Title |
IRF4 haploinsufficiency in a family with Whipple’s disease
|
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Published in |
eLife, March 2018
|
DOI | 10.7554/elife.32340 |
Pubmed ID | |
Authors |
Antoine Guérin, Gaspard Kerner, Nico Marr, Janet G Markle, Florence Fenollar, Natalie Wong, Sabri Boughorbel, Danielle T Avery, Cindy S, 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 |
Abstract |
Most humans are exposed toTropheryma 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 thatIRF4had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 2 | 25% |
France | 1 | 13% |
Portugal | 1 | 13% |
Unknown | 4 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 6 | 75% |
Scientists | 2 | 25% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 54 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 12 | 22% |
Student > Ph. D. Student | 8 | 15% |
Other | 7 | 13% |
Student > Master | 4 | 7% |
Student > Bachelor | 4 | 7% |
Other | 5 | 9% |
Unknown | 14 | 26% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 13 | 24% |
Immunology and Microbiology | 8 | 15% |
Medicine and Dentistry | 8 | 15% |
Agricultural and Biological Sciences | 3 | 6% |
Linguistics | 1 | 2% |
Other | 2 | 4% |
Unknown | 19 | 35% |