IRF4 haploinsufficiency in a family with Whipple’s disease
oleh: 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
| Format: | Article |
|---|---|
| Diterbitkan: | eLife Sciences Publications Ltd 2018-03-01 |
Deskripsi
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.