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Somatic Mutations in
- 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.).
- 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
Subjects
Details
- ISSN :
- 15334406
- Volume :
- 383
- Issue :
- 27
- Database :
- OpenAIRE
- Journal :
- The New England journal of medicine
- Accession number :
- edsair.pmid..........8619cd7f680f820c748afb4ee52d1640