|Coordinate||101,701,732 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||phosphoinositide-3-kinase regulatory subunit 1|
|Synonym(s)||p55alpha, p85alpha, PI3K, p50alpha|
|Chromosomal Location||101,680,563-101,768,217 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]
PHENOTYPE: Homozygotes for a targeted null mutation exhibit perinatal lethality associated with hepatic necrosis, chylous ascites, enlarged muscle fibers, calcification of cardiac tissue, and hypoglycemia. Mutants lacking only the major isoform are immunodeficient. [provided by MGI curators]
|Amino Acid Change||Leucine changed to Histidine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000056774]|
AA Change: L272H
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Meta Mutation Damage Score||0.6277|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: not good candidate; Verification probability: 0.136; ML prob: 0.186; human score: -1|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2020-07-29 6:45 PM by External Program|
|Record Created||2019-01-22 2:21 PM by Bruce Beutler|
The astro_boy phenotype was identified among G3 mice of the pedigree R4175, some of which showed increased frequencies of B1b cells in B1 cells in the peripheral blood (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 43 mutations. The B1b phenotype was linked by continuous variable mapping to two mutations in Pik3r1 (10170132A>T [p.L272H] and 101701733G>A [p.L272F]). The mutation at base pair 101,701,732 was presumed causative as it is predicted to cause damage to the protein (PolyPhen score = 1.000), while the 101701733G>A mutation is predicted to benign (PolyPhen score = 0.248). The causative mutation in Pik3r1 is a T to A transversion at base pair 101,701,732 (v38) on chromosome 13, or base pair 66,486 in the GenBank genomic region NC_000079 encoding Pik3r1. Linkage was found with an additive model of inheritance, wherein three homozygous variants and 19 heterozygous mice departed phenotypically from 13 homozygous reference mice with a P value of 0.000305 (Figure 2).
The mutation corresponds to residue 1,436 in the mRNA sequence NM_001077495 within exon 6 of 16 total exons.
The mutated nucleotide is indicated in red. The mutation results in a leucine to histidine substitution at residue 272 (L272H) in the p85α protein (PolyPhen-2 score = 1.000); the mutation is not predicted to affect the p55α and p50α isoforms.
|Illustration of Mutations in
Gene & Protein
Pik3r1 encodes p85α, a regulatory subunit of class IA phosphatidylinositol 3-kinases (PI3Ks). To form a functional class I PI3K, a p110 catalytic subunit forms a heterodimer with a p85 regulatory subunit (1;2). In activated cells, the p85 subunit recruits the p110 subunit to the plasma membrane and activates it (3-5). Conversely, the p85 subunit also inhibits the enzymatic activity of the p110 subunit in quiescent cells (6). The p85 subunits also mediate the interactions of the PI3Ks with the cytoplasmic domains of receptors as well as with adaptor proteins (7).
p85α, p55α, and p50α are splice variants of Pik3r1 (3;8;9). The p55α and p50α isoforms have two SH2 (Src homology 2) domains [nSH2 (N-terminal SH2 domain) and cSH2 (C-terminal SH2 domain)] and a p110-binding domain [iSH2 (inter SH2 domain)] (Figure 3). The p85α isoform has the nSH2, cSH2, and iSH2 domains, but also has a SH3 domain at the N-terminus (amino acids 6-78) and a RhoGAP domain (amino acids 126-298). Between the SH3 and RhoGAP domain and between the RhoGAP and nSH2 domain are proline-rich regions.
The astro_boy mutation results in a leucine to histidine substitution at residue 272 (L272H) in the p85α protein. Amino acid 272 in p85α is within the RhoGAP domain.
For more information about Pik3r1, please see the record for anubis.
PI3Ks are highly conserved lipid signaling kinases. After cell stimulation by growth factors, hormones, cytokines, or antigens, the PI3Ks are recruited to the inner face of the plasma membrane where they phosphorylate phosphatidylinositol (PtdIns), PtdIns 4-phosphate, and/or PtdIns-4,5-bisphosphate (PtdIns(4,5)P2; PIP2) at the D3 position of the inositol ring, generating their respective D3’ phosphorylated derivatives [e.g., PIP2 phosphorylation generates the second messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3; PIP3); (2;10); reviewed in (7;11)]. For more information on the PI3K signaling pathway, please see the record for sothe and stinger.
PIK3R1 mutations are linked to immunodeficiency-36 (IMD36; OMIM: #616005; (12)), agammalobulinemia-7 (AGM7; OMIM: #615214; (13)), and SHORT (Short stature, Hyperextensible joints, Ocular depression, Rieger anomaly, and Teeth delay) syndrome (OMIM: #269880; (14;15)). Patients with IMD36 had decreased numbers of naïve CD4+ and CD8+ T cells; one patient had decreased numbers of memory B cells (12). A patient with AGM7 exhibited defects in early B cell development (13).
Pik3r1-/- chimeric mice (using a Rag2-deficient blastocyst complementation system) had reduced numbers of peripheral blood mature B cells and reduced serum levels of IgM, IgG1, IgG2a, IgG3, and IgA (16). The remaining B cells exhibited reduced proliferative responses after exposure to anti-IgM, anti-CD40, and lipopolysaccharide; T cell development and proliferative responses were normal. The anubis mice exhibited defects in T cell development similar to patients with IMD36 (12), but in contrast to the Pik3r1-/- chimeric mice (16).
The immune phenotypes in the astro_boy mice indicates that loss of p85α-associated function.
