TMD8-PLCG2-R665W-KI Cell Line

PLCG2-R665W is a gain-of-function missense mutation in the phospholipase C gamma 2 (PLCG2) gene. This mutation substitutes arginine with tryptophan at position 665, located in the autoinhibitory SH2 domain of the PLCγ2 enzyme, which normally represses basal catalytic activity. The substitution disrupts this autoinhibition, leading to constitutive activation of PLCγ2. This results in sustained intracellular calcium flux, hyperactive downstream signaling (e.g., via NF-κB and MAPK pathways), and aberrant B-cell and myeloid cell activation. The PLCG2-R665W mutation is a primary genetic cause of *autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation* (APLAID), a rare autosomal dominant syndrome. Clinical manifestations include early-onset systemic autoinflammation (e.g., erythematous plaques, arthralgia), recurrent infections, and antibody deficiency. Unlike the related PLCG2-L845F mutation, APLAID driven by R665W typically lacks cold-induced urticaria. The mutation highlights the critical role of PLCγ2 autoinhibition in immune homeostasis and presents a target for developing specific kinase or PLCγ2 inhibitors.