Human PLCG2 Haploinsufficiency Results in a Novel NK Cell Immunodeficiency

• Published in: Journal of allergy and clinical immunology 2023-09, Vol.153 (1), p.216-229
• Main Authors: Alinger, Joshua B., Mace, Emily M., Porter, Justin.R., Mah-Som, Annelise Y., Daugherty, Allyssa L., Li, Stephanie, Throm, Allison A., Pingel, Jeanette T., Saucier, Nermina, Yao, Albert, Chinn, Ivan K., Lupski, James R., Ehlayel, Mohammad, Keller, Michael, Bowman, Greg R., Cooper, Megan A., Orange, Jordan S., French, Anthony R.
• Format: Article
• Language: English
• Subjects: haploinsufficiency; herpes virus; immunodeficiency; NK cell; PLCG2
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2023.09.002

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. 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. 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. 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. 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. Dominant-negative and gain-of-function variants in PLCG2 have been previously reported to cause cold urticaria, antibody deficiency, and autoinflammation. PLCG2 haploinsufficiency is a distinct and novel immunodeficiency leading to NK cell dysfunction and is associated with severe and/or recurrent herpesvirus infections.