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IRF4 haploinsufficiency in a family with Whipple’s disease

Antoine Guérin, View ORCID ProfileGaspard Kerner, Nico Marr, Janet G. Markle, Florence Fenollar, Natalie Wong, Sabri Boughorbel, Danielle T. Avery, Cindy S. Ma, Salim Bougarn, Matthieu Bouaziz, Vivien Beziat, View ORCID ProfileErika Della Mina, Tomi Lazarovt, 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, View ORCID ProfileJean-Laurent Casanova
doi: https://doi.org/10.1101/197145
Antoine Guérin
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EU
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Gaspard Kerner
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EU
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Nico Marr
Sidra Medical and Research Center, Doha, Qatar
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Janet G. Markle
St. Giles Laboratory of Human Genetics of InfectiousDiseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
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Florence Fenollar
Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille, URMITE, UM63, CNRS 7278, IRD 198, 13005 Marseille, France, EU
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Natalie Wong
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, AustraliaSt Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney NSW 2010, Australia
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Sabri Boughorbel
Sidra Medical and Research Center, Doha, Qatar
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Danielle T. Avery
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, AustraliaSt Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney NSW 2010, Australia
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Cindy S. Ma
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, AustraliaSt Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney NSW 2010, Australia
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Salim Bougarn
Sidra Medical and Research Center, Doha, Qatar
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Matthieu Bouaziz
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EU
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Vivien Beziat
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EU
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Erika Della Mina
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EU
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Tomi Lazarovt
Immunology Program and Ludwig Center, Memorial SloanKettering Cancer Center, New York, NY 10065, USA
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Lisa Worley
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, AustraliaSt Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney NSW 2010, Australia
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Tina Nguyen
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, AustraliaSt Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney NSW 2010, Australia
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Etienne Patin
Human Evolutionary Genetics, Department of Genomes & Genetics, Institut Pasteur, Paris 75015, France, EUCNRS URA3012, 75015 Paris, France, EUCenter of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, 75015 Paris, France, EU
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Caroline Deswarte
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EU
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Rubén Martinez-Barricarte
St. Giles Laboratory of Human Genetics of InfectiousDiseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
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Soraya Boucherit
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EU
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Xavier Ayral
Rheumatology Unit, Cochin Hospital, 75014 Paris, France, EU
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Sophie Edouard
Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille, URMITE, UM63, CNRS 7278, IRD 198, 13005 Marseille, France, EU
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Stéphanie Boisson-Dupuis
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EUSt. Giles Laboratory of Human Genetics of InfectiousDiseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
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Vimel Rattina
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EU
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Benedetta Bigio
St. Giles Laboratory of Human Genetics of InfectiousDiseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
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Guillaume Vogt
Paris Descartes University, Imagine Institute, 75015Paris, France, EU
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Frédéric Geissmann
Immunology Program and Ludwig Center, Memorial SloanKettering Cancer Center, New York, NY 10065, USAWeill Cornell Graduate School of Medical Sciences,New York, NY 10065, USA
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Lluis Quintana-Murci
Human Evolutionary Genetics, Department of Genomes & Genetics, Institut Pasteur, Paris 75015, France, EUCNRS URA3012, 75015 Paris, France, EUCenter of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, 75015 Paris, France, EU
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Damien Chaussabel
Sidra Medical and Research Center, Doha, Qatar
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Stuart G. Tangye
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, AustraliaSt Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney NSW 2010, Australia
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Didier Raoult
Research Unit of Infectious and Tropical Emerging Diseases, University Aix-Marseille, URMITE, UM63, CNRS 7278, IRD 198, 13005 Marseille, France, EU
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Laurent Abel
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EUSt. Giles Laboratory of Human Genetics of InfectiousDiseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
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Jacinta Bustamante
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EUSt. Giles Laboratory of Human Genetics of InfectiousDiseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USACenter for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris,Necker Hospital for Sick Children, 75015Paris, France, EU
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Jean-Laurent Casanova
Laboratory of Human Genetics of Infectious Diseases,Necker Branch, INSERM U1163, 75015 Paris, France, EUParis Descartes University, Imagine Institute, 75015Paris, France, EUSt. Giles Laboratory of Human Genetics of InfectiousDiseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USAPediatric Hematology and Immunology Unit, Assistance Publique-Hôpitaux de Paris,Necker Hospital for Sick Children, 75015 Paris, France, EUHoward Hughes Medical Institute, NewYork, NY 10065 USA
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  • For correspondence: casanova@rockefeller.edu
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Abstract

The pathogenesis of Whipple’s disease (WD) remains largely unknown, as WD strikes only a very small minority of the individuals infected with Tropheryma whipplei (Tw). Asymptomatic carriage of Tw is less rare. We studied a large multiplex French kindred, containing four otherwise healthy WD patients (mean age: 76.7 years) and five healthy carriers of Tw (mean age: 55 years). We used a strategy combining genome-wide linkage analysis and whole-exome sequencing to test the hypothesis that WD is inherited in an autosomal dominant (AD) manner, with age-dependent incomplete penetrance. WD was linked to 12 genomic regions covering 27 megabases in the four patients. These regions contained only one very rare non-synonymous variation: the R98W variant of IRF4. The five Tw carriers were heterozygous for R98W. Interferon regulatory factor 4 (IRF4) is a transcription factor with pleiotropic roles in immunity. We showed that R98W was a loss-of-function allele, like only five other exceedingly rare IRF4 alleles of a total of 39 rare and common non-synonymous alleles tested. Furthermore, heterozygosity for R98W led to a distinctive pattern of transcription in leukocytes following stimulation with BCG or Tw. Finally, we found that IRF4 had evolved under purifying selection and that R98W was not dominant-negative, suggesting that the IRF4 deficiency in this kindred was due to haploinsufficiency. Overall, haploinsufficiency at the IRF4 locus selectively underlies WD in this multiplex kindred. This deficiency displays AD inheritance with incomplete penetrance, and chronic carriage probably precedes WD by several decades in Tw-infected heterozygotes.

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Posted October 03, 2017.
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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 Beziat, Erika Della Mina, Tomi Lazarovt, 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
bioRxiv 197145; doi: https://doi.org/10.1101/197145
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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 Beziat, Erika Della Mina, Tomi Lazarovt, 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
bioRxiv 197145; doi: https://doi.org/10.1101/197145

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