Plcg2-flox Mouse

Plcg2, phospholipase C gamma 2, encodes a signaling protein crucial in NK-cell and B-cell signaling pathways [5]. It is involved in processes like B-cell receptor-induced calcium flux and extracellular signal-regulated kinase phosphorylation, which are vital for normal immune cell function [1].

Pathogenic variants of Plcg2 cause autosomal-dominant immune dysregulation, including PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID (APLAID) [1]. Functional classification of its variants shows that three-fourths lead to functional alteration of B-cell activation in vitro. Gain-of-function (GOF) and monoallelic loss-of-function (LOF) variants are common, with LOF variants associated with a new phenotypic cluster of humoral immune deficiency, autoinflammation, herpesvirus susceptibility, and NK-cell dysfunction [1]. Heterozygous LOF variants can lead to a novel form of immune dysregulation [1]. In cherubism, GOF Plcg2 variants may be a novel genetic driver, expanding the phenotypic landscape of autoinflammatory PLAID [3]. In non-small cell lung cancer, eccDNA-derived Plcg2 is upregulated, acting as an oncogene and potentially a biomarker for diagnosis and prognosis evaluation [2]. In colorectal cancer, high Plcg2 expression is associated with poor prognosis, promoting tumor progression and immune escape, and its knockdown can potentiate immune checkpoint blockade therapy [4]. Human Plcg2 haploinsufficiency results in a novel NK-cell immunodeficiency with herpesvirus susceptibility, as shown by in vitro studies and Plcg2+/- mice [5].

In summary, Plcg2 is essential for normal immune cell function, with its variants having diverse impacts on immune-related diseases. Studies using in vitro models and mouse models, such as Plcg2+/- mice, have been crucial in revealing its role in immune dysregulation, cancer, and immunodeficiency diseases, providing insights into disease mechanisms and potential therapeutic targets.