Human PLCG2 haploinsufficiency results in a novel natural killer cell immunodeficiency

Joshua B. Alinger, Emily M. Mace, Justin R. Porter, Annelise Y. Mah-Som, Allyssa L. Daugherty, Stephanie Li, Allison A. Throm, Jeanette T. Pingel, Nermina Saucier, Albert Yao, Ivan K. Chinn, James R. Lupski, Mohammad Ehlayel, Michael Keller, Greg R. Bowman, Megan A. Cooper, Jordan S. Orange, Anthony R. French

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Background: Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in natural killer (NK) cells, lymphocytes that 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. Objectives: The investigators aimed to identify the genetic cause of NK-cell immunodeficiency in 2 families and herein describe the functional consequences of 2 novel loss-of-function variants in PLCG2. Methods: The investigators employed whole-exome sequencing in conjunction with mass cytometry, microscopy, functional assays, and a mouse model of PLCG2 haploinsufficiency to investigate 2 families with NK-cell immunodeficiency. Results: The investigators identified novel heterozygous variants in PLCG2 in 2 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-cell 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 herpesvirus susceptibility, expanding the spectrum of PLCG2-related disease.

Original languageEnglish
Pages (from-to)216-229
Number of pages14
JournalJournal of Allergy and Clinical Immunology
Issue number1
StatePublished - Jan 2024


  • NK cell
  • PLCG2
  • haploinsufficiency
  • herpesvirus
  • immunodeficiency


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