Alternative titles; symbols
HGNC Approved Gene Symbol: PLCG1
Cytogenetic location: 20q12 Genomic coordinates (GRCh38): 20:41,137,543-41,177,626 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q12 | ?Immune dysregulation, autoimmunity, and autoinflammation | 620514 | Autosomal dominant | 3 |
The binding of various agonists to their specific cell surface receptors rapidly induces formation of 2 second-messenger molecules derived from phosphatidylinositol 4,5-bisphosphate, namely, diacylglycerol and inositol 1,4,5-triphosphate (IP3). The production of these second-messenger molecules is mediated by activated phosphatidyl inositol-specific phospholipase C (PLC) enzymes. There are several immunologically distinct enzymes with phosphatidylinositol-specific PLC activities. Stahl et al. (1988) purified, cloned, and expressed 1 of these PLC subtypes, which they referred to as PLC-148. They found that PLC-148 mRNA is expressed in most cell types and is present as a single-copy gene. Structural homology with SRC (190090) was noted.
By beta-galactosidase staining, Liao et al. (2002) showed that Plcg1 was widely expressed in mouse yolk sac. Abundant expression was also present in the embryo body, particularly in the first brachial arch, midline dorsal aorta, limbs, and allantois. Enzyme expression in the vasculature was readily apparent.
Chuang et al. (2001) demonstrated that bradykinin- or NGF-mediated potentiation of thermal sensitivity in vivo requires expression of VR1 (602076), a heat-activated ion channel on sensory neurons. Diminution of plasma membrane phosphatidylinositol-4,5,bisphosphate levels through antibody sequestration or PLC-mediated hydrolysis mimics the potentiating effects of bradykinin or NGF at the cellular level. Moreover, recruitment of PLC-gamma to TRK-alpha (191315) is essential for NGF-mediated potentiation of channel activity, and biochemical studies suggested that VR1 associates with this complex. Chuang et al. (2001) concluded that their studies delineate a biochemical mechanism through which bradykinin and NGF produce hypersensitivity and might explain how the activation of PLC signaling systems regulates other members of the TRP channel family.
Ye et al. (2002) demonstrated that PLCG1 acts as a guanine nucleotide exchange factor for PIKE (605476). PIKE is a nuclear GTPase that activates nuclear phosphatidylinositol-3-hydroxykinase (PI(3)K) activity, and mediates the physiologic activation by nerve growth factor (NGF; 162030) of nuclear PI(3)K activity. This enzymatic activity accounts for the mitogenic properties of PLCG1.
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 (600220) 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.
Bivona et al. (2003) demonstrated that in response to Src-dependent activation of PLCG1, the Ras guanine nucleotide exchange factor RasGRP1 (603962) translocates to the Golgi, where it activates Ras. Whereas calcium positively regulated Ras on the Golgi apparatus through RasGRP1, the same second messenger negatively regulated Ras on the plasma membrane by means of the Ras GTPase-activating protein CAPRI (607943). Ras activation after T-cell receptor stimulation in Jurkat cells, rich in RasGRP1, was limited to the Golgi apparatus through the action of CAPRI, demonstrating unambiguously a physiologic role for Ras on Golgi. Activation of Ras on Golgi also induced differentiation of PC12 cells, transformed fibroblasts, and mediated radioresistance. Thus, Bivona et al. (2003) concluded that activation of Ras on Golgi has important biologic consequences and proceeds through a pathway distinct from the one that activates Ras on the plasma membrane.
Van Rossum et al. (2005) developed a gestalt algorithm to detect hitherto 'invisible' pleckstrin homology (PH) and PH-like domains, and reported that the partial PH domain of PLCG1 interacts with a complementary partial PH-like domain of TRPC3 (602345) to elicit lipid binding and cell surface expression of TRPC3. Van Rossum et al. (2005) concluded that their findings imply a far greater abundance of PH domains than previously appreciated, and suggested that intermolecular PH-like domains represent a widespread signaling mode.
