Mutation in KARS: A novel mechanism for severe anaphylaxis

TitleMutation in KARS: A novel mechanism for severe anaphylaxis
Publication TypeJournal Article
Year of Publication2021
AuthorsRibó, Pau, Guo Yanru, Aranda Juan, Ainsua-Enrich Erola, Navinés-Ferrer Arnau, Guerrero Mario, Pascal Mariona, de la Cruz Cinthia, Orozco Modesto, Muñoz-Cano Rosa, and Martin Margarita
JournalJournal of Allergy and Clinical Immunology
Pagination1855 - 1864.e9
Date Published05/2021
ISBN Number0091-6749
KeywordsAnaphylaxis, KARS, lysyl-tRNA synthetase (LysRS), mast cells, microphthalmia transcription factor

BackgroundAnaphylaxis is a severe allergic reaction that can be lethal if not treated adequately. The underlying molecular mechanisms responsible for the severity are mostly unknown.ObjectiveThis 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.MethodsAnalysis 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.ResultsThe 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.ConclusionsA 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.

Short TitleJournal of Allergy and Clinical Immunology