A Hypermorphic Missense Mutation in PLCG2 , Encoding Phospholipase Cγ2, Causes a Dominantly Inherited Autoinflammatory Disease with Immunodeficiency
Open accessAbstract
Whole-exome sequencing was performed in a family affected by dominantly inherited inflammatory disease characterized by recurrent blistering skin lesions, bronchiolitis, arthralgia, ocular inflammation, enterocolitis, absence of autoantibodies, and mild immunodeficiency. Exome data from three samples, including the affected father and daughter and unaffected mother, were filtered for the exclusion of reported variants, along with benign variants, as determined by PolyPhen-2. A total of eight transcripts were identified as possible candidate genes. We confirmed a variant, c.2120C>A (p.Ser707Tyr), within PLCG2 as the only de novo variant that was present in two affected family members and not present in four unaffected members. PLCG2 encodes phospholipase Cγ2 (PLCγ2), an enzyme with a critical regulatory role in various immune and inflammatory pathways. The p.Ser707Tyr substitution is located in an autoinhibitory SH2 domain that is crucial for PLCγ2 activation. Overexpression of the altered p.Ser707Tyr protein and ex vivo experiments using affected individuals' leukocytes showed clearly enhanced PLCγ2 activity, suggesting increased intracellular signaling in the PLCγ2-mediated pathway. Recently, our laboratory identified in individuals with cold-induced urticaria and immune dysregulation PLCG2 exon-skipping mutations resulting in protein products with constitutive phospholipase activity but with reduced intracellular signaling at physiological temperatures. In contrast, the p.S…
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Mutations in PLCG2 that constitutively activate the enzyme contribute to autoinflammatory disorders and resistance mechanisms in cancer treatment.
“mutations in PLCG2 that constitutively activate the enzyme contribute to autoinflammatory disorders and resistance mechanisms in cancer treatment. 21 , 22 , 23”
From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [21]
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 [13]
No Ca2+ changes were seen in mock HEK293T cells stimulated with EGF.
“No Ca2+ changes were seen in mock HEK293T cells stimulated with EGF (Fig. 4d), confirming our previous ELISA IP-One results, and as previously observed [13].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [13]
A significant gain of function of PLCγ2 can lead to deleterious impacts on the immune system.
“These clearly indicate that a significant gain of function of PLCγ2 can lead to deleterious impacts on the immune system.”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [32]
Aberrant functions of different PLCs and PI3Ks in disease development are well established.
“Although not covered in this review, the importance of aberrant functions of different PLCs and PI3Ks in disease development is well established and continues to expand [11,62,67,72,134–138].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [135]
S707Y had previously been reported as a constitutively activating mutation in the dominantly inherited human disease APLAID.
“Whereas S707Y had previously been reported as a constitutively activating mutation in the dominantly inherited human disease APLAID”
The S707Y mutation in PLCγ2 has a gain-of-function effect owing to disruption of an autoinhibitory SH2 domain.
“It has been shown that the S707Y mutation in PLCγ2 has a gain-of-function effect owing to disruption of an autoinhibitory SH2 domain.21”
From Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib (2014) · cites this paper as [21]
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 [64]
PLCγ2 is implicated in immunodeficiency including PLAID and CVID.
“Given its prominent role in the adaptive immune system, PLCγ2 has been implicated in manifestations of immunodeficiency, including both the immunodeficiency syndrome, PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and common variable immunodeficiency (CVID).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [64]
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 [64]
APLAID patients exhibit phenotypic differences and similarities with PLAID, including involvement of the humoral immune and innate systems and various forms of inflammation.
“These patients exhibit both phenotypic differences and similarities with PLAID, including involvement of the humoral immune (Fig. 3A) and innate system (Fig. 3B) as well as various forms of inflammation (64).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [64]
Laboratory analysis of APLAID patients showed decreased IgM, IgG, and IgA levels, typically lacking class-switched memory B cells, with normal NK and T cell counts.
“Laboratory analysis of patients with APLAID showed decreased IgM, IgG, and IgA levels, typically lacking class-switched memory B cells, with normal NK and T cell counts.”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [64]
Common clinical features in APLAID include early-onset, recurrent blistering skin lesions, pulmonary disease, arthralgia, inflammatory eye and bowel disease, and mild immunodeficiency.
“Common clinical features in APLAID include early-onset, recurrent blistering skin lesions, pulmonary disease, arthralgia, inflammatory eye and bowel disease, and mild immunodeficiency (64).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [64]
These models recapitulate features of human diseases, including chronic inflammation accompanied by hyperreactive B-cells and expansion of innate inflammatory cells.
“These models seem to recapitulate features of the human diseases, including chronic inflammation accompanied by hyperreactive B-cells and expansion of innate inflammatory cells [102, 112]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [102]
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- Authors
- Zhou, Q., Lee, G.-S., Brady, J., Datta, S., Katan, M., Sheikh, A., Martins, M. S., Bunney, T. D., Santich, B. H., Moir, S., Kuhns, D. B., Priel, D. A. L., Ombrello, A., Stone, D., Ombrello, M. J., Khan, J., Milner, J. D., Kastner, D. L., & Aksentijevich, I.
- Affiliations
- National Human Genome Research Institute (US)
- Kangwon National University (KR)
- National Institute of Allergy and Infectious Diseases (US)
- University College London (GB)
- Science Applications International Corporation (United States) (US)
- National Cancer Institute (US)
- Corresponding author
- Kastner, Daniel L.
- Aksentijevich, Ivona
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 91
- Issue
- 4
- Pages
- 713-720
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3484656
- OpenAlex
- W2055177114
- Cited by
- 374
- References
- 5
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 23 · 2023: 25 · 2022: 20 · 2021: 33 · 2020: 37 · 2019: 38 · 2018: 34 · 2017: 24 · 2016: 25 · 2015: 34 · 2014: 21 · 2013: 19 · 2012: 4
- FWCI
- 10.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK
- National Institutes of Health (Z99 AR999999)
- 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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- PLCγ2, autoinflammatory disease, immunodeficiency, de novo mutations, blistering skin lesions, bronchiolitis, joint pain, ocular inflammation, enterocolitis, cold-induced urticaria, immune dysregulation, exome sequencing, nuclear family
- MeSH terms
- Exons, Female, Humans, Immunologic Deficiency Syndromes, Leukocytes, Genetic Linkage, Male, src Homology Domains, Genetic Predisposition to Disease, Mutation, Missense, Phospholipase C gamma, Hereditary Autoinflammatory Diseases, Exome
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