|Coordinate||117,577,874 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||phospholipase C, gamma 2|
|Chromosomal Location||117,498,291-117,635,142 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3. [provided by RefSeq, Mar 2014]
PHENOTYPE: Homozygotes for some null alleles show decreased B cell and impaired NK cell function. Other homozygous null alleles show aberrant separation of blood and lymphatic vessels. [provided by MGI curators]
|Limits of the Critical Region||117498291 - 117635140 bp|
|Amino Acid Change||Isoleucine changed to Phenylalanine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000079991]|
AA Change: I273F
|Predicted Effect||possibly damaging
PolyPhen 2 Score 0.800 (Sensitivity: 0.84; Specificity: 0.93)
|Meta Mutation Damage Score||0.2605|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: potential candidate; human score: -0.5; ML prob: 0.366|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Dominant|
|Last Updated||2019-09-04 9:40 PM by Diantha La Vine|
|Record Created||2017-06-04 10:51 AM by Xue Zhong|
The Poseidon2 phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R5226, some of which showed exhibited reduced frequencies of B1 cells in the peripheral blood (Figure 1) as well as diminished T-independent antibody response to 4-hydroxy-3-nitrophenylacetyl-Ficoll (NP-Ficoll) (Figure 2).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 62 mutations. Both of the above anomalies were linked by continuous variable mapping to a mutation in Plcg2: an A to T transversion at base pair 117,577,874 (v38) on chromosome 8, or base pair 79,600 in the GenBank genomic region NC_000074 encoding Plcg2. The strongest association was found with an additive model of inheritance to the normalized NP-Ficoll-associated phenotype, wherein nine variant homozygotes and 35 heterozygous mice departed phenotypically from 21 homozygous reference mice with a P value of 5.01 x 10-7 (Figure 3). A semidominant effect was observed in both of the assays.
The mutation corresponds to residue 1,018 in the mRNA sequence NM_172285 within exon 10 of 33 total exons.
The mutated nucleotide is indicated in red. The mutation results in an isoleucine to phenylalanine substitution at position 273 (I273F) in the phospholipase C gamma 2 (PLC-γ2) protein, and is strongly predicted by Polyphen-2 to be damaging (score = 0.800).
The Plcg2 gene encodes the 1265 amino acid PLC-γ2 that is a member of the PLC family (Figure 4). PLC enzymes act as effector molecules in the signal transduction process by hydrolyzing phosphatidylinositol 4,5 bisphosphate (PIP2) to generate two second messengers, diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). PLC isozymes contain a conserved domain structure consisting of the catalytic X and Y domains located between EF-hand motifs and a calcium-binding C2 domain. Most PLC proteins also contain a pleckstrin homology (PH) domain at their N-terminus. Additional domains are present in some PLC isozymes including the γ subtypes (PLC-γ1 and -γ2), which contain an additional PH domain split by two tandem Src homology 2 (SH2) domains and an SH3 domain (1). The Poseidon2 mutation alters I273 within the EF domain. The effect of the mutation on protein expression and localization has not been determined.
Please see the record for queen for more information about Plcg2.
The hydrolysis of PIP2 by PLC enzymes to produce DAG and IP3 is a critical step in the signal transduction process of many pathways. DAG is responsible for activating protein kinase C and possibly the TRP calcium influx channels, while IP3 modulates calcium responses within the cell by binding to receptors on the intracellular membrane to allow the mobilization of intracellular calcium (2). Plcg2 -/- mice display internal bleeding, osteopetrosis, impaired lymph node organogenesis and defects in the functioning of B cells, platelets, neutrophils, mast cells, dendritic cells (DCs), macrophages and natural killer (NK) cells (3-5). A nonsense mutation in Plcg2, resulting in a truncation in the N-terminal PH domain, causes aberrant separation of blood and lymphatic vessels (6). In addition, two ENU-generated Plcg2 point mutations located in the catalytic and split PH domains have been linked to inflammatory and autoimmune responses through PLC-γ2 hyperactivation in cells of both the innate and acquired immune system (7;8). Plcg2 -/- mice display decreased mature B cells, a block in pro-B cell differentiation, B-1 B cell deficiency, and an absence of T cell-independent (T-I) antibody production; the T cell-dependent responses are relatively normal (3;4). These phenotypes can be attributed to a defect in BCR and pre-BCR signaling with a concomitant deficiency in B-1 cells; the persistence of some peripheral B-2 cells allows the development of a T-D response. Calcium mobilization via PLC activation can be activated by Toll-like receptor (TLR) signaling (9;10). TLR signaling pathway culminates in MAPK and NF-κB activation resulting in the production of proinflammatory cytokines (11). Macrophages and DCs from PLC-γ2 deficient animals display abnormal calcium mobilization and reduced production of proinflammatory cytokines in response to peptidoglycan (PGN), a Gram-positive bacterial cell wall component recognized by TLR2 (see the record for languid), and lipopoysaccharide (LPS), a Gram-negative bacterial component recognized by TLR4 (see the record for lps3) (5). The phenotypes observed in Poseidon2 mice are consistent with those found in Plcg2 -/- mice as well as in mice with deficiencies in other BCR signaling molecules.
