IRF4 haploinsufficiency in a family with Whipple's disease

Antoine Guérin; Gaspard Kerner; Nico Marr; Janet G. 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; 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

doi:10.7554/eLife.32340

IRF4 haploinsufficiency in a family with Whipple's disease

Antoine Guérin, Gaspard Kerner, Nico Marr, Janet G. 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-BarricarteSoraya 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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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 language	English (US)
Article number	e32340
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.32340
State	Published - Mar 14 2018

Keywords

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

ASJC Scopus subject areas

General Neuroscience
General Immunology and Microbiology
General Biochemistry, Genetics and Molecular Biology

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10.7554/eLife.32340

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Guérin, A., Kerner, G., Marr, N., Markle, J. G., Fenollar, F., Wong, N., Boughorbel, S., Avery, D. T., Ma, C. S., Bougarn, S., Bouaziz, M., Béziat, V., Della Mina, E., Oleaga-Quintas, C., Lazarov, T., Worley, L., Nguyen, T., Patin, E., Deswarte, C., ... Casanova, J. L. (2018). IRF4 haploinsufficiency in a family with Whipple's disease. eLife, 7, Article e32340. https://doi.org/10.7554/eLife.32340

Guérin, A, Kerner, G, Marr, N, Markle, JG, 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, e32340. https://doi.org/10.7554/eLife.32340

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title = "IRF4 haploinsufficiency in a family with Whipple's disease",

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.",

keywords = "IRF4, Whipple's disease, haploinsufficiency, human, immunology, infectious disease, inflammation, microbiology, primary immunodeficiency",

author = "Antoine Gu{\'e}rin and Gaspard Kerner and Nico Marr and Markle, {Janet G.} and Florence Fenollar and Natalie Wong and Sabri Boughorbel and Avery, {Danielle T.} and Ma, {Cindy S.} and Salim Bougarn and Matthieu Bouaziz and Vivien B{\'e}ziat and {Della Mina}, Erika and Carmen Oleaga-Quintas and Tomi Lazarov and Lisa Worley and Tina Nguyen and Etienne Patin and Caroline Deswarte and Rub{\'e}n Martinez-Barricarte and Soraya Boucherit and Xavier Ayral and Sophie Edouard and St{\'e}phanie Boisson-Dupuis and Vimel Rattina and Benedetta Bigio and Guillaume Vogt and Fr{\'e}d{\'e}ric Geissmann and Lluis Quintana-Murci and Damien Chaussabel and Tangye, {Stuart G.} and Didier Raoult and Laurent Abel and Jacinta Bustamante and Casanova, {Jean Laurent}",

note = "Publisher Copyright: Copyright {\textcopyright} 2018, Gu{\'e}rin et al.",

year = "2018",

month = mar,

day = "14",

doi = "10.7554/eLife.32340",

language = "English (US)",

volume = "7",

journal = "eLife",

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T1 - IRF4 haploinsufficiency in a family with Whipple's disease

AU - Guérin, Antoine

AU - Kerner, Gaspard

AU - Marr, Nico

AU - Markle, Janet G.

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

PY - 2018/3/14

Y1 - 2018/3/14

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.

AB - 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.

KW - IRF4

KW - Whipple's disease

KW - haploinsufficiency

KW - human

KW - immunology

KW - infectious disease

KW - inflammation

KW - microbiology

KW - primary immunodeficiency

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U2 - 10.7554/eLife.32340

DO - 10.7554/eLife.32340

M3 - Article

C2 - 29537367

AN - SCOPUS:85054142742

SN - 2050-084X

VL - 7

JO - eLife

JF - eLife

M1 - e32340

ER -

IRF4 haploinsufficiency in a family with Whipple's disease

Abstract

Keywords

ASJC Scopus subject areas

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