IRF4 haploinsufficiency in a family with Whipple's disease
- INSERM U1163, France
- Sidra Medical and Research Center, Qatar
- The Rockefeller University, United States
- University Aix-Marseille (URMITE), France
- Garvan Institute of Medical Research, Australia
- Memorial Sloan Kettering Cancer Center, United States
- Institut Pasteur, France
- Cochin Hospital, France
- Imagine Institute, Paris Descartes University, France
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.
Data availability
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IRF4 haplo-insufficiency underlies a familial form of Whipple's diseasePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE102862).
Article and author information
Author details
Jean-Laurent Casanova
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.
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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IRF4 haploinsufficiency in a family with Whipple's disease
eLife 7:e32340.
https://doi.org/10.7554/eLife.32340
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