1) 94°C 2:00
The following sequence of 401 nucleotides is amplified (chromosome 8, + strand):
1 tatgtggctc tgaatgacat aggtttgaca ttgggtccag tctttgatca ccttgactag
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Suh, P. G., Park, J. I., Manzoli, L., Cocco, L., Peak, J. C., Katan, M., Fukami, K., Kataoka, T., Yun, S., and Ryu, S. H. (2008) Multiple Roles of Phosphoinositide-Specific Phospholipase C Isozymes. BMB Rep. 41, 415-434.
2. Wilde, J. I., and Watson, S. P. (2001) Regulation of Phospholipase C Gamma Isoforms in Haematopoietic Cells: Why One, Not the Other? Cell Signal. 13, 691-701.
3. Wang, D., Feng, J., Wen, R., Marine, J. C., Sangster, M. Y., Parganas, E., Hoffmeyer, A., Jackson, C. W., Cleveland, J. L., Murray, P. J., and Ihle, J. N. (2000) Phospholipase Cgamma2 is Essential in the Functions of B Cell and several Fc Receptors. Immunity. 13, 25-35.
4. Hashimoto, A., Takeda, K., Inaba, M., Sekimata, M., Kaisho, T., Ikehara, S., Homma, Y., Akira, S., and Kurosaki, T. (2000) Cutting Edge: Essential Role of Phospholipase C-Gamma 2 in B Cell Development and Function. J Immunol. 165, 1738-1742.
5. Aki, D., Minoda, Y., Yoshida, H., Watanabe, S., Yoshida, R., Takaesu, G., Chinen, T., Inaba, T., Hikida, M., Kurosaki, T., Saeki, K., and Yoshimura, A. (2008) Peptidoglycan and Lipopolysaccharide Activate PLCgamma2, Leading to Enhanced Cytokine Production in Macrophages and Dendritic Cells. Genes Cells. 13, 199-208.
6. Ichise, H., Ichise, T., Ohtani, O., and Yoshida, N. (2009) Phospholipase Cgamma2 is Necessary for Separation of Blood and Lymphatic Vasculature in Mice. Development. 136, 191-195.
7. 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., and Katan, M. (2009) Characterization of Phospholipase C Gamma Enzymes with Gain-of-Function Mutations. J Biol Chem. 284, 23083-23093.
8. 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., Fuchs, H., de Angelis, M. H., Nehls, M., Grosse, J., Wabnitz, P., Meyer, T. P., Yasuda, K., Schiemann, M., Schneider-Fresenius, C., Jagla, W., Russ, A., Popp, A., Josephs, M., Marquardt, A., Laufs, J., Schmittwolf, C., Wagner, H., Pfeffer, K., and Mudde, G. C. (2005) 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.
9. Chun, J., and Prince, A. (2006) Activation of Ca2+-Dependent Signaling by TLR2. J Immunol. 177, 1330-1337.
10. Zhou, X., Yang, W., and Li, J. (2006) Ca2+- and Protein Kinase C-Dependent Signaling Pathway for Nuclear Factor-kappaB Activation, Inducible Nitric-Oxide Synthase Expression, and Tumor Necrosis Factor-Alpha Production in Lipopolysaccharide-Stimulated Rat Peritoneal Macrophages. J Biol Chem. 281, 31337-31347.
|Science Writers||Anne Murray|
|Authors||Xue Zhong, Aijie Liu, Jin Huk Choi, and Bruce Beutler|