By Western blot analysis, Wen et al. (2004) showed that Plcg1 was expressed at all stages of mouse B-cell development, with higher expression in early B-cell progenitors, and that Plcg1 was activated by B-cell receptor (BCR) in primary immature/mature B cells and was involved in pre-BCR signaling. In the absence of Plcg2, expression of Plcg1 was reduced by approximately 50% and resulted in severely impaired early B-cell development at the pro-B-cell stage immediately prior to the pre-BCR checkpoint in Plcg1 +/- Plcg2 -/- mice, which was not observed in Plcg2 -/- mice. Moreover, in the absence of Plcg2, reduction of Plcg1 further impaired late B-cell maturation. In contrast, early B-cell development was largely normal, whereas late B-cell maturation was impaired in Plcg2 -/- mice, and overexpression of Plcg1 in Plcg2 -/- mice failed to restore BCR-mediated B-cell proliferation and maturation. Wen et al. (2004) concluded that both Plcg1 and Plcg2 are involved in B-cell development, with distinct roles in B-cell development.
Bristol et al. (1988) found by in situ hybridization that the PLCG1 gene is located on 20q12-q13.1. Southern blot analysis of DNA from human-mouse hybrid cells supported the assignment to chromosome 20. The location of both SRC and PLC148 on chromosome 20 is of interest. The region is often involved in interstitial deletions and breakpoints in myeloid malignancy. Using the highly polymorphic (dC-dA)n/(dG-dT)n dinucleotide repeat at the PLC1 locus, Rothschild et al. (1992) demonstrated close linkage to several chromosome 20 markers including adenosine deaminase (ADA; 608958); maximum lod = 57.24 at theta = 0.05. In addition, the PLC1 gene showed linkage to the MODY locus (125850); lod score = 4.57 at theta = 0.089.
Nelson et al. (1992) mapped the Plcg1 gene to mouse chromosome 2.
In a 10-year-old girl with immune dysregulation, autoimmunity, and autoinflammation (IDAA; 620514), Tao et al. (2023) identified a de novo heterozygous missense mutation in the PLCG1 gene (S1021F; 172420.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Detailed in vitro functional studies of cells (COS7 and Jurkat) transfected with the mutation and patient-derived T cells showed that the S1021F variant results in a gain of function with increased production of intracellular IP3 and elevated calcium flux, consistent with activation of downstream signaling pathways. These findings were associated with increased activation of the NFKB (see 164011), MAPK (see 602448), and ERK (see 601795) pathways and release of proinflammatory cytokines. Despite the widespread immune dysregulation identified through laboratory studies, the patient had only chronic anemia, chronic thrombocytopenia, and presence of multiple circulating autoantibodies.
Liao et al. (2002) found that Plcg1 -/- embryos displayed impaired development of critical elements of the embryonic blood formation and underwent embryonic lethality. Further analysis of the mutant embryos revealed absence of erythrogenesis and diminished vasculogenesis compared to wildtype.
In a 10-year-old girl with immune dysregulation, autoimmunity, and autoinflammation (IDAA; 620514), Tao et al. (2023) identified a de novo heterozygous c.3062C-T transition in the PLCG1 gene, resulting in a ser1021-to-phe (S1021F) substitution at a highly conserved residue in the catalytic Y-box domain. Molecular modeling indicated that the affected residue lies between the catalytic and regulatory domains, which may interrupt the autoinhibition of PLCG1 and result in constitutive activation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation did not affect PLCG1 protein expression. Detailed in vitro functional studies of cells (COS7 and Jurkat) transfected with the mutation and patient-derived T cells showed that the S1021F variant results in a gain of function with increased production of intracellular IP3 and elevated calcium flux, consistent with activation of downstream signaling pathways. These findings were associated with increased activation of the NFKB (see 164011), MAPK (see 602448), and ERK (see 601795) pathways and release of proinflammatory cytokines. RNA sequencing of patient blood cells showed enriched transcription of multiple genes in the innate immunity pathway, including type I and II interferon signatures, TNF (191160) signaling, NFKB-related genes, and proinflammatory mediators. Treatment of patient cells and transfected cells with a PLCG inhibitor rescued the enhanced signaling, calcium release, and transcription of inflammatory mediators in vitro. Treatment of mutant cells in vitro with a JAK (see 147795) inhibitor also normalized the inflammatory signature. Despite the widespread immune dysregulation identified through laboratory studies, the patient had only chronic anemia, chronic thrombocytopenia, and presence of multiple circulating autoantibodies.
