Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics

Abstract

Despite increasing understanding of its pathophysiology, the aetiology of systemic mast cell activation disease (MCAD) remains largely unknown. Research has shown that somatic mutations in kinases are necessary for the establishment of a clonal mast cell population, in particular mutations in the tyrosine kinase Kit and in enzymes and receptors with crucial involvement in the regulation of mast cell activity. However, other, as yet undetermined, abnormalities are necessary for the manifestation of clinical disease. The present article reviews molecular genetic research into the identification of disease-associated genes and their mutational alterations. The authors also present novel data on familial systemic MCAD and review the associated literature. Finally, the importance of understanding the molecular basis of inherited mutations in terms of diagnostics and therapy is emphasized.

Figure 1

Distribution of the following ratios: (i) of Q252(+)/Q252(−) expression intensity (i.e. the amount of PCR amplification product with and without the additional glutamine residue [Q]); (ii) of the GNNK(–) isoform compared to the GNNK(+) isoform [i.e. the amount of PCR amplification product without and with the tetrapeptide sequence glycine-asparagine-asparagine-lysine (GNNK)]; and (iii) of S715(−)/S715(+) expression intensity (i.e. the amount of PCR amplification product with and without the serine residue [S]). Comparison of the distribution of the ratios between patients with systemic mast cell activation disease (MCAD, filled symbols) and healthy probands (healthy persons, open symbols). Ordinate: Ratio of the expression intensities. The black bars represent the respective mean. P < 0·05, Fisher′s exact test; n.s., not significant.

Figure 2

Characteristics of the presently investigated population in terms of the familial aggregation of systemic mast cell activation disease (MCAD). In the index patients, the diagnosis was assigned according to the criteria for MCAD. Due to the anonymous nature of the survey of the control population, clinical diagnoses were assigned in the control group on the basis of a self-report checklist and the exclusion of relevant differential diagnoses (for the checklist, see ref. 92). Asterisks: number of affected persons/total number of persons in the respective group (percentage). A sample of 258 probands randomly recruited from the German inhabitants of the city of Bonn was used as a control group representative of the German population.