Alternative titles; symbols
HGNC Approved Gene Symbol: PLCG2
SNOMEDCT: 778004006;
Cytogenetic location: 16q23.3 Genomic coordinates (GRCh38): 16:81,779,291-81,962,685 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q23.3 | Autoinflammation, antibody deficiency, and immune dysregulation syndrome | 614878 | Autosomal dominant | 3 |
| Familial cold autoinflammatory syndrome 3 | 614468 | Autosomal dominant | 3 |
Enzymes of the phospholipase C family catalyze the hydrolysis of phospholipids to yield diacylglycerols and water-soluble phosphorylated derivatives of the lipid head groups. A number of these enzymes have specificity for phosphoinositides. Of the phosphoinositide-specific phospholipase C enzymes, C-beta is regulated by heterotrimeric G protein-coupled receptors, while the closely related C-gamma-1 (PLCG1; 172420) and C-gamma-2 enzymes are controlled by receptor tyrosine kinases. The C-gamma-1 and C-gamma-2 enzymes are composed of phospholipase domains that flank regions of homology to noncatalytic domains of the SRC oncogene product, SH2 and SH3.
Kang et al. (1996) noted that treatment with serum, TPA, retinoic acid, or 5-azacytidine increases the expression level of PLCG2 mRNA in B cells.
Patterson et al. (2002) showed that PLCG isoforms are required for agonist-induced Ca(2+) entry (ACE). Overexpressed wildtype rat Plcg1 or a lipase-inactive mutant Plcg1 each augmented ACE in rat PC12 cells, while a deletion mutant lacking the region containing the SH3 domain of Plcg1 was ineffective. RNA interference to deplete either Plcg1 or Plcg2 in PC12 and rat aortic smooth muscle A7r5 cells inhibited ACE. In chicken DT40 B lymphocytes expressing only Plcg2, overexpressed human muscarinic M5 receptors (M5R; 118496) activated ACE. Using DT40 PLC2 knockout cells, M5R stimulation of endoplasmic reticulum Ca(2+) store release was unaffected, but ACE was abolished. Normal ACE was restored by transient expression of rat Plcg2 or a lipase-inactive Plcg2 mutant. The results indicated a lipase-independent role of PLCG in the physiologic agonist-induced activation of Ca(2+) entry.
Kang et al. (1996) cloned and sequenced 1.5 kb of the PLCG2 promoter region. They reported that the promoter region lacks a TATA box but has Sp1, NF1, AP2, SRE, EBF, and CACCC box consensus sites.
Hernandez et al. (1994) assigned the PLCG2 gene to chromosome 16 by PCR amplification in a somatic cell hybrid mapping panel. Using a chromosome 16-specific somatic cell hybrid panel, they regionalized the gene to 16q24.1. They assigned the mouse Plcg2 gene to distal chromosome 8 by hybridizing a probe of the open reading frame to mouse DNAs from the European interspecific backcross.
Argeson et al. (1995) used an interspecific backcross to localize the Plcg2 gene to the central region of mouse chromosome 8.
Familial Cold Autoinflammatory Syndrome 3
In affected members of 3 unrelated families with familial cold autoinflammatory syndrome-3 (FCAS3; 614468), also known as PLCG2-associated antibody deficiency and immune dysregulation (PLAID), Ombrello et al. (2012) identified 3 different heterozygous intragenic deletions in the PLCG2 gene (600220.0001-600220.0003). The mutations were found by linkage analysis followed by candidate gene sequencing. Five of the 6 deletion breakpoints occurred within repetitive elements. Each of the 3 deletions involved the C-terminal Src-homology-2 (cSH2) domain, which is autoinhibitory and normally prevents constitutive enzymatic function. Transfection of COS-7 cells with PLCG2 constructs lacking the full domain, a deletion of exon 19, or a deletion of exons 20-22 resulted in increased basal and Rac-activated phospholipase activity compared to wildtype. Despite this gain of function, distal signaling and PLCG2-dependent functions were decreased in patient immune cells at physiologic temperatures. The paradoxical loss of downstream function may have resulted from chronic signaling with negative feedback. Patient B cells and natural killer cells both showed defective calcium flux in response to receptor activation on their cell surfaces. However, patient B cells showed increased calcium levels and increased activation with decreasing temperature, whereas control cells did not. Transfection of mutant PLCG2 into mast cells led to spontaneous degranulation at 20 degrees Celsius, which was not seen in controls. The findings indicated that defective receptor signaling in mutant B cells was temperature-dependent and caused abnormal activation and class-switching, resulting in antibody deficiency and impaired central tolerance. The increased activation of mast cells at subphysiologic temperatures was responsible for the cold urticaria.
