title: Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.
abstract: 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.).
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ombrello
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Guangping
authors.initials: G
authors.lastname: Sun
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.forename: Shrimati
authors.initials: S
authors.lastname: Datta
authors.forename: Parizad
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authors.lastname: Torabi-Parizi
authors.forename: Naeha
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authors.lastname: Subramanian
authors.forename: Tom D
authors.initials: TD
authors.lastname: Bunney
authors.forename: Rhona W
authors.initials: RW
authors.lastname: Baxendale
authors.forename: Marta S
authors.initials: MS
authors.lastname: Martins
authors.forename: Neil
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authors.lastname: Romberg
authors.forename: Hirsh
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authors.lastname: Komarow
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: Hun Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Jason
authors.initials: J
authors.lastname: Ho
authors.forename: Glenn
authors.initials: G
authors.lastname: Cruse
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Jung
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.forename: Celeste
authors.initials: C
authors.lastname: Nelson
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Brien
authors.forename: Laura
authors.initials: L
authors.lastname: Wisch
authors.forename: Kelly
authors.initials: K
authors.lastname: Stone
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Chhavi
authors.initials: C
authors.lastname: Gandhi
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wanderer
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Cirulli
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Eric O
authors.initials: EO
authors.lastname: Long
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Matilda
authors.initials: M
authors.lastname: Katan
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D003080:Cold Temperature / Q000009:adverse effects; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics*; D018076:DNA, Complementary / Q000032:analysis / Q000302:isolation & purification; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D051966:Phospholipase C gamma / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D018076:DNA, Complementary; D051966:Phospholipase C gamma