PURPOSE OF THE STUDY.
To perform Mendelian analysis of 3 families with cold-induced urticaria and identify and elucidate immunologic pathways and mechanisms.
STUDY POPULATION.
Three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity.
METHODS.
Immunophenotyping, including flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays, was used. Genetic studies, including linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing, were performed.
RESULTS.
Cold-induced urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA, circulating natural killer cells, and class-switched memory B cells were reduced. Linkage analysis led to the identification of an interval on chromosome 16q that included PLCG2, which encodes phospholipase Cγ2, a signaling molecule expressed in B cells, natural killer cells, and mast cells. Genomic sequencing identified 3 distinct in-frame deletions that co-segregated with disease. These deletions, located within a region encoding an inhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37oC but enhanced signaling at subphysiologic temperatures.
CONCLUSIONS.
Genomic deletions in PLCG2 cause gain of function of phospholipase Cγ2, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype that includes both deficient and excessive immune function.
REVIEWER COMMENTS.
This is a very interesting “experiment of nature” that provides a great deal of insight into phospholipase-mediated signaling. It is fascinating that the PLCG2 mutations identified in this report could lead to both impaired and excessive immune function and that this can be affected by temperature.
- Copyright © 2012 by the American Academy of Pediatrics