The following is a summary of “A gain-of-function variation in PLCG1 causes a new immune dysregulation disease,” published in the November 2023 issue of Allergy & Immunology by Tao, et al.

Phospholipase C (PLC) γ1 plays a pivotal role in regulating various signaling pathways, yet germline mutations in PLCG1 associated with human disease have not been reported. For a study, researchers sought to investigate the molecular pathogenesis of a PLCG1 activating variant in a patient exhibiting immune dysregulation. The objective was to understand the impact of a novel de novo heterozygous PLCG1 variant (p.S1021F) on immune function and signaling pathways in a patient with early-onset immune dysregulation.

Whole exome sequencing was employed to identify pathogenic variants. Various molecular and cellular assays, including RNA sequencing, single-cell RNA sequencing, quantitative PCR, cytometry by time of flight, immunoblotting, flow cytometry, luciferase assay, IP-One ELISA, calcium flux assay, and cytokine measurements, were conducted using patient peripheral blood mononuclear cells (PBMCs) and T cells, as well as COS-7 and Jurkat cell lines. These analyses aimed to elucidate the inflammatory signatures and assess the impact of the PLCG1 variant on protein function and immune signaling.

The study revealed a gain-of-function de novo heterozygous PLCG1 variant (p.S1021F) in the patient, leading to increased inositol-1,4,5-trisphosphate production, intracellular Ca²⁺ release, and heightened phosphorylation of key signaling molecules. Transcriptomic and protein expression analyses at the single-cell level demonstrated exacerbated inflammatory responses in the patient’s T cells and monocytes. The activating variant enhanced NF-κB and type II interferon pathways in T cells and hyperactivated NF-κB and type I interferon pathways in monocytes. Treatment with PLCγ1 or Janus kinase inhibitors reversed the upregulated gene expression profile in vitro.

The study underscored the critical role of PLCγ1 in maintaining immune homeostasis and provided insights into the immune dysregulation resulting from PLCγ1 activation. The findings also suggested potential therapeutic avenues for targeting PLCγ1 in the context of immune-related disorders.

Source: jacionline.org/article/S0091-6749(23)00859-X/fulltext