Plcg2-KO Mouse

Plcg2, phospholipase C gamma 2, is involved in immune-related signaling pathways. It plays a crucial role in B-cell activation, with its normal function likely contributing to proper immune responses [1]. Mutations in Plcg2 can lead to various immune-related disorders, indicating its importance in maintaining immune homeostasis. Gene knockout or conditional knockout mouse models would be valuable tools to study its function in vivo.

Pathogenic variants of Plcg2 cause autosomal-dominant immune dysregulation. Functionally, three-fourths of the variants lead to functional alteration of B-cell activation in vitro. There are gain-of-function (GOF) and monoallelic loss-of-function (LOF) variants. Both GOF and LOF variants are associated with susceptibility to infection and autoinflammation. A new phenotypic cluster including humoral immune deficiency, autoinflammation, herpesvirus susceptibility, and natural killer cell dysfunction was seen with multiple heterozygous LOF variants [1]. In non-small cell lung cancer, Plcg2 can exist in extrachromosomal circular DNA (eccDNA), and its overexpression promotes metastasis by regulating mitochondrial respiration [2]. GOF Plcg2 variants may also be a novel genetic driver of cherubism, expanding the phenotypic landscape of autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation [3]. In Alzheimer's disease, a protective nonsynonymous variant in Plcg2 was identified, and its expression is upregulated in the brains of patients, correlated with amyloid plaque density and inflammatory response-related pathways [4,6]. In chronic lymphocytic leukemia, while mutations in Plcg2 have been associated with ibrutinib resistance, they are absent in a significant fraction of patients relapsing on ibrutinib [5,7]. In colorectal cancer, high expression of Plcg2 is associated with poor prognosis, and it promotes tumor progression, immunosuppressive microenvironment, and immune escape. Targeting Plcg2 can potentiate immune checkpoint blockade therapy [8].

In summary, Plcg2 is essential for immune-related functions, with its dysregulation contributing to various diseases such as immune dysregulation syndromes, certain cancers, and Alzheimer's disease. Studies using gene knockout or conditional knockout models could further clarify its precise roles in these disease conditions, providing potential targets for therapeutic interventions.

References:

1. Baysac, Kathleen, Sun, Guangping, Nakano, Hiroto, Milner, Joshua D, Ombrello, Michael J. 2023. PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants. In The Journal of allergy and clinical immunology, 153, 230-242. doi:10.1016/j.jaci.2023.08.036. https://pubmed.ncbi.nlm.nih.gov/37769878/

2. Yang, Yongfeng, Yang, Ying, Huang, Hong, Zhang, Li, Li, Weimin. 2023. PLCG2 can exist in eccDNA and contribute to the metastasis of non-small cell lung cancer by regulating mitochondrial respiration. In Cell death & disease, 14, 257. doi:10.1038/s41419-023-05755-7. https://pubmed.ncbi.nlm.nih.gov/37031207/

3. Chester, Jennifer G, Carcamo, Benjamin, Gudis, David A, Chung, Wendy K, Milner, Joshua D. 2024. PLCG2 variants in cherubism. In The Journal of allergy and clinical immunology, 154, 1554-1558. doi:10.1016/j.jaci.2024.08.016. https://pubmed.ncbi.nlm.nih.gov/39197752/

4. Sims, Rebecca, van der Lee, Sven J, Naj, Adam C, Williams, Julie, Schellenberg, Gerard D. 2017. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. In Nature genetics, 49, 1373-1384. doi:10.1038/ng.3916. https://pubmed.ncbi.nlm.nih.gov/28714976/

5. Bonfiglio, Silvia, Sutton, Lesley-Ann, Ljungström, Viktor, Rosenquist, Richard, Ghia, Paolo. . BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib. In Blood advances, 7, 2794-2806. doi:10.1182/bloodadvances.2022008821. https://pubmed.ncbi.nlm.nih.gov/36696464/

6. Tsai, Andy P, Dong, Chuanpeng, Lin, Peter Bor-Chian, Bissel, Stephanie J, Nho, Kwangsik. 2022. PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease. In Genome medicine, 14, 17. doi:10.1186/s13073-022-01022-0. https://pubmed.ncbi.nlm.nih.gov/35180881/

7. Lampson, Benjamin L, Brown, Jennifer R. 2018. Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia? In Expert review of hematology, 11, 185-194. doi:10.1080/17474086.2018.1435268. https://pubmed.ncbi.nlm.nih.gov/29381098/

8. Zhou, Xueliang, Lin, Joshua, Shao, Yanfei, Zhang, Sen, Sun, Jing. 2024. Targeting PLCG2 Suppresses Tumor Progression, Orchestrates the Tumor Immune Microenvironment and Potentiates Immune Checkpoint Blockade Therapy for Colorectal Cancer. In International journal of biological sciences, 20, 5548-5575. doi:10.7150/ijbs.98200. https://pubmed.ncbi.nlm.nih.gov/39494327/