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IRF4 haploinsufficiency in a family with Whipple's disease


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.

Type Journal
ISBN 2050-084X (Electronic) 2050-084X (Linking)
Authors Guerin, A.; Kerner, G.; Marr, N.; Markle, J. G.; Fenollar, F.; Wong, N.; Boughorbel, S.; Avery, D. T.; Ma, C. S.; Bougarn, S.; Bouaziz, M.; Beziat, V.; Della Mina, E.; Oleaga-Quintas, C.; Lazarovt, T.; Worley, L.; Nguyen, T.; Patin, E.; Deswarte, C.; Martinez-Barricarte, R.; Boucherit, S.; Ayral, X.; Edouard, S.; Boisson-Dupuis, S.; Rattina, V.; Bigio, B.; Vogt, G.; Geissmann, F.; Quintana-Murci, L.; Chaussabel, D.; Tangye, S. G.; Raoult, D.; Abel, L.; Bustamante, J.; Casanova, J. L.
Responsible Garvan Author Prof Stuart Tangye
Publisher Name eLife
Published Date 2018-03-14
Published Volume 7
Published Issue 7
Published Pages e32340
Status Always Electronic
DOI 10.7554/eLife.32340
URL link to publisher's version