Alt. symbols: GRB1 | p85-ALPHA | p85

Approved name: phosphoinositide-3-kinase regulatory subunit 1
Alt. names: phosphoinositide-3-kinase, regulatory subunit 1 (alpha) | phosphoinositide-3-kinase regulatory subunit alpha

Location: 5q13.1: 68215740 - 68301821 (+)
Gene type: protein_coding, 33 transcripts.

Scores: LoFtool: 0.295000 | pLI: 0.99824049 | LOEUF: 0.228

HGNC: 8979

NCBI: 5295, RefSeq: NG_012849.2

Ensembl: ENSG00000145675.16

LRG_453 | Status: public

OMIM: 171833

Expression | ProteinAtlas

PIK3R1 encodes the PI3K class IA regulatory subunits (p85?, p55?, p50?), though p85? is the most abundant. Though it can also bind p110? and p110?, p85? forms the PI3K? enzyme in combination with a p110? catalytic subunit to engage and transduce signaling from immune cell surface receptors such as BCRs, TCRs, cytokine and costimulatory receptors (PMID: 27616589). As a regulatory subunit, p85? can prevent proteolytic degradation of p110, inhibit p110 catalytic activity and recruit p110 subunit to phosphotyrosines on plasma membrane proteins.

Monoallelic PIK3R1 mutations are associated with two autosomal dominant conditions - Activated p110-d syndrome 2 (APDS2) [MIM:616005], and SHORT syndrome [MIM:269880], a multi-system progeroid syndrome associated with Akt/mTor pathway downregulation. Moreover, a rare homozygous nonsense mutation leading to absent p85? has been described in one patient with a specific and severe block in early B-cell differentiation, designated autosomal recessive Agammaglobulinemia 7 [OMIM:615214] (PMID: 2235193 3). APDS2 is generally caused by monoallelic splice acceptor and donor site mutations in exon 11 (coding exon 10) that result in in-frame exon-skipping and the generation of a shortened p85? with retained ability to stabilize p110? but lost inhibitory activity, thus resulting in inappropriate gain of Akt/mTOR signaling (PMID: 25488983, 27076228, 27221134). This explains why so many of the features of APDS2 phenocopy APDS1 - recurrent early-onset sino-pulmonary infections, diverse autoimmune and autoinflammatory manifestations, persistent EBV and/or CMV viremia, and chronic benign lymphoproliferative disease as well as increased risk for B-cell malignancies. Patients also show impaired B-cell maturation with aberrant responses to stimuli and subsequent self-destruction resulting in progressive B-cell lymphopenia and increased frequency of transitional B cells, as well as accelerated T cell maturation and senescence resulting in decreased naive CD4+ and CD8+ T-cell numbers and increased number and frequency of CD8+ effector/memory T cells. However, some non-immunologic manifestations such as growth retardation, joint hyperextensibility, insulin resistance, and neurodevelopmental delay may be reminiscent of SHORT syndrome (PMID: 26497935). However, both clinical and immune phenotypes can be extremely variable, making it possible for APDS to also be diagnosed as CVID, combined immunodeficiency or hyper-IgM syndrome (PMID: 25939554, 27076228, 27221134). [Load More]