A novel Fc gamma RIIa Q27W gene variant is associated with common variable immune deficiency through defective Fc gamma RIIa downstream signaling

We identified a novel Q27W Fc gamma RIIa variant that was found more frequently in common variable immunodeficiency (CVID) or CVID-like children. We analyzed the possible functional consequence of the Q27W Fc gamma RIIa mutation in human cells. We used peripheral blood mononuclear cells from Q27W Fc gamma RIIa patients and healthy controls, and cultured cells that overexpress the Q27W and common Fc gamma RIIa variants. The Q27W Fc gamma RIIa mutation does not disrupt Fc gamma RIIa surface expression in peripheral blood mononuclear cells. Mononuclear cells express multiple Fc gamma R, precluding careful analysis of Q27W Fc gamma RIIa functional deviation. For functional analysis of Fc gamma RIIa function, we therefore overexpressed the Q27W Fc gamma RIIa and common Fc-yRIla variant in IIA1.6 cells that are normally deficient in Fc gamma R. We show that Fc gamma RIIa triggering-induced signaling is obstructed, as measured by both decrease in calcium flux and defective MAPK phosphorylation. In conclusion, we here describe a novel Q27W Fc gamma RIIa variant that causes delayed downstream signaling. This variant may contribute to CVID. (C) 2014 Elsevier Inc. All rights reserved.