Alt. symbols: APLAID | FCAS3 | PLCIV | PLCgamma2

Approved name: phospholipase C gamma 2
Alt. names: phospholipase C, gamma 2 (phosphatidylinositol-specific)

Location: 16q23.3: 81738248 - 81962685 (+)
Gene type: protein_coding, 42 transcripts.

Scores: LoFtool: 0.221000 | pLI: 0.99999305 | LOEUF: 0.281

HGNC: 9066

NCBI: 5336, RefSeq: NG_032019.2

Ensembl: ENSG00000197943.13

LRG_376 | Status: public

OMIM: 600220

Expression | ProteinAtlas

PLCG2 encodes phosphoinositide phospholipase C-gamma-2 (PLCgamma2), a crucial enzyme in B cell receptor (BCR) signaling. Together with BTK, VAV, PI3K and SLP65, PLCgamma2 transmits BCR-mediated signaling from micro-signalosomes. Once activated by BTK-mediated phosphorylation, it catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into secondary messenger molecules: DAG and inositol 1,4,5-trisphosphate (IP3), which activate partially overlapping signaling pathways for B cell activation and proliferation, such as the NF-κB or the MAPK/ERK pathways. IP3 is involved in regulating intracellular Ca2+ levels and thereby activates NFAT (nuclear factor of activated T cells) family members via calmodulin. DAG mediates protein kinase C (PKC) activation, which induces RAS-MAPK signaling.

PLCG2 mutations are associated with 2 AD conditions - Familial cold autoinflammatory syndrome 3 (FCAS3) [OMIM: 614468], otherwise known as PLAID, and APLAID (Autoinflammation, antibody deficiency, and immune dysregulation PLCG2-associated) [OMIM: 614878]. FCAS3/PLAID is characterized by cutaneous urticaria, erythema, and pruritus in response to cold exposure, antibody deficiency, defective B-cell number and function, increased susceptibility to infection, and increased risk of autoimmune disorde rs. These patients harbor large deletions (4.8-8.2Kb) affecting an autoregulatory domain of the protein, leading to gain of enzymatic function but loss of distal signaling and PLCG2-dependent downstream functions. When exposed to evaporative cooling, these patients experience massive enzyme activation, resulting in cold-sensitive urticaria, but at physiological temperatures, PLCγ2 activity is actually reduced, resulting in impaired immune cell function and susceptibility to recurrent infections. In addition to low IgM and IgA levels, these patients also show low NK cell counts, low to absent class-switched B cells with abnormal BCR editing, and poor B cell expansion and switched Ig secretion in response to SAC and CpG dinucleotides in vitro. Patient B and NK cells both show defective Ca2+ flux in response to receptor activation on their cell surfaces. In contrast, APLAID arises from heterozygous missense GOF mutations (i.e. S707Y, L848P) resulting in constitutive enzyme activation (PMID: 23000145, 30619256). Like for PLAID patients, recurrent sinopulmonary infections, reduced IgM and IgA levels and low to nearly absent class-switched memory B cells are seen, but NK cell counts are normal, while NK T cell levels are reduced. However, mucocutaneous lesions are not cold-triggered but may worsen with heat and sun exposure, with patients showing recurrent blistering skin lesions harboring dense inflammatory infiltrates. Moreover, significant and extensive end-organ damage from both inflammation and autoantibody-mediated immune complex formation is seen, including interstitial pneumonitis, arthralgia, eye inflammation, IBD/enterocolitis, cellulitis, sensorineural deafness and cutis laxa (PMID: 32671674). [Load More]