Alt. symbols: PI3CG | PI3K | PI3Kgamma | PIK3 | p110gamma | p120PI3K

Approved name: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma
Alt. names: phosphoinositide-3-kinase, catalytic, gamma polypeptide, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma

Location: 7q22.3: 106865278 - 106908980 (+)
Gene type: protein_coding, 5 transcripts.

Scores: LoFtool: 0.490000 | pLI: 0.56396387 | LOEUF: 0.595

HGNC: 8978

NCBI: 5294, RefSeq: NG_050579.1

Ensembl: ENSG00000105851.11

LRG_ | Status: none

OMIM: 601232

Expression | ProteinAtlas

PIK3CG encodes the class I catalytic subunit of PI3K. Like other class I catalytic subunits (p110-alpha p110-beta, and p110-delta), the encoded protein binds a p85 regulatory subunit to form PI3K. Class I PI3Ks phosphorylate PtdIns(4,5)P2 to produce PtdIns(3,4,5)P3. PIP3 recruits PH domain-containing proteins to the membrane, including AKT1 and PDPK1, and therefore acts as a second messenger that potently activates diverse signaling cascades secondary to growth factors, cytokines, chemokines, and antigen receptor stimulation, among other inputs. Together with PIK3CD is involved in natural killer (NK) cell development, in T-lymphocyte development, in neutrophil respiratory burst. It is also required for B-lymphocyte development and signaling.

Bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110gamma catalytic subunit of PI3Kgamma, have been recently reported in a female patient with a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis. The patient showed also reduced peripheral blood memory B, memory CD8 T, and regulatory T cells and increased CXCR3+ homing CD4 T cells. The author also described that PI3Kgamma-deficient macrophages and monocytes produced ele vated inflammatory IL-12 and IL-23 in a GSK3alfa/beta-dependent manner upon TLR stimulation. The childhood of patient A.1 was remarkable for recurrent sinopulmonary, ear, skin, and urinary tract infections (commonly with S. aureus), chronic nasal congestion, and eczema. Additional episodes of colitis were sometimes associated with stool cultures positive for C. difficile and Salmonella. Vaccination responses were protective for tetanus, borderline protective for diphtheria, and protective for 4 of 23 pneumococcal strains. Warm autoimmune hemolytic anemia at nine years of age (preceding the initial pneumonitis by several months) was treated with steroids and blood transfusions; a recurrence of autoimmune cytopenias at seventeen years prompted CD20+ B cell depletion with rituximab. The patient inherited the p.R982fs mutation from her healthy mother and the p.R1021P (kinase domain) from her healthy father. The authors assessed PIK3CG expression in T cell blasts and found reduced p110gamma protein in both parents and virtually absent expression in the patient. The R982fs mutation is predicted to cause nonsense-mediated decay due to a premature stop codon in the penultimate exon. The R1021P substitution in the kinase domain destabilizes hydrogen bonds predicted to be necessary for protein stability and nearly completely abolishes in vitro recombinant kinase activity of p110gamma alone or bound to either p84 or p101 subunit. In addition, a p.V282A monoallelic mutation in PIK3CG has been described in a 44-year-old man who presented with a history of chronic purulent sinusitis, a chronic fungal rash of the scrotum, and chronic pelvic pain; tough the functional consequence of this variant was not addressed in that study. [Load More]