Abstract
Systemic mast cell activation syndrome is a mast cell disorder characterized by an unregulated increased activation of mast cells leading to a pathologically enhanced release of mediators. Mutations in tyrosine kinase kit which crucially determines mast cell activity have been suggested as a necessary condition for the development of a clinically symptomatic mast cell disease. At the level of mRNA in mast cell progenitor cells of 20 patients with systemic mast cell activation syndrome and of 20 gender- and age-matched healthy volunteers, the tyrosine kinase kit was investigated for genetic alterations by means of RT-PCR and direct sequencing of the amplificates. In mast cells of 13 out of these 20 patients, multiple predominantly novel potential functionally activating point mutations or complex alterations of the mRNA sequence encoding the tyrosine kinase kit were detected. In contrast, in 19 of the 20 healthy subjects, no functionally relevant alterations of c-kit transcripts were detected. The present findings support the idea that the systemic mast cell activation syndrome is a clonal disease most commonly associated with variable activating mutations in the tyrosine kinase kit.
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Acknowledgements
The technical assistance of Mrs. R. Müller and Mrs. P. Spitzlei is gratefully acknowledged. We wish to thank all patients and healthy volunteers as well as the staff of the blood bank of the University Hospital of Bonn. The study was supported by grants of the Deutsche Krebshilfe, Novartis UK and the Förderclub Mastzellforschung.
Authors’ contributions
All authors contributed to the study design and drafting of the report. KM, UWK, JH, and TF recruited the patients and performed the clinical checkup of the patients. GJM, KM, and UWK did the mutational analysis. Statistical analyses were done by GJM. All authors have seen and approved the final version of the manuscript.
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Molderings, G.J., Meis, K., Kolck, U.W. et al. Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. Immunogenetics 62, 721–727 (2010). https://doi.org/10.1007/s00251-010-0474-8
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DOI: https://doi.org/10.1007/s00251-010-0474-8