eLife (Mar 2018)
IRF4 haploinsufficiency in a family with Whipple’s disease
- Antoine Guérin,
- Gaspard Kerner,
- Nico Marr,
- Janet G Markle,
- Florence Fenollar,
- Natalie Wong,
- Sabri Boughorbel,
- Danielle T Avery,
- Cindy S Ma,
- Salim Bougarn,
- Matthieu Bouaziz,
- Vivien Béziat,
- Erika Della Mina,
- Carmen Oleaga-Quintas,
- Tomi Lazarov,
- Lisa Worley,
- Tina Nguyen,
- Etienne Patin,
- Caroline Deswarte,
- Rubén Martinez-Barricarte,
- Soraya Boucherit,
- Xavier Ayral,
- Sophie Edouard,
- Stéphanie Boisson-Dupuis,
- Vimel Rattina,
- Benedetta Bigio,
- Guillaume Vogt,
- Frédéric Geissmann,
- Lluis Quintana-Murci,
- Damien Chaussabel,
- Stuart G Tangye,
- Didier Raoult,
- Laurent Abel,
- Jacinta Bustamante,
- Jean-Laurent Casanova
Affiliations
- Antoine Guérin
- ORCiD
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
- Gaspard Kerner
- ORCiD
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
- Nico Marr
- Sidra Medicine, Doha, Qatar
- Janet G Markle
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States
- Florence Fenollar
- Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille, URMITE, UM63, CNRS 7278, IRD 198, Marseille, France
- Natalie Wong
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
- Sabri Boughorbel
- Sidra Medicine, Doha, Qatar
- Danielle T Avery
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
- Cindy S Ma
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
- Salim Bougarn
- Sidra Medicine, Doha, Qatar
- Matthieu Bouaziz
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
- Vivien Béziat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
- Erika Della Mina
- ORCiD
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
- Carmen Oleaga-Quintas
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
- Tomi Lazarov
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States; Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, United States
- Lisa Worley
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
- Tina Nguyen
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
- Etienne Patin
- Human Evolutionary Genetics Unit, Department of Genomes and Genetics, Institut Pasteur, Paris, France; CNRS UMR2000, Paris, France; Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris, France
- Caroline Deswarte
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
- Rubén Martinez-Barricarte
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States
- Soraya Boucherit
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
- Xavier Ayral
- Rheumatology Unit, Cochin Hospital, Paris, France
- Sophie Edouard
- Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille, URMITE, UM63, CNRS 7278, IRD 198, Marseille, France
- Stéphanie Boisson-Dupuis
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States
- Vimel Rattina
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France
- Benedetta Bigio
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States
- Guillaume Vogt
- Imagine Institute, Paris Descartes University, Paris, France
- Frédéric Geissmann
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States; Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, United States; Weill Cornell Graduate School of Medical Sciences, New York, United States
- Lluis Quintana-Murci
- Human Evolutionary Genetics Unit, Department of Genomes and Genetics, Institut Pasteur, Paris, France; CNRS UMR2000, Paris, France; Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris, France
- Damien Chaussabel
- Sidra Medicine, Doha, Qatar
- Stuart G Tangye
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
- Didier Raoult
- Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille, URMITE, UM63, CNRS 7278, IRD 198, Marseille, France
- Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States
- Jacinta Bustamante
- ORCiD
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States; Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France
- Jean-Laurent Casanova
- ORCiD
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Paris Descartes University, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, United States; Pediatric Hematology and Immunology Unit, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute, New York, United States
- DOI
- https://doi.org/10.7554/eLife.32340
- Journal volume & issue
-
Vol. 7
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.
Keywords
