is of fundamental importance to the modulation of ubiquitin homeostasis and to the majority of downstream ubiquitylation-dependent cellular processes. Direct sequencing analysis of exon 3 containing the prevalent variants p.Met41Leu, p.Met41Val, and/or p.Met41Thr is usually used to confirm the disease-associated mutations. METHODS: We studied the clinical, biochemical, and molecular genetic characteristics of a 59-year-old man with a 2-year history of arthritis, fever, night sweats, nonspecific skin rash, lymphadenopathy, and myelodysplastic syndrome with multilineage dysplasia. RESULTS: The mutational analysis revealed a previously undescribed sequence variant c.1430G>C in exon 14 (p.Gly477Ala) in the gene UBA1. In vitro enzymatic analyses showed that p.Gly477Ala led to both decreased E1 ubiquitin thioester formation and E2 enzyme charging. CONCLUSION: We report a case of a patient of European ancestry with clinical manifestations of VEXAS syndrome associated with a newly identified dysfunctional UBA-1 enzyme variant. Due to the patient's insufficient response to various immunosuppressive treatments, allogeneic hematopoietic stem cell transplantation was performed, which resulted in significant improvement of clinical and laboratory manifestations of the disease.

Center for Human Genetics and Genomics and Division of Rheumatology Department of Medicine New York University School of Medicine New York

Center for Human Genetics and Genomics New York University School of Medicine New York

Institute of Hematology and Blood Transfusion and Institute of Clinical and Experimental Haematology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Hematology and Blood Transfusion Prague Czech Republic

Institute of Rheumatology and Department of Rheumatology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Rheumatology Department of Rheumatology and Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

National Institute for Dental and Craniofacial Research NIH Bethesda Maryland

Zobrazit více v PubMed

Muratore F, Marvisi C, Castrignanò P, et al. VEXAS Syndrome: A Case Series From a Single-Center Cohort of Italian Patients With Vasculitis. Arthritis Rheumatol 2022;74:665–670. PubMed PMC

Beck DB, Ferrada MA, Sikora KA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2020;383:2628–2638. PubMed PMC

Koster MJ, Kourelis T, Reichard KK, et al. Clinical Heterogeneity of the VEXAS Syndrome: A Case Series. Mayo Clin Proc 2021;96:2653–2659. PubMed

Georgin-Lavialle S, Terrier B, Guedon AF, et al. Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients. Br J Dermatol 2022;186:564–574. PubMed

Koster MJ, Warrington KJ. VEXAS within the spectrum of rheumatologic disease. Semin Hematol 2021;58:218–225. PubMed

Obiorah IE, Patel BA, Groarke EM, et al. Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1. Blood Adv 2021;5:3203–3215. PubMed PMC

Groarke EM, Dulau-Florea AE, Kanthi Y. Thrombotic manifestations of VEXAS syndrome. Semin Hematol 2021;58:230–238. PubMed

Grayson PC, Patel BA, Young NS. VEXAS syndrome. Blood 2021;137:3591–3594. PubMed PMC

Heiblig M, Patel BA, Groarke EM, et al. Toward a pathophysiology inspired treatment of VEXAS syndrome. Semin Hematol 2021;58:239–246. PubMed

Diarra A, Duployez N, Fournier E, et al. Successful allogeneic hematopoietic stem cell transplantation in patients with VEXAS syndrome: a 2-center experience. Blood Adv 2022;6:998–1003. PubMed PMC

Beck DB, Werner A, Kastner DL, et al. Disorders of ubiquitylation: unchained inflammation. Nat Rev Rheumatol 2022;18:435–47. PubMed PMC

Aksentijevich I, Zhou Q. NF-kappaB pathway in autoinflammatory diseases: dysregulation of protein modifications by ubiquitin defines a new category of autoinflammatory diseases. Front Immunol 2017;8:399. PubMed PMC

Handley-Gearhart PM, Trausch-Azar JS, Ciechanover A, et al. Rescue of the complex temperature-sensitive phenotype of Chinese hamster ovary E36ts20 cells by expression of the human ubiquitin-activating enzyme cDNA. Biochem J 1994;304:1015–1020. PubMed PMC

Poulter JA, Collins JC, Cargo C, et al. Novel somatic mutations in UBA1 as a cause of VEXAS syndrome (Letter). Blood 2021;137:3676–3681. PubMed PMC

Al-Hakim A, Poulter JA, Mahmoud D, et al. Allogeneic haematopoietic stem cell transplantation for VEXAS syndrome: UK experience. Br J Haematol 2022; 199:777–781. PubMed

Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes