CoChat
Sign Up
Cited by 425Immunodeficiency and Autoimmune DisordersInflammasome and immune disordersMast cells and histamine

Cold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions

Open access
Ombrello, Michael J., Remmers, Elaine F., Sun, Guangping, Freeman, Alexandra F., Datta, Shrimati, Torabi-Parizi, Parizad, Subramanian, Naeha, Bunney, Tom D. +31 more·2012·New England Journal of Medicine
DOI 10.1056/nejmoa1102140PMC PMC3298368
Open this paper in CoChat — free accountOpen PDF

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.).

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1056/nejmoa1102140

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Inherited mutations at the PLCG2 locus cause PLCγ2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation.

    “Inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation.”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [63]

    The Discussion (page unavailable) attributes a dominantly inherited syndrome of cold urticaria and immune dysregulation to PLCG2 deletions and links the B-cell abnormalities to antibody deficiency. The Results (page unavailable) also report variable immunodeficiency. The paper describes inflammatory manifestations but does not establish that some affected subjects had autoinflammation specifically. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • PLAID is specifically driven by a gain-of-function amino acid mutation in the PLCG2 gene.

    “PLAID is specifically driven by a gain-of-function amino acid mutation in the PLCγ2 gene (63, 64), whereas CVID is much more genetically diverse with 2% of published cases of CVID estimated to be due to mutations in the PLCG2 gene (65).”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [63]

    The Discussion reports that PLAID-associated PLCG2 deletions cause constitutive phospholipase activity, supporting the gain-of-function aspect. But the Results (Linkage and Mutational Analysis) identify genomic deletions spanning exons in all three families, not a gain-of-function amino acid mutation. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • PLAID patients typically exhibit cold urticaria beginning in infancy, but otherwise share common clinical manifestations of CVID such as granulomatous disease, allergy, autoimmune disease, and abnormally low serum IgG with recurrent infections.

    “Patients with PLAID typically exhibit symptoms of cold urticaria, a form of cold temperature-induced hives, beginning in infancy, but otherwise shares many of the common clinical manifestations of CVID such as granulomatous disease, allergy, autoimmune disease, and an abnormally low concentration of serum IgG with recurrent infections (63, 66).”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [63]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Genomic deletions or somatic mutations within the regulatory domain of PLCG2 constitutively activate PLCG2 and lead to BTK inhibitor resistance in leukemia patients.

    “Specifically, genomic deletions (exon 19 or exons 20 through 22) or somatic mutations (R665W or S707Y) within the regulatory domain of PLCG2 constitutively activate PLCG2 and lead to BTK inhibitor resistance in leukemia patients 20,21 .”

    From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [20]

    The Results (Functional Studies of Mutant PLCγ2; page not provided) report that exon 19 and exons 20–22 deletions increased basal phospholipase activity, and the Discussion describes constitutive activity. The paper studies inherited deletions associated with immune dysregulation; it does not report the R665W or S707Y somatic mutations or show that these changes cause BTK inhibitor resistance in leukemia patients. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • PLCG2 variants/hypermorphic mutations cause inherited immune disorders (PLAID and APLAID) with autoinflammation and immune dysregulation.

    “Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function.”

    From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [12]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 41 · Cited by 425

Research works printed but not linked: 37

  1. [1]Bennett CL Christie J Ramsdell F The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 Nat Genet 2001 27 20 1 11137993
  2. [2]Brunkow ME Jeffery EW Hjerrild KA Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse Nat Genet 2001 27 68 73 11138001
  3. [3]Chatila TA Blaeser F Ho N JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome J Clin Invest 2000 106 R75 R81 11120765 PMC387260
  4. [4]Wildin RS Ramsdell F Peake J X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy Nat Genet 2001 27 18 20 11137992
  5. [5]Nagamine K Peterson P Scott HS Positional cloning of the APECED gene Nat Genet 1997 17 393 8 9398839
  6. [6]Hoffman HM Mueller JL Broide DH Wanderer AA Kolodner RD Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome Nat Genet 2001 29 301 5 11687797 PMC4322000
  7. [7]Gandhi C Healy C Wanderer AA Hoffman HM Familial atypical cold urticaria: description of a new hereditary disease J Allergy Clin Immunol 2009 124 1245 50 19910034 PMC2794966
  8. [8]Wanderer AA Hoffman HM The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes Immunol Allergy Clin North Am 2004 24 259 86 15120151
  9. [9]Kaplan AP Garofalo J Sigler R Hauber T Idiopathic cold urticaria: in vitro demonstration of histamine release upon challenge of skin biopsies N Engl J Med 1981 305 1074 7 6168912
  10. [10]Abecasis GR Cherny SS Cookson WO Cardon LR Merlin — rapid analysis of dense genetic maps using sparse gene flow trees Nat Genet 2002 30 97 101 11731797
  11. [11]Pelak K Shianna KV Ge D The characterization of twenty sequenced human genomes PLoS Genet 2010 6 9 pii e1001111 PMC2936541 20838461
  12. [13]Kim HS Das A Gross CC Bryceson YT Long EO Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase Immunity 2010 32 175 86 20189481 PMC2843589
  13. [14]Bryceson YT Rudd E Zheng C Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients Blood 2007 110 1906 15 17525286 PMC1976360
  14. [15]Ho J Moir S Wang W Enhancing effects of adjuvanted 2009 pandemic H1N1 influenza A vaccine on memory B-cell responses in HIV-infected individuals AIDS 2011 25 295 302 21157297 PMC3791488
  15. [16]Wardemann H Yurasov S Schaefer A Young JW Meffre E Nussenzweig MC Predominant autoantibody production by early human B cell precursors Science 2003 301 1374 7 12920303
  16. [17]Ng YS Wardemann H Chelnis J Cunningham-Rundles C Meffre E Bruton's tyrosine kinase is essential for human B cell tolerance J Exp Med 2004 200 927 34 15466623 PMC2213290
  17. [18]Bunney TD Katan M PLC regulation: emerging pictures for molecular mechanisms Trends Biochem Sci 2011 36 88 96 20870410
  18. [21]Rodriguez R Matsuda M Storey A Katan M Requirements for distinct steps of phospholipase Cgamma2 regulation, membrane-raft-dependent targeting and subsequent enzyme activation in B-cell signalling Biochem J 2003 374 269 80 12780340 PMC1223588
  19. [22]Gresset A Hicks SN Harden TK Sondek J Mechanism of phosphorylation-induced activation of phospholipase C-gamma isozymes J Biol Chem 2010 285 35836 47 20807769 PMC2975207
  20. [23]Poulin B Sekiya F Rhee SG Intramolecular interaction between phosphorylated tyrosine-783 and the C-terminal Src homology 2 domain activates phospholipase C-gamma1 Proc Natl Acad Sci U S A 2005 102 4276 81 15764700 PMC555506
  21. [24]Cooke MP Heath AW Shokat KM Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells J Exp Med 1994 179 425 38 8294858 PMC2191355
  22. [25]Healy JI Dolmetsch RE Timmerman LA Different nuclear signals are activated by the B cell receptor during positive versus negative signaling Immunity 1997 6 419 28 9133421
  23. [26]Dolmetsch RE Lewis RS Goodnow CC Healy JI Differential activation of transcription factors induced by Ca2+ response amplitude and duration Nature 1997 386 855 8 Erratum, Nature 1997;388:308 9126747
  24. [27]Daniels RL Takashima Y McKemy DD Activity of the neuronal cold sensor TRPM8 is regulated by phospholipase C via the phospholipid phosphoinositol 4,5-bisphosphate J Biol Chem 2009 284 1570 82 19019830 PMC2615505
  25. [28]Dufour JF Arias IM Turner TJ Inositol 1,4,5-trisphosphate and calcium regulate the calcium channel function of the hepatic inositol 1,4,5-trisphosphate receptor J Biol Chem 1997 272 2675 81 9006903
  26. [29]van Blitterswijk WJ Verheij M Anti-cancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects Curr Pharm Des 2008 14 2061 74 18691116
  27. [30]van Rossum DB Patterson RL Sharma S Phospholipase Cgamma1 controls surface expression of TRPC3 through an intermolecular PH domain Nature 2005 434 99 104 15744307
  28. [31]Sherman WB Seebohm PM Passive transfer of cold urticaria J Allergy 1950 21 414 24 14774055
  29. [32]Yu P Constien R Dear N Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry Immunity 2005 22 451 65 15845450
  30. [33]Abe K Fuchs H Boersma A A novel N-ethyl-N-nitrosourea-induced mutation in phospholipase Cgamma2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model Arthritis Rheum 2011 63 1301 11 21305534
  31. [34]Foerster C Voelxen N Rakhmanov M B cell receptor-mediated calcium signaling is impaired in B lymphocytes of type Ia patients with common variable immunodeficiency J Immunol 2010 184 7305 13 20495065
  32. [35]Aspalter RM Sewell WA Dolman K Farrant J Webster AD Deficiency in circulating natural killer (NK) cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia Clin Exp Immunol 2000 121 506 14 10971518 PMC1905722
  33. [36]Warnatz K Salzer U Rizzi M B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans Proc Natl Acad Sci U S A 2009 106 13945 50 19666484 PMC2722504
  34. [37]Losi CG Silini A Fiorini C Mutational analysis of human BAFF receptor TNFRSF13C (BAFF-R) in patients with common variable immunodeficiency J Clin Immunol 2005 25 496 502 16160919
  35. [38]Pan-Hammarström Q Salzer U Du L Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency Nat Genet 2007 39 429 30 17392797 PMC2931279
  36. [39]van Zelm MC Reisli I van der Burg M An antibody-deficiency syndrome due to mutations in the CD19 gene N Engl J Med 2006 354 1901 12 16672701
  37. [40]Grimbacher B Hutloff A Schlesier M Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency Nat Immunol 2003 4 261 8 12577056

