title: A novel FcγRIIa Q27W gene variant is associated with common variable immune deficiency through defective FcγRIIa downstream signaling.
abstract: We identified a novel Q27W FcγRIIa variant that was found more frequently in common variable immunodeficiency (CVID) or CVID-like children. We analyzed the possible functional consequence of the Q27W FcγRIIa mutation in human cells. We used peripheral blood mononuclear cells from Q27W FcγRIIa patients and healthy controls, and cultured cells that overexpress the Q27W and common FcγRIIa variants. The Q27W FcγRIIa mutation does not disrupt FcγRIIa surface expression in peripheral blood mononuclear cells. Mononuclear cells express multiple FcγR, precluding careful analysis of Q27W FcγRIIa functional deviation. For functional analysis of FcγRIIa function, we therefore overexpressed the Q27W FcγRIIa and common FcγRIIa variant in IIA1.6 cells that are normally deficient in FcγR. We show that FcγRIIa 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 FcγRIIa variant that causes delayed downstream signaling. This variant may contribute to CVID.
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Thijs W H
authors.initials: TWH
authors.lastname: Flinsenberg
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Willemijn J
authors.initials: WJ
authors.lastname: Janssen
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Eszter
authors.initials: E
authors.lastname: Herczenik
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Boross
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Nederend
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Lieneke H
authors.initials: LH
authors.lastname: Jongeneel
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Rianne C
authors.initials: RC
authors.lastname: Scholman
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Jaap-Jan
authors.initials: JJ
authors.lastname: Boelens
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Marielle E
authors.initials: ME
authors.lastname: van Gijn
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Joris M
authors.initials: JM
authors.lastname: van Montfrans
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Jeanette H
authors.initials: JH
authors.lastname: Leusen
authors.affiliation: Laboratory of Translational Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands. Electronic address: mboes@umcutrecht.nl.
authors.forename: Marianne
authors.initials: M
authors.lastname: Boes
mesh_terms: D000293:Adolescent; D002118:Calcium / Q000378:metabolism; D002648:Child; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology; D014644:Genetic Variation; D006801:Humans; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium
keywords: CVID; Children; Fc gamma receptor; Immune cell activation; Receptor signaling; Susceptibility gene