Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder

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.