IRF4 haploinsufficiency in a multiplex family with Whipple’s disease

<i>Tropheryma whipplei</i> is the bacterial agent responsible for Whipple's disease (WD). However, WD occurs only very rarely in Tw-infected individuals. We investigated the cause of disease in two relatives with WD. We studied a son and his mother, both presenting an articular form of WD, at the ages of 38 and 60 years, respectively, these episodes occurring five years apart. Both were otherwise healthy. We performed whole-exome sequencing, characterized a candidate variant biochemically, and performed an immunological analysis on the patients' leukocytes. Both patients were heterozygous for a rare missense variant of the gene encoding the transcription factor IRF4 (p.R25S), for which haploinsufficiency was previously reported to underlie WD in a large multiplex family. This variant was hypomorphic for DNA binding and transcription induction. It did not exert negative dominance. Immunity was otherwise normal in these two patients. Haploinsufficiency for IRF4 can thus underlie WD in <i>T. whipplei</i>-infected individuals from at least two unrelated families.

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Publication Details

Journal
Journal of Human Immunity
Published
2025-11-11
DOI
https://doi.org/10.70962/jhi.20250009
Citations
1
Primary Topic
Whipple's Disease and Interleukins
Type
article
Field-Weighted Citation Impact
1.47

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article

IRF4 haploinsufficiency in a multiplex family with Whipple’s disease

Tom Le Voyer, Sébastien Ottaviani, Antoine Dossier, Mathieu Blot et al.
1 citations
Journal of Human Immunity
Whipple's Disease and Interleukins
1.47
article

IRF4 haploinsufficiency in a multiplex family with Whipple’s disease

Tom Le Voyer, Sébastien Ottaviani, Antoine Dossier, Mathieu Blot, Achille Aouba, R. Outh, Guillaume Vogt, Radjiv Goulabchand, Camille Soudée, L. Galicier, Guillaume Lefèvre, Stéphanie Dublanc, Aurélien Guffroy, N. Schleinitz, Thierry Bienvenu, Jean‐Christophe Lagier, Marc Scherlinger, Jean‐Laurent Casanova, Jérémie Rosain, Pierre Cougoul, Sylvain Audia, Jonathan London, Xavier Puéchal, Vincent Meynier, Jean-Philippe Vernhes, Jean‐François Emile, Thibault Sixt, Vincent Gendrin, Jacinta Bustamante, Florence Fenollar, Vivien Béziat, Marc Blondel, A. Robbins, G. Le Guenno, Hailun Li, Amélie Servettaz, Agnès Ferroni, Sinem Ünal, Paul Legendre, Antoine Néel, Aurélie Jourdes, Nabil Bel Feki
article en
1 citations

Abstract

<i>Tropheryma whipplei</i> is the bacterial agent responsible for Whipple's disease (WD). However, WD occurs only very rarely in Tw-infected individuals. We investigated the cause of disease in two relatives with WD. We studied a son and his mother, both presenting an articular form of WD, at the ages of 38 and 60 years, respectively, these episodes occurring five years apart. Both were otherwise healthy. We performed whole-exome sequencing, characterized a candidate variant biochemically, and performed an immunological analysis on the patients' leukocytes. Both patients were heterozygous for a rare missense variant of the gene encoding the transcription factor IRF4 (p.R25S), for which haploinsufficiency was previously reported to underlie WD in a large multiplex family. This variant was hypomorphic for DNA binding and transcription induction. It did not exert negative dominance. Immunity was otherwise normal in these two patients. Haploinsufficiency for IRF4 can thus underlie WD in <i>T. whipplei</i>-infected individuals from at least two unrelated families.

Journal of Human ImmunityVol. 2(1)
Howard Hughes Medical Institute (US), Inserm (FR), Université Paris Cité (FR), Balfour Hospital (GB), Hospital for Sick Children (CA), Hôpital Cochin (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut des Maladies Génétiques Imagine (FR), Université Paris 8 (FR), Rockefeller University (US)
St. Giles Foundation, Institut Necker-Enfants Malades, Fondation Maladies Rares, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Stavros Niarchos Foundation, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Center for Research Resources
Openalex Percentile: Top 14%
Whipple's Disease and Interleukins
1.47
DOIOpen Access PDFOpenAlex
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