Autoinflammation, Antibody Deficiency, and Immune Dysregulation
In a father and daughter with autoinflammation, antibody deficiency, and immune dysregulation (APLAID; 614878), Zhou et al. (2012) identified a heterozygous missense mutation in the PLCG2 gene (S707Y; 600220.0004). The mutation was identified by exome sequencing and was demonstrated to result in a gain of function with increased intracellular calcium flux through the IP3 signaling pathway. The disorder was characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, eyes, and gastrointestinal tract. The patients had a mild humoral immune deficiency associated with recurrent sinopulmonary infections, but no evidence of circulating autoantibodies. Zhou et al. (2012) noted that APLAID was a distinct disorder from PLAID, which they had described earlier (Ombrello et al., 2012), although both disorders shared impaired humoral immune function. In APLAID, the S707Y mutation enhances PLCG2 activation at physiologic temperatures, which the authors speculated may result from the creation of an extra phosphorylation site and compromised autoinhibition leading to a slight increase in basal enzymatic activity that is not sufficient for triggering negative feedback.
In an 11-year-old girl with APLAID, Neves et al. (2018) identified a de novo heterozygous missense mutation in the PLCG2 gene (L848P; 600220.0005). The mutation was identified by exome sequencing and confirmed by Sanger sequencing.
Mao et al. (2006) noted that Plcg1 -/- mice die in utero, whereas Plcg2 -/- mice are viable but have internal bleeding, reduced B-cell numbers, and defective platelet, mast cell, and natural killer cell functions. Mao et al. (2006) found that Plcg2 -/- mice had an osteopetrotic phenotype, with increased trabecular bone volume and similar osteoblast, but increased osteoclast, numbers compared with wildtype mice. Isolated Plcg2 -/- bone marrow macrophages were unable to differentiate to osteoclasts, independent of the source of osteoblasts, even in the presence of Mcsf (CSF1; 120420). Mao et al. (2006) found that Plcg2, independent of Plcg1, was required for Rankl (TNFSF11; 602642)-mediated osteoclastogenesis. Specifically, upregulation of Nfatc1 (600489) was dependent on Rankl-mediated phosphorylation of Plcg2 downstream of Dap12 (TYROBP; 604142) and Fc receptor-gamma (FCER1G; 147139).
Yu et al. (2005) identified a dominant mouse mutant, Ali5, with a point mutation (D993G) in the Plcg2 gene. The mice developed spontaneous swollen and inflamed paws, with dermatitis in the skin of the paws and ears. The skin infiltrate included granulocytes, macrophages, lymphocytes, eosinophils, and mast cells. The chronic inflammation led to bone involvement and destruction and arthritis. Some also developed signs of glomerulonephritis and keratitis. The disease had an autoimmune component mediated by autoantibody immune complexes, as well as B and T cell-independent inflammation. The mutation enhanced the ability of the Plcg2 protein to remain at the cytoplasmic membrane, which enhanced or prolonged its activity postactivation. The underlying mechanism was a gain of function leading to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. The study identified Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T hematopoietic cells. Everett et al. (2009) identified a second mouse mutant, Ali14, with a gain-of-function Y495C mutation in the spPH domain of the Plcg2 gene. The mutant protein showed enhanced activation in response to EGF stimulation and constitutive activation, likely by compromising autoinhibition.
In affected members of a family with familial cold autoinflammatory syndrome-3 (FCAS3; 614468), Ombrello et al. (2012) identified a heterozygous 5.9-kb deletion in the PLCG2 gene, resulting in the deletion of exon 19 within the C-terminal Src-homology-2 (cSH2) domain, which is autoinhibitory and normally prevents constitutive enzymatic function. In vitro functional expression studies showed a defect in downstream signaling in immune cells. The deletion was not found in 200 control individuals. The phenotype was characterized by cold-induced urticaria and variable immunologic defects, including antibody deficiency and autoimmune disease.
In affected members of a family with familial cold autoinflammatory syndrome-3 (FCAS3; 614468), Ombrello et al. (2012) identified a heterozygous 8.2-kb deletion in the PLCG2 gene, resulting in the deletion of exons 20 through 22 within the C-terminal Src-homology-2 (cSH2) domain, which is autoinhibitory and normally prevents constitutive enzymatic function. In vitro functional expression studies showed a defect in downstream signaling in immune cells. The deletion was not found in 200 control individuals. The phenotype was characterized by cold-induced urticaria and variable immunologic defects, including antibody deficiency and autoimmune disease.
In affected members of a family with familial cold autoinflammatory syndrome-3 (FCAS3; 614468), Ombrello et al. (2012) identified a heterozygous 4.8-kb deletion in the PLCG2 gene, resulting in a deletion of the C-terminal Src-homology-2 (cSH2) domain, which is autoinhibitory and normally prevents constitutive enzymatic function. In vitro functional expression studies showed a defect in downstream signaling in immune cells. The deletion was not found in 200 control individuals. The phenotype was characterized by cold-induced urticaria and variable immunologic defects, including antibody deficiency and autoimmune disease.
