Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

Published

Journal Article

BACKGROUND: Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. METHODS: We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. RESULTS: Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase Cγ(2) (PLCγ(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures. CONCLUSIONS: Genomic deletions in PLCG2 cause gain of PLCγ(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.).

Full Text

Cited Authors

  • Ombrello, MJ; Remmers, EF; Sun, G; Freeman, AF; Datta, S; Torabi-Parizi, P; Subramanian, N; Bunney, TD; Baxendale, RW; Martins, MS; Romberg, N; Komarow, H; Aksentijevich, I; Kim, HS; Ho, J; Cruse, G; Jung, M-Y; Gilfillan, AM; Metcalfe, DD; Nelson, C; O'Brien, M; Wisch, L; Stone, K; Douek, DC; Gandhi, C; Wanderer, AA; Lee, H; Nelson, SF; Shianna, KV; Cirulli, ET; Goldstein, DB; Long, EO; Moir, S; Meffre, E; Holland, SM; Kastner, DL; Katan, M; Hoffman, HM; Milner, JD

Published Date

  • January 26, 2012

Published In

Volume / Issue

  • 366 / 4

Start / End Page

  • 330 - 338

PubMed ID

  • 22236196

Pubmed Central ID

  • 22236196

Electronic International Standard Serial Number (EISSN)

  • 1533-4406

Digital Object Identifier (DOI)

  • 10.1056/NEJMoa1102140

Language

  • eng

Conference Location

  • United States