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-BarricarteSoraya 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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish (US)
Article numbere32340
StatePublished - Mar 14 2018


  • IRF4
  • Whipple's disease
  • haploinsufficiency
  • human
  • immunology
  • infectious disease
  • inflammation
  • microbiology
  • primary immunodeficiency

ASJC Scopus subject areas

  • General Neuroscience
  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology


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