In a father and daughter with autoinflammation, antibody deficiency, and immune dysregulation (APLAID; 614878), Zhou et al. (2012) identified a heterozygous 2120C-A transversion in exon 20 of the PLCG2 gene, resulting in a ser707-to-tyr (S707Y) substitution at a highly conserved residue in the cSH2 domain, which is an autoinhibitory regulatory region. The mutation, which was identified by exome sequencing, was not found in exome databases or in 1,488 control chromosomes. Transfection of the mutant S707T construct in HEK293 and COS-7 cells resulted in increased EGF-stimulated production of intracellular IP3 and increased intracellular calcium release, consistent with it being a hypermorphic mutation. Similar results were obtained upon stimulation of patient peripheral blood mononuclear cells. The disorder was characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, eyes, and gastrointestinal tract. The patients had a mild humoral immune deficiency associated with recurrent sinopulmonary infections, but no evidence of circulating autoantibodies.
In an 11-year-old girl with autoinflammation, antibody deficiency, and immune dysregulation (APLAID; 614878), Neves et al. (2018) identified a de novo heterozygous T-C transition in the PLCG2 gene, resulting in a leu848-to-pro (L848P) mutation in the conserved split pleckstrin homology (spPH) domain. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Molecular modeling suggested that the mutation would affect the PLCG2 structure. Site-directed mutagenesis of L848P in COS-7 cells showed increased basal and EGF-stimulated activity in comparison to wildtype, suggesting a gain of function.
Argeson, A. C., Druck, T., Veronese, M. L., Knopf, J. L., Buchberg, A. M., Huebner, K., Siracusa, L. D. Phospholipase C-gamma-2 (Plcg2) and phospholipase C-gamma-1 (Plcg1) map to distinct regions in the human and mouse genomes. Genomics 25: 29-35, 1995. [PubMed: 7774933] [Full Text: https://doi.org/10.1016/0888-7543(95)80106-v]
Everett, K. L., Bunney, T. D., Yoon, Y., Rodrigues-Lima, F., Harris, R., Driscoll, P. C., Abe, K., Fuchs, H., de Angelis, M. H., Yu, P., Cho, W., Katan, M. Characterization of phospholipase C-gamma enzymes with gain-of-function mutations. J. Biol. Chem. 284: 23083-23093, 2009. [PubMed: 19531496] [Full Text: https://doi.org/10.1074/jbc.M109.019265]
Hernandez, D., Egan, S. E., Yulug, I. G., Fisher, E. M. C. Mapping the gene that encodes phosphatidylinositol-specific phospholipase C-gamma-2 in the human and the mouse. Genomics 23: 504-507, 1994. [PubMed: 7835906] [Full Text: https://doi.org/10.1006/geno.1994.1533]
Kang, J. S., Kohlhuber, F., Hug, H., Marme, D., Eick, D., Ueffing, M. Cloning and functional analysis of the hematopoietic cell-specific phospholipase C-gamma-2 promoter. FEBS Lett. 399: 14-20, 1996. [PubMed: 8980110] [Full Text: https://doi.org/10.1016/s0014-5793(96)01276-8]
Mao, D., Epple, H., Uthgenannt, B., Novack, D. V., Faccio, R. PLC-gamma-2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J. Clin. Invest. 116: 2869-2879, 2006. [PubMed: 17053833] [Full Text: https://doi.org/10.1172/JCI28775]
Neves, J. F., Doffinger, R., Barcena-Morales, G., Martins, C., Papapietro, O., Plagnol, V., Curtis, J., Martins, M., Kumararatne, D., Cordeiro, A. I., Neves, C., Borrego, L. M., Katan, M., Nejentsev, S. Novel PLCG2 mutation in a patient with APLAID and cutis laxa. Front. Immun. 9: 2863, 2018. Note: Electronic Article. [PubMed: 30619256] [Full Text: https://doi.org/10.3389/fimmu.2018.02863]
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., and 27 others. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. New Eng. J. Med. 366: 330-338, 2012. [PubMed: 22236196] [Full Text: https://doi.org/10.1056/NEJMoa1102140]
Patterson, R. L., van Rossum, D. B., Ford, D. L., Hurt, K. J., Bae, S. S., Suh, P.-G., Kurosaki, T., Snyder, S. H., Gill, D. L. Phospholipase C-gamma is required for agonist-induced Ca(2+) entry. Cell 111: 529-541, 2002. [PubMed: 12437926] [Full Text: https://doi.org/10.1016/s0092-8674(02)01045-0]
Yu, P., Constien, R., Dear, N., Katan, M., Hanke, P., Bunney, T. D., Kunder, S., Quintanilla-Martinez, L., Huffstadt, U., Schroder, A., Jones, N. P., Peters, T., and 19 others. Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C-gamma-2 that specifically increases external Ca2+ entry. Immunity 22: 451-465, 2005. [PubMed: 15845450] [Full Text: https://doi.org/10.1016/j.immuni.2005.01.018]
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. A hypermorphic missense mutation in PLCG2, encoding phospholipase C-gamma-2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am. J. Hum. Genet. 91: 713-720, 2012. [PubMed: 23000145] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.006]