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Fatal Lymphoproliferative Disease in Two Siblings Lacking Functional FAAP24

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Abstract

Hereditary defects in several genes have been shown to disturb the normal immune response to EBV and to give rise to severe EBV-induced lymphoproliferation in the recent years. Nevertheless, in many patients, the molecular basis of fatal EBV infection still remains unclear. The Fanconi anemia-associated protein 24 (FAAP24) plays a dual role in DNA repair. By association with FANCM as component of the FA core complex, it recruits the FA core complex to damaged DNA. Additionally, FAAP24 has been shown to evoke ATR-mediated checkpoint responses independently of the FA core complex. By whole exome sequencing, we identified a homozygous missense mutation in the FAAP24 gene (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.

In order to analyze the functionality of the variant FAAP24 allele, we used herpes virus saimiri-transformed patient T cells to test endogenous cellular FAAP24 functions that are known to be important in DNA damage control. We saw an impaired FANCD2 monoubiquitination as well as delayed checkpoint responses, especially affecting CHK1 phosphorylation in patient samples in comparison to healthy controls. The phenotype of this FAAP24 mutation might have been further accelerated by an EBV strain that harbors an EBNA2 allele with enhanced activities compared to the prototype laboratory strain B95.8. This is the first report of an FAAP24 loss of function mutation found in human patients with EBV-associated lymphoproliferation.

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Acknowledgments

We thank Monika Schmidt, Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen-Nürnberg, for the technical assistance with HVS transformation of primary patient T cells and Conny Kuklik-Roos for performing the luciferase assays.

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    Authors and Affiliations

    1. Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany

      Svenja Daschkey, Kirsten Bienemann, René Martin Linka, Andrea Hönscheid, Michael Gombert, Sebastian Ginzel & Arndt Borkhardt

    2. Hospital for Children and Adolescents, University Leipzig, Leipzig, Germany

      Volker Schuster

    3. Children’s Hospital, University of Würzburg, Würzburg, Germany

      Hans Wolfgang Kreth

    4. Insitute of Toxicology, Heinrich Heine University, Düsseldorf, Germany

      Gerhard Fritz

    5. Center for Medical Biotechnology, Biological Faculty, University Duisburg-Essen, Essen, Germany

      Christian Johannes

    6. Virological Institute, Clinical and Molecular Virology, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

      Bernhard Fleckenstein

    7. Department of Gene Vectors, Helmholtz Center Munich, Munich, Germany

      Bettina Kempkes

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    1. Svenja Daschkey
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    Correspondence to Kirsten Bienemann.

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    Ethical Approval

    All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

    Authorship

    SD, KB, and AB designed the study. VS and HWK treated the patients and provided patient samples as well as clinical, immunological, and virological information. SD, RML, AH, GF, CJ, BF, and BK performed the research. MG and SG developed the in-house exome sequencing and data analysis pipeline. SD and KB drafted the manuscript.

    Disclosures

    No author has any financial or other potential conflict of interest to disclose.

    The project was funded by a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft) to KB and a grant from the Deutsche Krebshilfe to BK.

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    Svenja Daschkey and Kirsten Bienemann contributed equally to this work.

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    Figure S1

    Validation of the FAAP24 SNP in immortalized T cells A) and B) on the genomic level, C) on transcriptomic level, and D) on proteomic level. (TIF 1500 kb)

    Figure S2

    Schematic structures of the wild-type (gray) and the mutant A) FAAP24 gene (red) and B) FAAP24 protein (blue). The mutation is indicated as a red line at position 4428 (C4428T) on DNA level and 212 (T212M) on protein level. Abbreviations: E exon, UTR untranslated region, wt wild-type, HhH helix-hairpin-helix, ERCC4 excision repair cross-complementation group 4. (TIF 462 kb)

    Figure S3

    No upregulation of FAAP24 after PHA and CD3/CD28 stimulation in primary T cells shown A) on the transcriptomic level by qRT-PCR. Standard deviations are indicated as error bars. (TIF 156 kb)

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    Daschkey, S., Bienemann, K., Schuster, V. et al. Fatal Lymphoproliferative Disease in Two Siblings Lacking Functional FAAP24. J Clin Immunol 36, 684–692 (2016). https://doi.org/10.1007/s10875-016-0317-y

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