A gain-of-function variation in PLCG1 causes a new immune dysregulation disease

Background Phospholipase C (PLC) γ1 is a critical enzyme regulating nuclear factor-κB (NF-κB), extracellular signal-related kinase, mitogen-activated protein kinase, and nuclear factor of activated T cells signaling pathways , yet germline PLCG1 mutation in human disease has not been reported. Objective We aimed to investigate the molecular pathogenesis of a PLCG1 activating variant in a patient with immune dysregulation . Methods Whole exome sequencing was used to identify the patient’s pathogenic variants. Bulk? 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 in patient PBMCs and T cells and COS-7 and Jurkat cell lines were used to define inflammatory signatures and assess the impact of the PLCG1 variant on protein function and immune signaling. Results We identified a novel and de novo heterozygous PLCG1 variant, p.S1021F, in a patient presenting with early-onset immune dysregulation disease. We demonstrated that the S1021F variant is a gain-of-function variant, leading to increased inositol-1,4,5-trisphosphate production, intracellular Ca 2+ release, and increased phosphorylation of extracellular signal-related kinase, p65, and p38. The transcriptome and protein expression at the single-cell level revealed exacerbated inflammatory responses in the patient’s T cells and monocytes . The PLCG1 activating variant resulted in enhanced NF-κB and type II interferon pathways in T cells, and hyperactivated NF-κB and type I interferon pathways in monocytes. Treatment with either PLCγ1 inhibitor or Janus kinase inhibitor reversed the upregulated gene expression profile in?vitro . Conclusions Our study highlights the critical role of PLCγ1 in maintaining immune homeostasis . We illustrate immune dysregulation as a consequence of PLCγ1 activation and provide insight into therapeutic targeting of PLCγ1.

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