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Somatic Mutations in

Authors :
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
Peter C, Grayson
Source :
Arthritis Rheumatol
Publication Year :
2020

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.).

Details

ISSN :
15334406
Volume :
383
Issue :
27
Database :
OpenAIRE
Journal :
The New England journal of medicine
Accession number :
edsair.pmid..........8619cd7f680f820c748afb4ee52d1640