Genomic deletions of phospholipase Cγ2 abolish autoinhibition, causing a new syndrome of cold urticaria, antibody deficiency, and susceptibility to both autoimmunity and infection

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NHGRI	IMMUNO/INFLAM-23

* FARE Award Winner

Authors

• MJ Ombrello
• EF Remmers
• G Sun
• A Freeman
• H Komarow
• S Datta
• P Torabi-Parizi
• N Subramanian
• TD Bunney
• RW Baxendale
• HS Kim
• J Ho
• E Long
• S Moir
• E Meffre
• S Holland
• M Katan
• DL Kastner
• H Hoffman
• JD Milner

Abstract

Mendelian analysis of disorders of immune regulation can provide molecular insight into pathways utilized for host defense and immune tolerance. We report three families with a dominantly inherited complex of cold urticaria, antibody deficiency, and susceptibility to autoimmunity and infection. To better understand the interface between autoimmunity and immunodeficiency, we sought to identify the cause of this phenotype. Cold urticaria was present in every patient, while additional immune phenotypes were present in 26/27. Affected subjects had decreased circulating class-switched memory B and NK cells, and defective B cell central tolerance. Patient B cells also had impaired ligand-mediated activation, which was restored at subphysiologic temperatures. Linkage analysis of one family identified one 7Mb candidate interval on chromosome 16q. Given its role in B and NK cells, we selected PLCG2 for mutational analysis. In each family, a private deletion of PLCG2 perfectly cosegregated with cold urticaria, and none were found in 400 healthy control chromosomes. Each deletion caused constitutive phospholipase activity, but paradoxically resulted in diminished activation of downstream signaling pathways. We describe a novel immunodysregulatory syndrome in which coding mutations in PLCG2 cause signaling abnormalities in multiple leukocyte subsets and a pleiotropic clinical phenotype encompassing both excessive and impaired immune function.

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