Publication Date
1-1-2024
Journal
The Journal of Allergy and Clinical Immunology
DOI
10.1016/j.jaci.2023.09.002
PMID
37714437
PMCID
PMC11389843
PubMedCentral® Posted Date
1-1-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Humans, Mice, Haploinsufficiency, Herpesviridae Infections, Immunologic Deficiency Syndromes, Killer Cells, Natural, Signal Transduction, Phospholipase C gamma, NK cell, PLCG2, haploinsufficiency, immunodeficiency, herpes virus
Abstract
Background:
Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in NK cells, lymphocytes which recognize and lyse herpesvirus-infected cells; however, the genetic etiology is rarely diagnosed. PLCG2 encodes a signaling protein in NK cell and B cell signaling. Dominant-negative or gain-of-function variants in PLCG2 cause cold urticaria, antibody deficiency, and autoinflammation. However, loss-of-function variants and haploinsufficiency have not been reported to date.
Objective:
We aimed to identify the genetic cause of NK cell immunodeficiency in two families, and herein describe the functional consequences of two novel loss-of-function variants in PLCG2.
Methods:
We employed whole exome sequencing in conjunction with mass cytometry, microscopy, functional assays, and a mouse model of PLCG2 haploinsufficiency to investigate two families with NK cell immunodeficiency.
Results:
We identified novel heterozygous variants in PLCG2 in two families with severe and/or recurrent herpesvirus infections. In vitro studies demonstrated that these variants were loss-of-function due to haploinsufficiency with impaired NK calcium flux and cytotoxicity. In contrast to previous PLCG2 variants, B cell function remained intact. Plcg2+/− mice also displayed impaired NK cell function with preserved B cell function, phenocopying human disease.
Conclusions:
PLCG2 haploinsufficiency represents a distinct syndrome from previous variants characterized by NK cell immunodeficiency with herpes virus susceptibility, expanding the spectrum of PLCG2-related disease.
Clinical Implication:
We identified PLCG2 heterozygous variants in 2 families with severe and/or recurrent herpesvirus infections. This report demonstrates the impact of PLCG2 haploinsufficiency.
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