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Altered spectrum of somatic hypermutation in common variable immunodeficiency disease characteristic of defective repair of mutations

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Abstract

Pathogenic common variable immunodeficiency diseases (CVID) are genetic, usually inherited diseases for which a limited number of genetic defects have been implicated. As CVID presents with a wide range of clinical characteristics, there are likely diverse and for the most part unidentified genetic causes. In some individuals, defects in somatic hypermutation (SHM) have been suggested as the underlying cause of CVID. To address the mechanisms of SHM defects in CVID, we conducted a comprehensive mutational analysis of immunoglobulin heavy chain sequences from CVID patients. We identified several remarkably specific alterations in the spectra of SHM in comparison to healthy individuals. We provide evidence that some CVID cases are associated with defective repair of AID-induced mutations by the DNA mismatch repair (MMR) machinery. Our findings together with reports of increased chromosomal radiosensitivity and associated lymphoproliferative disorders amongst CVID patients, suggest that altered DNA damage repair may be a cause of CVID.

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Acknowledgements

This Research was supported by grants from the Canadian Institutes of Health Research (CIHR) and The Arthritis Society of Canada (TAS of Canada). BD is supported by CIHR and TAS of Canada. VRSKD is supported by Mathematics of Information Technology and Complex Systems (MITACS), GEOmatics for Informed DEcision (GEOIDE), Natural Sciences and Engineering Research Council of Canada (NSERC) and Canada Research Chairs (CRC) through Prof. Jianhong Wu, Center for Disease Modeling, York University and TAS of Canada through GEW. GEW would like to thank Clare Hall, University of Cambridge, UK. AM is supported by CIHR. ML is supported by CIHR and The industrial research and innovation fund (IRIF, Newfoundland). Authors are indebted to Dr. Igor Rogozin (NCBI, NIH, Bethesda, USA) for advice on CLUSTERM.

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Authors and Affiliations

  1. The School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada, M3J 1P3

    Bhargavi Duvvuri & Gillian E. Wu

  2. Department of Biology, York University, Toronto, Ontario, Canada

    Venkata R. S. K. Duvvuri, Jörg Grigull & Gillian E. Wu

  3. MITACS Center for Disease Modeling, York Institute of Health Research, Toronto, Ontario, Canada

    Venkata R. S. K. Duvvuri

  4. Department of Mathematics and Statistics, York University, Toronto, Ontario, Canada

    Jörg Grigull

  5. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    Alberto Martin

  6. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Intitutet, Karolinska University Hospital, Huddinge F79, 141 86, Stockholm, Sweden

    Qiang Pan-Hammarström

  7. Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, Room 1809A, Health Sciences Building, 300 Prince Phillip Drive, St. John’s, NL, A1B 3V6, Canada

    Mani Larijani

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  1. Bhargavi Duvvuri
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  2. Venkata R. S. K. Duvvuri
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  3. Jörg Grigull
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  4. Alberto Martin
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  5. Qiang Pan-Hammarström
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  7. Mani Larijani
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Correspondence to Bhargavi Duvvuri or Mani Larijani.

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Supplementary Table 1

Mutation spectra of patients compared with the control group (PDF 99 kb)

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Duvvuri, B., Duvvuri, V.R.S.K., Grigull, J. et al. Altered spectrum of somatic hypermutation in common variable immunodeficiency disease characteristic of defective repair of mutations. Immunogenetics 63, 1–11 (2011). https://doi.org/10.1007/s00251-010-0483-7

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  • DOI: https://doi.org/10.1007/s00251-010-0483-7

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