IRF4 haploinsufficiency in a family with Whipple's disease
Antoine Guerin
(1)
,
Gaspard Kerner
(1)
,
Nico Marr
(2)
,
Janet G. Markle
(3)
,
Florence Fenollar
(4)
,
Natalie Wong
(5, 6)
,
Sabri Boughorbel
(2)
,
Danielle T. Avery
(7, 6)
,
Cindy S. Ma
(7, 6)
,
Salim Bougarn
(2)
,
Matthieu Bouaziz
(1)
,
Vivien Beziat
(1)
,
Erika Della Mina
(1)
,
Carmen Oleaga-Quintas
(1)
,
Tomi Lazarov
(8)
,
Lisa Worley
(7, 6)
,
Tina Nguyen
(7, 6)
,
Etienne Patin
(9, 10)
,
Caroline Deswarte
(1)
,
Ruben Martinez-Barricarte
(3)
,
Soraya Boucherit
(1)
,
Xavier Ayral
(11)
,
Sophie Edouard
(12)
,
Stephanie Boisson-Dupuis
(1, 3, 13)
,
Vimel Rattina
(13)
,
Benedetta Bigio
(3)
,
Guillaume Vogt
(1)
,
Frederic Geissmann
(8, 14)
,
Lluis Quintana-Murci
(9, 10)
,
Damien Chaussabel
(2)
,
Stuart G. Tangye
(7, 6)
,
Didier Raoult
(12)
,
Laurent Abel
(13, 3)
,
Jacinta Bustamante
(1, 3, 15)
,
Jean-Laurent Casanova
(16, 1, 3, 17)
1
IMAGINE - U1163 -
Imagine - Institut des maladies génétiques
2 Sidra Medicine [Doha, Qatar]
3 St. Giles Laboratory of Human Genetics of Infectious Diseases
4 VITROME - Vecteurs - Infections tropicales et méditerranéennes
5 Garvan Institute of medical research
6 St. Vincent’s Clinical School, Faculty of Medicine
7 Immunology Program
8 Memorial Sloane Kettering Cancer Center [New York]
9 C3BI - Centre de Bioinformatique, Biostatistique et Biologie Intégrative
10 Génétique Evolutive Humaine - Human Evolutionary Genetics
11 IC UM3 (UMR 8104 / U1016) - Institut Cochin
12 MEPHI - Microbes évolution phylogénie et infections
13 Equipe Inserm U1163 - Human genetics of infectious diseases : Mendelian predisposition
14 Weill Medical College of Cornell University [New York]
15 Centre d'Etude des Déficits Immunitaires
16 Hôpital Necker - Enfants Malades [AP-HP]
17 HHMI - Howard Hughes Medical Institute
2 Sidra Medicine [Doha, Qatar]
3 St. Giles Laboratory of Human Genetics of Infectious Diseases
4 VITROME - Vecteurs - Infections tropicales et méditerranéennes
5 Garvan Institute of medical research
6 St. Vincent’s Clinical School, Faculty of Medicine
7 Immunology Program
8 Memorial Sloane Kettering Cancer Center [New York]
9 C3BI - Centre de Bioinformatique, Biostatistique et Biologie Intégrative
10 Génétique Evolutive Humaine - Human Evolutionary Genetics
11 IC UM3 (UMR 8104 / U1016) - Institut Cochin
12 MEPHI - Microbes évolution phylogénie et infections
13 Equipe Inserm U1163 - Human genetics of infectious diseases : Mendelian predisposition
14 Weill Medical College of Cornell University [New York]
15 Centre d'Etude des Déficits Immunitaires
16 Hôpital Necker - Enfants Malades [AP-HP]
17 HHMI - Howard Hughes Medical Institute
Gaspard Kerner
- Fonction : Auteur
- PersonId : 791513
- ORCID : 0000-0003-0146-9428
Nico Marr
- Fonction : Auteur
- PersonId : 762966
- ORCID : 0000-0002-1927-7072
Florence Fenollar
- Fonction : Auteur
- PersonId : 761559
- ORCID : 0000-0002-7517-0173
- IdRef : 070502811
Erika Della Mina
- Fonction : Auteur
- PersonId : 791248
- ORCID : 0000-0001-8733-7623
Etienne Patin
- Fonction : Auteur
- PersonId : 179015
- IdHAL : etienne-patin
- ORCID : 0000-0002-9911-4459
- IdRef : 132614553
Caroline Deswarte
- Fonction : Auteur
- PersonId : 772685
- ORCID : 0000-0002-8775-3368
Soraya Boucherit
- Fonction : Auteur
- PersonId : 791179
- ORCID : 0000-0002-8819-7594
Benedetta Bigio
- Fonction : Auteur
- PersonId : 791514
- ORCID : 0000-0001-7291-5638
Lluis Quintana-Murci
- Fonction : Auteur
- PersonId : 754080
- IdHAL : lluis-quintana-murci
- ORCID : 0000-0003-2429-6320
- IdRef : 127109897
Damien Chaussabel
- Fonction : Auteur
- PersonId : 761494
- ORCID : 0000-0002-6131-7242
Didier Raoult
- Fonction : Auteur
- PersonId : 8465
- IdHAL : didier-raoult
- ORCID : 0000-0002-2895-5824
- IdRef : 035496169
Laurent Abel
- Fonction : Auteur
- PersonId : 756191
- ORCID : 0000-0001-7016-6493
- IdRef : 07779432X
Jacinta Bustamante
- Fonction : Auteur
- PersonId : 757899
- ORCID : 0000-0002-3439-2482
- IdRef : 124593461
Jean-Laurent Casanova
- Fonction : Auteur
- PersonId : 756193
- ORCID : 0000-0002-7782-4169
- IdRef : 073388726
Résumé
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.
