Overview

NIH scientists led an international team of researchers toward discovery of a new, adult-onset inflammatory disease abbreviated the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome.  Middle-aged men with this condition experienced fevers, low blood cell counts, and inflammation of the skin, lungs, cartilage, and blood vessels. The men did not respond well to therapy and were at increased risk for early death. The scientists found that the disorder is caused by a mutation in the UBA1 gene, which is located on the X chromosome. The findings appeared October 27, 2020 in the New England Journal of Medicine.

New diseases are usually discovered by analyzing people with similar symptoms, then looking for a gene that is causing the condition. This study highlights the potential of using a genome-first approach to help doctors evaluate and treat inflammatory diseases. This strategy may be useful for rheumatic diseases that affect the bone, joint, and muscle. Such diseases are often difficult to diagnose due to the complexity and variety of signs and symptoms associated with these conditions.

Select Highlights

• Researchers studied the genomes of over 2,500 men and women who had a range of inflammatory symptoms to look for clues about the cause(s) of the symptoms. The search uncovered a group of men with mutations in the UBA1 gene that prevent the gene product from functioning normally.
• Based on clinical symptoms, these men were previously diagnosed with a range of different rheumatic diseases, including relapsing polychondritis, polyarteritis nodosa, and giant cell arteritis.
• All of the men with UBA1 gene mutations were over the age of 40 and none had family members with the mutant gene. This led the researchers to speculate the mutation was not inherited, but instead developed in certain cells later in life.
• The scientists used sequencing methods to discover that the UBA1 gene mutation was found in myeloid cells, specialized white blood cells that play a role in inflammation and the immune response. In myeloid cells that contained a mutant UBA1 gene, many genes associated with an inflammatory immune response were unnecessarily activated. This finding suggested that these cells were driving the inflammatory symptoms.
• The zebrafish uba1 gene is highly similar to the human UBA1 gene. The scientists studied zebrafish that lacked the uba1 gene to better understand what occurs in men who have a UBA1 gene mutation. As in the men, zebrafish that lacked the uba1 gene had activated inflammatory genes, confirming that when UBA1 is missing or mutated, inflammation can run amok. Without the uba1 gene, zebrafish also had fewer myeloid cells, and died sooner than normal zebrafish. The results support that the previously undiagnosed inflammatory condition in middle-aged men was caused by UBA1 gene mutations.

Perspectives

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“Rheumatic diseases are among the most complex conditions in all of medicine. Diagnosing these diseases often requires doctors to recognize complicated patterns of symptoms that can be very different from patient to patient. The discovery of VEXAS proves that it is possible to simplify these diseases down to their essential elements. When we understand rheumatic diseases at the molecular level, more effective strategies to diagnose and treat these conditions will inevitably follow.”

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“From a purely scientific point of view, this work highlights the utility of genotype-first strategies in discovering totally new and unexpected diseases, the importance of somatic mutation in adult-onset rheumatic disease, and the potential importance of the X-chromosome in human illnesses. But equally importantly, this work is a wonderful example of the power of interdisciplinary collaboration in advancing biomedical research. VEXAS was discovered by a diverse group of brilliant and driven young investigators who coalesced around the common purpose of solving a medical mystery. It has been a privilege to have been a part of that very special adventure.”

NIH researchers from NIAMS, NHGRI, the National Institute of Dental and Craniofacial Research (NIDCR), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute (NCI), and the National Eye Institute (NEI) contributed to this study.

Learn more

• Scientists use clues in the human genome to discover new inflammatory syndrome
• What is VEXAS Syndrome? (Vasculitis Translational Research Program)

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Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, Balanda N, Ross DL, Ospina Cardona D, Wu Z, Patel B, Manthiram K, Groarke EM, Gutierrez-Rodrigues F, Hoffmann P, Rosenzweig S, Nakabo S, Dillon LW, Hourigan CS, Tsai WL, Gupta S, Carmona-Rivera C, Asmar AJ, Xu L, Oda H, Goodspeed W, Barron KS, Nehrebecky M, Jones A, Laird RS, Deuitch N, Rowczenio D, Rominger E, Wells KV, Lee CR, Wang W, Trick M, Mullikin J, Wigerblad G, Brooks S, Dell'Orso S, Deng Z, Chae JJ, Dulau-Florea A, Malicdan MCV, Novacic D, Colbert RA, Kaplan MJ, Gadina M, Savic S, Lachmann HJ, Abu-Asab M, Solomon BD, Retterer K, Gahl WA, Burgess SM, Aksentijevich I, Young NS, Calvo KR, Werner A, Kastner DL, Grayson PC. N Engl J Med. 2020 Oct 27. doi: 10.1056/NEJMoa2026834. Online ahead of print. PMID: 33108101