Authors
Ombrello, M. J., Remmers, E. F., Sun, G., Freeman, A. F., Datta, S., Torabi-Parizi, P., Subramanian, N., Bunney, T. D., Baxendale, R. W., Martins, M. S., Romberg, N., Komarow, H., Aksentijevich, I., Kim, H. S., Ho, J., Cruse, G., Jung, M.-Y., Gilfillan, A. M., Metcalfe, D. D., Nelson, C., O'Brien, M., Wisch, L., Stone, K., Douek, D. C., Gandhi, C., Wanderer, A. A., Lee, H., Nelson, S. F., Shianna, K. V., Cirulli, E. T., Goldstein, D. B., Long, E. O., Moir, S., Meffre, E., Holland, S. M., Kastner, D. L., Katan, M., Hoffman, H. M., & Milner, J. D.
Affiliations
  • National Institutes of Health (US)
  • National Human Genome Research Institute (US)
  • National Institute of Allergy and Infectious Diseases (US)
  • University College London (GB)
  • Yale University (US)
  • University of Ulsan (KR)
  • University of California San Diego (US)
  • University of Colorado Health (US)
  • University of California, Los Angeles (US)
  • Duke University (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2012-01-26
Volume
366
Issue
4
Pages
330-338
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1102140
PMC
PMC3298368
OpenAlex
W2124369311
Cited by
425
References
41
Citations by year
2026: 14 · 2025: 20 · 2024: 17 · 2023: 27 · 2022: 27 · 2021: 34 · 2020: 42 · 2019: 36 · 2018: 28 · 2017: 21 · 2016: 34 · 2015: 36 · 2014: 36 · 2013: 34 · 2012: 17
FWCI
17.20
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • National Institutes of Health (Z99 AR999999, 5u19ai082713-05, AI‐061093, AI‐082713)
  • University of California, San Diego
  • National Human Genome Research Institute
  • National Institute of General Medical Sciences (T32GM007754)
  • National Institute of Allergy and Infectious Diseases (AI 061093, T32AI007469, U19-AI-082713, T32 AI-07469, AI082713, R01AI071087, AI071087, P01AI061093, ZIAAI001098, R21AI095848)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases
  • National Center for Research Resources (UL1RR031980)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
Keywords
cold urticaria, PLCγ2, gain-of-function mutations, in-frame deletion, autoinhibitory domain, common variable immunodeficiency, antibody deficiency, autoimmune thyroiditis, autoimmunity, infection susceptibility, natural killer cells, class-switched memory B cells, chromosome 16q, immune regulation, Mendelian inheritance
MeSH terms
Autoimmune Diseases, Cold Temperature, Female, Humans, Immunologic Deficiency Syndromes, Male, Pedigree, Phenotype, Sequence Deletion, Sequence Analysis, DNA, DNA, Complementary, Polymorphism, Single Nucleotide, Phospholipase C gamma, Cryopyrin-Associated Periodic Syndromes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review