IRF4 haploinsufficiency in a family with Whipple's disease

Antoine Guérin, Gaspard Kerner, Nico Marr, Janet 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-Barricarte & 15 others Soraya 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 journalArticle

Abstract

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)
JournaleLife
Volume7
DOIs
StatePublished - Mar 14 2018
Externally publishedYes

Fingerprint

Tropheryma
Whipple Disease
Haploinsufficiency
Penetrance
Transcription Factors
Transcriptome
Immunity
Leukocytes
Mutation

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Guérin, A., Kerner, G., Marr, N., Markle, J., Fenollar, F., Wong, N., ... Casanova, J. L. (2018). IRF4 haploinsufficiency in a family with Whipple's disease. eLife, 7. https://doi.org/10.7554/eLife.32340

IRF4 haploinsufficiency in a family with Whipple's disease. / Guérin, Antoine; Kerner, Gaspard; Marr, Nico; Markle, Janet; Fenollar, Florence; Wong, Natalie; Boughorbel, Sabri; Avery, Danielle T.; Ma, Cindy S.; Bougarn, Salim; Bouaziz, Matthieu; Béziat, Vivien; Della Mina, Erika; Oleaga-Quintas, Carmen; Lazarov, Tomi; Worley, Lisa; Nguyen, Tina; Patin, Etienne; Deswarte, Caroline; Martinez-Barricarte, Rubén; Boucherit, Soraya; Ayral, Xavier; Edouard, Sophie; Boisson-Dupuis, Stéphanie; Rattina, Vimel; Bigio, Benedetta; Vogt, Guillaume; Geissmann, Frédéric; Quintana-Murci, Lluis; Chaussabel, Damien; Tangye, Stuart G.; Raoult, Didier; Abel, Laurent; Bustamante, Jacinta; Casanova, Jean Laurent.

In: eLife, Vol. 7, 14.03.2018.

Research output: Contribution to journalArticle

Guérin, A, Kerner, G, Marr, N, Markle, J, Fenollar, F, Wong, N, Boughorbel, S, Avery, DT, Ma, CS, Bougarn, S, Bouaziz, M, Béziat, V, Della Mina, E, Oleaga-Quintas, C, Lazarov, 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, SG, Raoult, D, Abel, L, Bustamante, J & Casanova, JL 2018, 'IRF4 haploinsufficiency in a family with Whipple's disease', eLife, vol. 7. https://doi.org/10.7554/eLife.32340
Guérin A, Kerner G, Marr N, Markle J, Fenollar F, Wong N et al. IRF4 haploinsufficiency in a family with Whipple's disease. eLife. 2018 Mar 14;7. https://doi.org/10.7554/eLife.32340
Guérin, Antoine ; Kerner, Gaspard ; Marr, Nico ; Markle, Janet ; Fenollar, Florence ; Wong, Natalie ; Boughorbel, Sabri ; Avery, Danielle T. ; Ma, Cindy S. ; Bougarn, Salim ; Bouaziz, Matthieu ; Béziat, Vivien ; Della Mina, Erika ; Oleaga-Quintas, Carmen ; Lazarov, Tomi ; Worley, Lisa ; Nguyen, Tina ; Patin, Etienne ; Deswarte, Caroline ; Martinez-Barricarte, Rubén ; Boucherit, Soraya ; Ayral, Xavier ; Edouard, Sophie ; Boisson-Dupuis, Stéphanie ; Rattina, Vimel ; Bigio, Benedetta ; Vogt, Guillaume ; Geissmann, Frédéric ; Quintana-Murci, Lluis ; Chaussabel, Damien ; Tangye, Stuart G. ; Raoult, Didier ; Abel, Laurent ; Bustamante, Jacinta ; Casanova, Jean Laurent. / IRF4 haploinsufficiency in a family with Whipple's disease. In: eLife. 2018 ; Vol. 7.
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abstract = "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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AU - Guérin, Antoine

AU - Kerner, Gaspard

AU - Marr, Nico

AU - Markle, Janet

AU - Fenollar, Florence

AU - Wong, Natalie

AU - Boughorbel, Sabri

AU - Avery, Danielle T.

AU - Ma, Cindy S.

AU - Bougarn, Salim

AU - Bouaziz, Matthieu

AU - Béziat, Vivien

AU - Della Mina, Erika

AU - Oleaga-Quintas, Carmen

AU - Lazarov, Tomi

AU - Worley, Lisa

AU - Nguyen, Tina

AU - Patin, Etienne

AU - Deswarte, Caroline

AU - Martinez-Barricarte, Rubén

AU - Boucherit, Soraya

AU - Ayral, Xavier

AU - Edouard, Sophie

AU - Boisson-Dupuis, Stéphanie

AU - Rattina, Vimel

AU - Bigio, Benedetta

AU - Vogt, Guillaume

AU - Geissmann, Frédéric

AU - Quintana-Murci, Lluis

AU - Chaussabel, Damien

AU - Tangye, Stuart G.

AU - Raoult, Didier

AU - Abel, Laurent

AU - Bustamante, Jacinta

AU - Casanova, Jean Laurent

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N2 - 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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KW - immunology

KW - infectious disease

KW - inflammation

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KW - microbiology

KW - primary immunodeficiency

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