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Analyzing the Functions of Mast Cells In Vivo Using 'Mast Cell Knock-in' Mice
Published on: May 27, 2015
Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell
Gerhard J Molderings1, Ulrich W Kolck, Christian Scheurlen
1Institut für Pharmakologie und Toxikologie, Universitätsklinikum Bonn, Germany. molderings@uni-bonn.de
Objective:
Sequencing efforts to discover mutations in the tyrosine kinase Kit related to systemic mast cell disorders have so far been focused mainly on only a few of the 21 exons of the encoding gene c-kit, thus considerably limiting the possibility to quantitatively reveal pathogenetic relationships. The purpose of this study was to analyze and compare the total sequence of Kit tyrosine kinase at the level of the mRNAs obtained from patients with clear systemic signs of a pathologically increased mast cell mediator release and those from healthy volunteers.
Material And Methods:
Kit encoding mRNA isolated from mast cell progenitors in peripheral blood from 17 patients with a mast cell activation disorder and from 5 healthy volunteers as well as from the human mast cell leukemia cell line HMC1 was analyzed for alterations.
Results:
Multiple novel point mutations and six isoforms of Kit which are due to alternative mRNA splicing were detected. One isoform, the insertion of a glutamine residue at amino acid position 252, was found to be a new splice variant expressed in all patients but in none of the healthy volunteers.
Conclusions:
Systemic mast cell activation disorder was pathogenetically characterized by two or more alterations in the Kit tyrosine kinase providing not only a means of confirming the diagnosis, but also of assessing prognosis and of starting adequate therapeutic interventions. The insertion of Q252 appears to be pathognomic for that disease, providing a novel means for the identification of chronic non-specific gastrointestinal symptoms as manifestations of a systemic mast cell activation disorder.
Insights
Researchers identified novel Kit tyrosine kinase mutations and splice variants in systemic mast cell disorders. A specific Q252 insertion in Kit mRNA is a potential diagnostic marker for these conditions.
Area of Science:
- Genetics
- Oncology
- Immunology
Background:
- Systemic mast cell disorders involve abnormal mast cell activation.
- Previous Kit tyrosine kinase gene (c-kit) mutation studies were limited to a few exons.
- A comprehensive analysis of Kit tyrosine kinase is needed to understand pathogenetic relationships.
Purpose of the Study:
- To analyze and compare the complete Kit tyrosine kinase mRNA sequence.
- To identify mutations and isoforms in patients with systemic mast cell disorders compared to healthy volunteers.
Main Methods:
- Analysis of Kit mRNA from mast cell progenitors in peripheral blood of 17 patients and 5 healthy volunteers.
- Utilized the human mast cell leukemia cell line HMC1 for comparison.
Main Results:
- Detected multiple novel point mutations in Kit.
- Identified six Kit isoforms resulting from alternative mRNA splicing.
- Discovered a novel splice variant, Q252 insertion, present in all patients but absent in healthy volunteers.
Conclusions:
- Systemic mast cell activation disorder can be characterized by two or more Kit tyrosine kinase alterations.
- These alterations aid in diagnosis, prognosis, and therapeutic intervention.
- The Q252 insertion is a potential pathognomic marker for systemic mast cell activation disorder, aiding in identifying gastrointestinal symptoms as manifestations.
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