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Article Dans Une Revue eLife Année : 2018

IRF4 haploinsufficiency in a family with Whipple's disease

Nico Marr
Xavier Ayral
  • Fonction : Auteur
Damien Chaussabel

Résumé

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.
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hal-01789213 , version 1 (22-05-2018)

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Antoine Guerin, Gaspard Kerner, Nico Marr, Janet G. Markle, Florence Fenollar, et al.. IRF4 haploinsufficiency in a family with Whipple's disease. eLife, 2018, 7, pp.e32340. ⟨10.7554/eLife.32340⟩. ⟨hal-01789213⟩
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