Bivona, T. G., Perez de Castro, I., Ahearn, I. M., Grana, T. M., Chiu, V. K., Lockyer, P. J., Cullen, P. J., Pellicer, A., Cox, A. D., Philips, M. R. Phospholipase C-gamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424: 694-698, 2003. [PubMed: 12845332] [Full Text: https://doi.org/10.1038/nature01806]
Bristol, A., Hall, S. M., Kriz, R. W., Stahl, M. L., Fan, Y. S., Byers, M. G., Eddy, R. L., Shows, T. B., Knopf, J. L. Phospholipase C-148: chromosomal location and deletion mapping of functional domains. Cold Spring Harbor Symp. Quant. Biol. 53: 915-920, 1988. [PubMed: 3254788] [Full Text: https://doi.org/10.1101/sqb.1988.053.01.105]
Chuang, H., Prescott, E. D., Kong, H., Shields, S., Jordt, S.-E., Basbaum, A. I., Chao, M. V., Julius, D. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411: 957-962, 2001. [PubMed: 11418861] [Full Text: https://doi.org/10.1038/35082088]
Liao, H.-J., Kume, T., McKay, C., Xu, M.-J., Ihle, J. N., Carpenter, G. Absence of erythrogenesis and vasculogenesis in Plcg1-deficient mice. J. Biol. Chem. 277: 9335-9341, 2002. [PubMed: 11744703] [Full Text: https://doi.org/10.1074/jbc.M109955200]
Nelson, K. K., Knopf, J. L., Siracusa, L. D. Localization of phospholipase C-gamma 1 to mouse chromosome 2. Mammalian Genome 3: 597-600, 1992. [PubMed: 1358284] [Full Text: https://doi.org/10.1007/BF00350627]
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]
Rothschild, C. B., Akots, G., Fajans, S. S., Bowden, D. W. A microsatellite polymorphism associated with the PLC1 (phospholipase C) locus: identification, mapping, and linkage to the MODY locus on chromosome 20. Genomics 13: 560-564, 1992. [PubMed: 1639386] [Full Text: https://doi.org/10.1016/0888-7543(92)90125-c]
Stahl, M. L., Ferenz, C. R., Kelleher, K. L., Kriz, R. W., Knopf, J. L. Sequence similarity of phospholipase C with the non-catalytic region of src. Nature 332: 269-272, 1988. [PubMed: 2831461] [Full Text: https://doi.org/10.1038/332269a0]
Tao, P., Han, X., Wang, Q., Wang, S., Zhang, J., Liu, L., Fan, X., Liu, C., Liu, M., Guo, L., Lee, P. Y., Aksentijevich, I., Zhou, Q. A gain-of-function variation in PLCG1 causes a new immune dysregulation disease. J. Allergy Clin. Immun. 152: 1292-1302, 2023. [PubMed: 37422272] [Full Text: https://doi.org/10.1016/j.jaci.2023.06.020]
van Rossum, D. B., Patterson, R. L., Sharma, S., Barrow, R. K., Kornberg, M., Gill, D. L., Snyder, S. H. Phospholipase C-gamma-1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature 434: 99-104, 2005. [PubMed: 15744307] [Full Text: https://doi.org/10.1038/nature03340]
Wen, R., Chen, Y., Schuman, J., Fu, G., Yang, S., Zhang, W., Newman, D. K., Wang, D. An important role of phospholipase Cgamma1 in pre-B-cell development and allelic exclusion. EMBO J. 23: 4007-4017, 2004. [PubMed: 15372077] [Full Text: https://doi.org/10.1038/sj.emboj.7600405]
Ye, K., Aghdasi, B., Luo, H. R., Moriarity, J. L., Wu, F. Y., Hong, J. J., Hurt, K. J., Bae, S. S., Suh, P.-G., Snyder, S. H. Phospholipase C-gamma-1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE. Nature 415: 541-544, 2002. [PubMed: 11823862] [Full Text: https://doi.org/10.1038/415541a]