A homozygous truncating mutation of FGL2 is associated with immune dysregulation.

The Journal of allergy and clinical immunology 2023 Feb

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The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2-/- mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function. Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies. Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro. The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2V205fs mutant failed to suppress T-cell proliferation. We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient. Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Citation

Erin Janssen, Mohammad F Alosaimi, Anas M Alazami, Abdullah Alsuliman, Ayodele Alaiya, Bandar Al-Saud, Hamoud Al-Mousa, Tariq Jassim Al-Zaid, Emma Smith, Craig D Platt, Hibah Alruwaili, Sarah Albanyan, Sulaiman M Al-Mayouf, Raif S Geha. A homozygous truncating mutation of FGL2 is associated with immune dysregulation. The Journal of allergy and clinical immunology. 2023 Feb;151(2):572-578.e1