1. Somatic Mutations in
- Author
-
David B, Beck, Marcela A, Ferrada, Keith A, Sikora, Amanda K, Ombrello, Jason C, Collins, Wuhong, Pei, Nicholas, Balanda, Daron L, Ross, Daniela, Ospina Cardona, Zhijie, Wu, Bhavisha, Patel, Kalpana, Manthiram, Emma M, Groarke, Fernanda, Gutierrez-Rodrigues, Patrycja, Hoffmann, Sofia, Rosenzweig, Shuichiro, Nakabo, Laura W, Dillon, Christopher S, Hourigan, Wanxia L, Tsai, Sarthak, Gupta, Carmelo, Carmona-Rivera, Anthony J, Asmar, Lisha, Xu, Hirotsugu, Oda, Wendy, Goodspeed, Karyl S, Barron, Michele, Nehrebecky, Anne, Jones, Ryan S, Laird, Natalie, Deuitch, Dorota, Rowczenio, Emily, Rominger, Kristina V, Wells, Chyi-Chia R, Lee, Weixin, Wang, Megan, Trick, James, Mullikin, Gustaf, Wigerblad, Stephen, Brooks, Stefania, Dell'Orso, Zuoming, Deng, Jae J, Chae, Alina, Dulau-Florea, May C V, Malicdan, Danica, Novacic, Robert A, Colbert, Mariana J, Kaplan, Massimo, Gadina, Sinisa, Savic, Helen J, Lachmann, Mones, Abu-Asab, Benjamin D, Solomon, Kyle, Retterer, William A, Gahl, Shawn M, Burgess, Ivona, Aksentijevich, Neal S, Young, Katherine R, Calvo, Achim, Werner, Daniel L, Kastner, and Peter C, Grayson
- Subjects
Aged, 80 and over ,Inflammation ,Male ,Genotype ,Giant Cell Arteritis ,Immunoblotting ,Mutation, Missense ,Genetic Diseases, X-Linked ,Sequence Analysis, DNA ,Syndrome ,Ubiquitin-Activating Enzymes ,Middle Aged ,Sweet Syndrome ,Article ,Autoimmune Diseases ,Polyarteritis Nodosa ,Myelodysplastic Syndromes ,Cytokines ,Humans ,Exome ,Polychondritis, Relapsing ,Age of Onset ,Multiple Myeloma ,Aged - Abstract
Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The geneUsing a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
- Published
- 2020