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Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease

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Abstract

Recently, evidence was provided for common familial occurrence of systemic mast cell activation disease (MCAD), i.e., mast cell disorders characterized by aberrant release of mast cell mediators and/or accumulation of pathological mast cells in potentially any tissue. Since there is accumulating evidence that epigenetic processes may have transgenerational consequences, the aim of the present study was to investigate by two different experimental approaches whether epigenetic effects may contribute to the familial occurrence of MCAD. (1) High throughput profiling of the methylation status of the genomic DNA in leukocytes from MCAD patients in comparison to healthy subjects revealed for the first time an association of MCAD with alterations in DNA methylation comprising genes encoding proteins crucially involved in DNA/RNA repair and processing, apoptosis, cell activity, and exocytosis/cell communication. A set of 195 differentially methylated CpG sites could be regarded as candidates for a MCAD signature at the methylation level of the DNA. (2) In a cohort of MCAD patients, a correlation between age at symptom onset and year of birth (reflecting different generations) was observed suggesting the presence of the phenomenon of anticipation. In conclusion, the present findings suggest that epigenetic processes could substantially contribute to the transgenerational transmission of MCAD.

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Acknowledgments

The technical assistance of Mrs. Nadine Fricker and Mrs. Sandra Barth is gratefully acknowledged. The study was supported by grants of the B. Braun-Stiftung, Germany and the Förderclub Mastzellforschung e.V., Germany.

Ethical standards

The study was approved by the Ethics Committee of the University of Bonn (Germany) and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All probands gave informed consent prior to the investigation according to the guidelines of the local Ethics Committee.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Britta Haenisch

  2. Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany

    Britta Haenisch

  3. Department of Psychiatry, University of Bonn, Bonn, Germany

    Britta Haenisch

  4. Bonn-Aachen International Center for IT (B-IT), Algorithmic Bioinformatics, University of Bonn, Bonn, Germany

    Holger Fröhlich

  5. Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland

    Stefan Herms

  6. Institute of Human Genetics, University Hospital of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany

    Stefan Herms & Gerhard J. Molderings

Authors
  1. Britta Haenisch
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  2. Holger Fröhlich
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  4. Gerhard J. Molderings
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Corresponding author

Correspondence to Gerhard J. Molderings.

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Online Resource Fig. S1

Required sample size to detect a twofold change of methylation at Bonferroni corrected p value of 0.05 and statistical power of 80 % (PDF 53 kb)

Online Resource Fig. S2

Pedigree of a family with a high familial loading of mast cell activation disease showing anticipation (PDF 53 kb)

Online Resource Fig. S3

Sample clustering (Ward’s method) before and after normalization (PDF 53 kb)

Online Resource Table S1

CpG sites with significantly (adjusted p value <0.05) different methylation between patient and control samples (XLS 110 kb).

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Haenisch, B., Fröhlich, H., Herms, S. et al. Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease. Immunogenetics 66, 287–297 (2014). https://doi.org/10.1007/s00251-014-0768-3

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  • DOI: https://doi.org/10.1007/s00251-014-0768-3

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