Mutation in KARS: A novel mechanism for severe anaphylaxis

Anaphylaxis is a severe allergic reaction that can be lethal if not treated adequately. The underlying molecular mechanisms responsible for the severity are mostly unknown. This study is based on a clinical case of a patient with extremely severe anaphylaxis to paper wasp venom. This patient has a m...

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Bibliographic Details
Published in:Journal of allergy and clinical immunology 2021-05, Vol.147 (5), p.1855-1864.e9
Main Authors: Ribó, Pau, Guo, Yanru, Aranda, Juan, Ainsua-Enrich, Erola, Navinés-Ferrer, Arnau, Guerrero, Mario, Pascal, Mariona, de la Cruz, Cinthia, Orozco, Modesto, Muñoz-Cano, Rosa, Martin, Margarita
Format: Article
Language:English
Subjects:
Amino acids
Anaphylaxis
Antibodies
Bone marrow
Cell activation
Confocal microscopy
Consciousness
Degranulation
Enzymes
Evolution
Fainting
Genetic counseling
Hypersensitivity
Hypotension
Immunoglobulin E
Inflammation
KARS
Kinases
lysyl-tRNA synthetase (LysRS)
Mast cells
microphthalmia transcription factor
Microscopy
Molecular modelling
Mutation
Proline
Prostaglandin D2
Protein biosynthesis
Proteins
Software
Transcription activation
Transfection
tRNA
Venom
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Summary:Anaphylaxis is a severe allergic reaction that can be lethal if not treated adequately. The underlying molecular mechanisms responsible for the severity are mostly unknown. This study is based on a clinical case of a patient with extremely severe anaphylaxis to paper wasp venom. This patient has a mutation in the KARS gene, which encodes lysyl-tRNA synthetase (LysRS), a moonlight protein with a canonical function in protein synthesis and a noncanonical function in antigen dependent–FcεRI activation in mast cells. In this study, the objective was to characterize the mutation at the molecular level. Analysis of the KARS mutation was carried out using biochemical and functional approaches, cell transfection, Western blot, confocal microscopy, cell degranulation, prostaglandin D2 secretion, and proteases gene transcription. Structural analysis using molecular dynamics simulations and well-tempered metadynamics was also performed. The mutation found, P542R (proline was replaced by arginine at aminoacid 542), affects the location of the protein as we show in biochemical and structural analyses. The mutation resembles active LysRS and causes a constitutive activation of the microphthalmia transcription factor, which is involved in critical mast cell functions such as synthesis of mediators and granule biogenesis. Moreover, the structural analysis provides insights into how LysRS works in mast cell activation. A link between the aberrant LysRS-P542R function and mast cell–exacerbated activation with increase in proinflammatory mediator release after antigen-IgE–dependent response could be established. [Display omitted]
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2020.12.637