IRF4 Haploinsufficiency in a Family With Whipple's Disease

Elife. 2018 Mar 14;7:e32340. doi: 10.7554/eLife.32340.


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: IRF4; Whipple's disease; haploinsufficiency; human; immunology; infectious disease; inflammation; microbiology; primary immunodeficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Female
  • Genetic Predisposition to Disease / genetics
  • Haploinsufficiency / genetics*
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Leukocytes / microbiology
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Penetrance
  • Tropheryma / genetics*
  • Tropheryma / pathogenicity
  • Whipple Disease / genetics*
  • Whipple Disease / microbiology
  • Whipple Disease / pathology


  • Interferon Regulatory Factors
  • interferon regulatory factor-4