Loss-of-phosphorylation of IKZF1 results in gain-of-function associated with immune dysregulation.

IKAROS IKZF1 Immunedysregulation T(H)2 differentiation gain-of-function genetic inborn errors of immunity mutation phosphorylation

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 Mar 2024
Historique:
received: 12 04 2023
revised: 21 01 2024
accepted: 25 01 2024
medline: 5 3 2024
pubmed: 5 3 2024
entrez: 4 3 2024
Statut: aheadofprint

Résumé

Immune dysregulation often presents as autoimmunity, inflammation and/or lymphoproliferation. Several germline genetic defects have been associated with immune dysregulation including heterozygous gain-of-function (GOF) mutations in IKZF1, an essential transcription factor for hematopoiesis containing zinc finger domains (ZFs). However, in a large part of patients the genetic origin of their immunedysregulation remains undetermined. A family with two members presenting immune dysregulation signs was studied to identify the genetic cause of their disease. Whole exome sequencing, analysis of immunological parameters, functional assays including western blotting, EMSA during cell cycle and T helper differentiation were performed. The two patients carried a novel heterozygous mutation in IKZF1 (IKZF1 Disturbed IKZF1 phosphorylation represents a novel GOF mechanism (gain-of-function by loss-of-phosphorylation; GOF-LOP), associated with immune dysregulation, highlighting the regulatory role of IKZF1 during cell cycle progression through phosphorylation.

Sections du résumé

BACKGROUND BACKGROUND
Immune dysregulation often presents as autoimmunity, inflammation and/or lymphoproliferation. Several germline genetic defects have been associated with immune dysregulation including heterozygous gain-of-function (GOF) mutations in IKZF1, an essential transcription factor for hematopoiesis containing zinc finger domains (ZFs). However, in a large part of patients the genetic origin of their immunedysregulation remains undetermined.
OBJECTIVE OBJECTIVE
A family with two members presenting immune dysregulation signs was studied to identify the genetic cause of their disease.
METHODS METHODS
Whole exome sequencing, analysis of immunological parameters, functional assays including western blotting, EMSA during cell cycle and T helper differentiation were performed.
RESULTS RESULTS
The two patients carried a novel heterozygous mutation in IKZF1 (IKZF1
CONCLUSION CONCLUSIONS
Disturbed IKZF1 phosphorylation represents a novel GOF mechanism (gain-of-function by loss-of-phosphorylation; GOF-LOP), associated with immune dysregulation, highlighting the regulatory role of IKZF1 during cell cycle progression through phosphorylation.

Identifiants

DOI: 10.1016/j.jaci.2024.01.029 PMID: 38438084
pubmed: 38438084
pii: S0091-6749(24)00230-6
doi: 10.1016/j.jaci.2024.01.029
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Auteurs

Akihiro Hoshino (A)

Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France.

Benoît Heid Picard (BH)

Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France;; Université de Paris-Cité, Paris, France.

Sophia Polychronopoulou (S)

Department of Pediatric Hematology-Oncology (T.A.O), Aghia Sophia Children's Hospital, Goudi-Athens, Greece.

Charikleia Kelaidi (C)

Department of Pediatric Hematology-Oncology (T.A.O), Aghia Sophia Children's Hospital, Goudi-Athens, Greece.

Saba Azarnoush (S)

Department of Pediatric Immuno-Hematology, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.

Sven Kracker (S)

Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, Paris, France;; Université de Paris-Cité, Paris, France.

Frédéric Rieux-Laucat (F)

Université de Paris-Cité, Paris, France;; Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Imagine Institute, Paris, France.

David Boutboul (D)

Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France.

Sylvain Latour (S)

Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France;; Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, Paris, France;. Electronic address: sylvain.latour@inserm.fr.

Classifications MeSH