Domaines
Maladies infectieusesFormat du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Résumé |
en
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.
|
Titre |
en
IRF4 haploinsufficiency in a family with Whipple's disease
|
Auteur(s) |
Antoine Guerin
1
, Gaspard Kerner
1
, Nico Marr
2
, Janet G. Markle
3
, Florence Fenollar
4
, Natalie Wong
5, 6
, Sabri Boughorbel
2
, Danielle T. Avery
7, 6
, Cindy S. Ma
7, 6
, Salim Bougarn
2
, Matthieu Bouaziz
1
, Vivien Beziat
1
, Erika Della Mina
1
, Carmen Oleaga-Quintas
1
, Tomi Lazarov
8
, Lisa Worley
7, 6
, Tina Nguyen
7, 6
, Etienne Patin
9, 10
, Caroline Deswarte
1
, Ruben Martinez-Barricarte
3
, Soraya Boucherit
1
, Xavier Ayral
11
, Sophie Edouard
12
, Stephanie Boisson-Dupuis
1, 3, 13
, Vimel Rattina
13
, Benedetta Bigio
3
, Guillaume Vogt
1
, Frederic Geissmann
8, 14
, Lluis Quintana-Murci
9, 10
, Damien Chaussabel
2
, Stuart G. Tangye
7, 6
, Didier Raoult
12
, Laurent Abel
13, 3
, Jacinta Bustamante
1, 3, 15
, Jean-Laurent Casanova
16, 1, 3, 17
1
IMAGINE - U1163 -
Imagine - Institut des maladies génétiques
( 247401 )
- IHU Imagine,
156 rue de Vaugirard, 75015 PARIS
et
24 Boulevard du Montparnasse, 75015 Paris
- France
2
Sidra Medicine [Doha, Qatar]
( 534573 )
- Al Gharrafa Street, Ar-Rayyan, Doha
- Qatar
3
St. Giles Laboratory of Human Genetics of Infectious Diseases
( 478202 )
- 1230 York Ave, New York, NY 10065
- États-Unis
4
VITROME -
Vecteurs - Infections tropicales et méditerranéennes
( 527045 )
- IHU Méditerranée Infection
19-21 Bd Jean Moulin
13005 Marseille
- France
5
Garvan Institute of medical research
( 471053 )
- Darlinghurst, New South Wales 2010
- Australie
6
St. Vincent’s Clinical School, Faculty of Medicine
( 471065 )
- Australie
7
Immunology Program
( 471054 )
- Australie
8
Memorial Sloane Kettering Cancer Center [New York]
( 346710 )
- 1275 York Avenue
New York, NY 10065
- États-Unis
9
C3BI -
Centre de Bioinformatique, Biostatistique et Biologie Intégrative
( 463018 )
- 25-28 rue du docteur Roux, 75724 Paris cedex 15
- France
10
Génétique Evolutive Humaine - Human Evolutionary Genetics
( 534817 )
- Département Génomes et Génétique - 25-28 rue du Docteur Roux, F-75724 Paris Cedex 15
- France
11
IC UM3 (UMR 8104 / U1016) -
Institut Cochin
( 106187 )
- 22 rue Méchain, 75014 Paris
- France
12
MEPHI -
Microbes évolution phylogénie et infections
( 527038 )
- IHU Méditerranée Infection
19-21 Bd Jean Moulin
13005 Marseille
- France
13
Equipe Inserm U1163 -
Human genetics of infectious diseases : Mendelian predisposition
( 530926 )
- Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris
- France
14
Weill Medical College of Cornell University [New York]
( 507473 )
- Manhattan
- États-Unis
15
Centre d'Etude des Déficits Immunitaires
( 171997 )
- Hôpital Necker-Enfants Malades, 75015, Paris, France
- France
16
Hôpital Necker - Enfants Malades [AP-HP]
( 414766 )
- 149 Rue de Sèvres 75015 Paris
- France
17
HHMI -
Howard Hughes Medical Institute
( 91969 )
- États-Unis
|
Date de publication |
2018
|
Audience |
Internationale
|
Comité de lecture |
Oui
|
Vulgarisation |
Non
|
Langue du document |
Anglais
|
Nom de la revue |
|
Licence |
Paternité
|
Date de publication électronique |
2018-03-14
|
Volume |
7
|
Page/Identifiant |
e32340
|
Domaine(s) |
|
Projet(s) Européen(s) |
|
Projet(s) ANR |
|
Mots-clés |
en
Whipple's disease, primary immunodeficiency, IRF4, haploinsufficiency 44
|
DOI | 10.7554/eLife.32340 |
Origine :
Fichiers produits par l'(les) auteur(s)
Loading...