1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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IRF4 haploinsufficiency in a family with Whipple's disease

  1. Antoine Guérin
  2. Gaspard Kerner
  3. Nico Marr
  4. Janet G Markle
  5. Florence Fenollar
  6. Natalie Wong
  7. Sabri Boughorbel
  8. Danielle T Avery
  9. Cindy S Ma
  10. Salim Bougarn
  11. Matthieu Bouaziz
  12. Vivien Beziat
  13. Erika Della Mina
  14. Carmen Oleaga-Quintas
  15. Tomi Lazarovt
  16. Lisa Worley
  17. Tina Nguyen
  18. Etienne Patin
  19. Caroline Deswarte
  20. Rubén Martinez-Barricarte
  21. Soraya Boucherit
  22. Xavier Ayral
  23. Sophie Edouard
  24. Stéphanie Boisson-Dupuis
  25. Vimel Rattina
  26. Benedetta Bigio
  27. Guillaume Vogt
  28. Frédéric Geissmann
  29. Lluis Quintana-Murci
  30. Damien Chaussabel
  31. Stuart G Tangye
  32. Didier Raoult
  33. Laurent Abel
  34. Jacinta Bustamante
  35. Jean-Laurent Casanova  Is a corresponding author
  1. INSERM U1163, France
  2. Sidra Medical and Research Center, Qatar
  3. The Rockefeller University, United States
  4. University Aix-Marseille (URMITE), France
  5. Garvan Institute of Medical Research, Australia
  6. Memorial Sloan Kettering Cancer Center, United States
  7. Institut Pasteur, France
  8. Cochin Hospital, France
  9. Imagine Institute, Paris Descartes University, France
Research Article
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Cite this article as: eLife 2018;7:e32340 doi: 10.7554/eLife.32340

Abstract

Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.

Article and author information

Author details

  1. Antoine Guérin

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Gaspard Kerner

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0146-9428
  3. Nico Marr

    Sidra Medical and Research Center, Doha, Qatar
    Competing interests
    The authors declare that no competing interests exist.
  4. Janet G Markle

    St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Florence Fenollar

    Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille (URMITE), Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Natalie Wong

    Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Sabri Boughorbel

    Sidra Medical and Research Center, Doha, Qatar
    Competing interests
    The authors declare that no competing interests exist.
  8. Danielle T Avery

    Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Cindy S Ma

    Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Salim Bougarn

    Sidra Medical and Research Center, Doha, Qatar
    Competing interests
    The authors declare that no competing interests exist.
  11. Matthieu Bouaziz

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Vivien Beziat

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Erika Della Mina

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8733-7623
  14. Carmen Oleaga-Quintas

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Tomi Lazarovt

    Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Lisa Worley

    Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  17. Tina Nguyen

    Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  18. Etienne Patin

    Department of Genomes and Genetics, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  19. Caroline Deswarte

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  20. Rubén Martinez-Barricarte

    St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Soraya Boucherit

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  22. Xavier Ayral

    Rheumatology Unit, Cochin Hospital, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  23. Sophie Edouard

    Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille (URMITE), Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  24. Stéphanie Boisson-Dupuis

    St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Vimel Rattina

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  26. Benedetta Bigio

    St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  27. Guillaume Vogt

    Imagine Institute, Paris Descartes University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  28. Frédéric Geissmann

    Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  29. Lluis Quintana-Murci

    Department of Genomes and Genetics, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  30. Damien Chaussabel

    Sidra Medical and Research Center, Doha, Qatar
    Competing interests
    The authors declare that no competing interests exist.
  31. Stuart G Tangye

    Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  32. Didier Raoult

    Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille (URMITE), Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  33. Laurent Abel

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  34. Jacinta Bustamante

    Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  35. Jean-Laurent Casanova

    St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, United States
    For correspondence
    casanova@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7782-4169

Funding

Centre National de la Recherche Scientifique

  • Lluis Quintana-Murci

Agence Nationale de la Recherche (ANR-14-CE14-0008-02)

  • Lluis Quintana-Murci

Agence Nationale de la Recherche (ANR-14-CE14-0007-02)

  • Lluis Quintana-Murci

H2020 European Research Council

  • Lluis Quintana-Murci

National Health and Medical Research Council (1113904)

  • Stuart G Tangye

University of New South Wales

  • Lisa Worley
  • Tina Nguyen

Agence Nationale de la Recherche (ANR-16-CE17-0005-01)

  • Antoine Guérin

National Institutes of Health (5R01AI089970-02)

  • Jean-Laurent Casanova

National Health and Medical Research Council (1042925)

  • Cindy S Ma

Office of Health and Medical Research

  • Cindy S Ma
  • Stuart G Tangye

H2020 European Research Council (281297)

  • Lluis Quintana-Murci
  • Jean-Laurent Casanova

Seventh Framework Programme (FP/2007-2013)

  • Lluis Quintana-Murci

Agence Nationale de la Recherche (ANR-IFNPHOX (ANR-13-ISV3-001-01))

  • Jacinta Bustamante

Agence Nationale de la Recherche (ANR-10-LABX-62-IBEID)

  • Lluis Quintana-Murci
  • Laurent Abel
  • Jean-Laurent Casanova

Agence Nationale de la Recherche (ANR-GENMSMD (ANR-16-CE17-0005-01))

  • Jacinta Bustamante

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Informed consent was obtained from all family members, and the study was approved by the national ethics committee.

Reviewing Editor

  1. Jos WM van der Meer, Radboud University Medical Centre, Netherlands

Publication history

  1. Received: September 28, 2017
  2. Accepted: March 12, 2018
  3. Accepted Manuscript published: March 14, 2018 (version 1)
  4. Version of Record published: April 24, 2018 (version 2)

Copyright

© 2018, Guérin et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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