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Article Dans Une Revue Blood Advances Année : 2022

Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation

Tala Shahin
Daniel Mayr
  • Fonction : Auteur
Mohamed Shoeb
  • Fonction : Auteur
Hye Sun Kuehn
  • Fonction : Auteur
Birgit Hoeger
Sarah Giuliani
Lisa Gawriyski
Özlem Yüce Petronczki
  • Fonction : Auteur
Jérôme Hadjadj
  • Fonction : Auteur
Sevgi Köstel Bal
  • Fonction : Auteur
Samaneh Zoghi
Matthias Haimel
Raul Jimenez Heredia
  • Fonction : Auteur
David Boutboul
  • Fonction : Auteur
Michael Triebwasser
  • Fonction : Auteur
Fanny Rialland-Battisti
Nathalie Costedoat Chalumeau
  • Fonction : Auteur
Pierre Quartier
Stuart Tangye
Thomas Fleisher
  • Fonction : Auteur
Nima Rezaei
Neil Romberg
Markku Varjosalo
Florian Halbritter
Frédéric Rieux-Laucat
Irinka Castanon
Sergio Rosenzweig
  • Fonction : Auteur
Kaan Boztug
  • Fonction : Auteur

Résumé

Abstract Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3 encoding Ikaros and Aiolos have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of proinflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation.

Dates et versions

hal-03864209 , version 1 (21-11-2022)

Identifiants

Citer

Tala Shahin, Daniel Mayr, Mohamed Shoeb, Hye Sun Kuehn, Birgit Hoeger, et al.. Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation. Blood Advances, 2022, 6 (7), pp.2444-2451. ⟨10.1182/bloodadvances.2021006367⟩. ⟨hal-03864209⟩

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