Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome.

ALPS FADD LOH autoimmunity

Journal

The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002

Informations de publication

Date de publication:
02 Oct 2023
Historique:
received: 23 03 2023
revised: 18 09 2023
accepted: 22 09 2023
pubmed: 5 10 2023
medline: 5 10 2023
entrez: 4 10 2023
Statut: aheadofprint

Résumé

The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated. We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent. We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4 We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations. The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.

Sections du résumé

BACKGROUND BACKGROUND
The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated.
OBJECTIVE OBJECTIVE
We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent.
METHODS METHODS
We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4
RESULTS RESULTS
We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations.
CONCLUSIONS CONCLUSIONS
The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.

Identifiants

DOI: 10.1016/j.jaci.2023.09.028 PMID: 37793571
pubmed: 37793571
pii: S0091-6749(23)01209-5
doi: 10.1016/j.jaci.2023.09.028
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Auteurs

Olivier Pellé (O)

University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.

Solange Moreno (S)

University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.

Myriam Ricarda Lorenz (MR)

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Quentin Riller (Q)

University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.

Marita Fuehrer (M)

Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen, Ulm, Germany; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Marie-Claude Stolzenberg (MC)

University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.

Maria Elena Maccari (ME)

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Christelle Lenoir (C)

University of Paris Cité, Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.

Morgane Cheminant (M)

Clinical Hematology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; French National Reference Centre for Primary Immunodeficiencies (CEREDIH), Paris, France.

Tanja Hinze (T)

Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.

Holger F Hebart (HF)

Department of Internal Medicine, Kliniken Ostalb, Stauferklinikum, Mutlangen, Germany.

Christoph König (C)

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.

Adrien Schvartz (A)

University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.

Yohann Schmitt (Y)

University of Paris Cité, Paris, France; Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 and INSERM US24/CNRS UAR3633, Paris, France.

Angélique Vinit (A)

Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.

Emilie Henry (E)

Genomics Platform, Translational Research Department, Research Center, Institut Curie, Paris Sciences et Lettres (PSL) Research University, Paris, France.

Aurore Touzart (A)

Laboratory of Onco-Hematology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Institut Necker-Enfants Malades (INEM), INSERM U1151, Paris, France.

Patrick Villarese (P)

Laboratory of Onco-Hematology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Institut Necker-Enfants Malades (INEM), INSERM U1151, Paris, France.

Pierre Isnard (P)

Institut Necker-Enfants Malades (INEM), INSERM U1151, Paris, France; Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Nathalie Neveux (N)

Laboratory of Biological Nutrition, Faculty of Pharmacy, Paris University, Paris, France; Clinical Chemistry Department, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Judith Landman-Parker (J)

Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP) Armand Trousseau, Paris, France.

Capucine Picard (C)

University of Paris Cité, Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM UMR 1163, Paris, France; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.

Fanny Fouyssac (F)

Pediatric Oncology and Hematology Unit, Children Hospital, Vandoeuvre-les-Nancy, Paris, France.

Bénédicte Neven (B)

University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Pediatric Immuno-hematology and Rheumatology Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.

Bodo Grimbacher (B)

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Carsten Speckmann (C)

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Alain Fischer (A)

University of Paris Cité, Paris, France; Pediatric Immuno-hematology and Rheumatology Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France; Collège de France, Paris, France.

Sylvain Latour (S)

University of Paris Cité, Paris, France; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.

Klaus Schwarz (K)

Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen, Ulm, Germany.

Stephan Ehl (S)

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Frédéric Rieux-Laucat (F)

University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France. Electronic address: frederic.rieux-laucat@inserm.fr.

Anne Rensing-Ehl (A)

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Aude Magérus (A)

University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France. Electronic address: aude.magerus@inserm.fr.

Classifications MeSH