1) 94°C 2:00
The following sequence of 401 nucleotides is amplified (chromosome 13, - strand):
1 ttttgaacct gcagaactac agagccctga agactgcatc cagctgttga agaagctcat
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Chantry, D., Vojtek, A., Kashishian, A., Holtzman, D. A., Wood, C., Gray, P. W., Cooper, J. A., and Hoekstra, M. F. (1997) P110delta, a Novel Phosphatidylinositol 3-Kinase Catalytic Subunit that Associates with P85 and is Expressed Predominantly in Leukocytes. J Biol Chem. 272, 19236-19241.
2. Senis, Y. A., Atkinson, B. T., Pearce, A. C., Wonerow, P., Auger, J. M., Okkenhaug, K., Pearce, W., Vigorito, E., Vanhaesebroeck, B., Turner, M., and Watson, S. P. (2005) Role of the p110delta PI 3-Kinase in Integrin and ITAM Receptor Signalling in Platelets. Platelets. 16, 191-202.
3. Jimenez, C., Hernandez, C., Pimentel, B., and Carrera, A. C. (2002) The p85 Regulatory Subunit Controls Sequential Activation of Phosphoinositide 3-Kinase by Tyr Kinases and Ras. J Biol Chem. 277, 41556-41562.
4. Glassford, J., Vigorito, E., Soeiro, I., Madureira, P. A., Zoumpoulidou, G., Brosens, J. J., Turner, M., and Lam, E. W. (2005) Phosphatidylinositol 3-Kinase is Required for the Transcriptional Activation of Cyclin D2 in BCR Activated Primary Mouse B Lymphocytes. Eur J Immunol. 35, 2748-2761.
5. Yu, J., Zhang, Y., McIlroy, J., Rordorf-Nikolic, T., Orr, G. A., and Backer, J. M. (1998) Regulation of the p85/p110 Phosphatidylinositol 3'-Kinase: Stabilization and Inhibition of the p110alpha Catalytic Subunit by the p85 Regulatory Subunit. Mol Cell Biol. 18, 1379-1387.
6. Fransson, S., Uv, A., Eriksson, H., Andersson, M. K., Wettergren, Y., Bergo, M., and Ejeskar, K. (2012) P37delta is a New Isoform of PI3K p110delta that Increases Cell Proliferation and is Overexpressed in Tumors. Oncogene. 31, 3277-3286.
7. Vanhaesebroeck, B., Leevers, S. J., Ahmadi, K., Timms, J., Katso, R., Driscoll, P. C., Woscholski, R., Parker, P. J., and Waterfield, M. D. (2001) Synthesis and Function of 3-Phosphorylated Inositol Lipids. Annu Rev Biochem. 70, 535-602.
8. Ueki, K., Algenstaedt, P., Mauvais-Jarvis, F., and Kahn, C. R. (2000) Positive and Negative Regulation of Phosphoinositide 3-Kinase-Dependent Signaling Pathways by Three Different Gene Products of the p85alpha Regulatory Subunit. Mol Cell Biol. 20, 8035-8046.
9. Inukai, K., Anai, M., Van Breda, E., Hosaka, T., Katagiri, H., Funaki, M., Fukushima, Y., Ogihara, T., Yazaki, Y., Kikuchi, Oka, Y., and Asano, T. (1996) A Novel 55-kDa Regulatory Subunit for Phosphatidylinositol 3-Kinase Structurally Similar to p55PIK is Generated by Alternative Splicing of the p85alpha Gene. J Biol Chem. 271, 5317-5320.
10. Vanhaesebroeck, B., Welham, M. J., Kotani, K., Stein, R., Warne, P. H., Zvelebil, M. J., Higashi, K., Volinia, S., Downward, J., and Waterfield, M. D. (1997) P110delta, a Novel Phosphoinositide 3-Kinase in Leukocytes. Proc Natl Acad Sci U S A. 94, 4330-4335.
11. Rommel, C., Camps, M., and Ji, H. (2007) PI3K Delta and PI3K Gamma: Partners in Crime in Inflammation in Rheumatoid Arthritis and Beyond? Nat Rev Immunol. 7, 191-201.
12. Deau, M. C., Heurtier, L., Frange, P., Suarez, F., Bole-Feysot, C., Nitschke, P., Cavazzana, M., Picard, C., Durandy, A., Fischer, A., and Kracker, S. (2015) A Human Immunodeficiency Caused by Mutations in the PIK3R1 Gene. J Clin Invest. 125, 1764-1765.
13. Conley, M. E., Dobbs, A. K., Quintana, A. M., Bosompem, A., Wang, Y. D., Coustan-Smith, E., Smith, A. M., Perez, E. E., and Murray, P. J. (2012) Agammaglobulinemia and Absent B Lineage Cells in a Patient Lacking the p85alpha Subunit of PI3K. J Exp Med. 209, 463-470.
14. Chudasama, K. K., Winnay, J., Johansson, S., Claudi, T., Konig, R., Haldorsen, I., Johansson, B., Woo, J. R., Aarskog, D., Sagen, J. V., Kahn, C. R., Molven, A., and Njolstad, P. R. (2013) SHORT Syndrome with Partial Lipodystrophy due to Impaired Phosphatidylinositol 3 Kinase Signaling. Am J Hum Genet. 93, 150-157.
15. Dyment, D. A., Smith, A. C., Alcantara, D., Schwartzentruber, J. A., Basel-Vanagaite, L., Curry, C. J., Temple, I. K., Reardon, W., Mansour, S., Haq, M. R., Gilbert, R., Lehmann, O. J., Vanstone, M. R., Beaulieu, C. L., FORGE Canada Consortium, Majewski, J., Bulman, D. E., O'Driscoll, M., Boycott, K. M., and Innes, A. M. (2013) Mutations in PIK3R1 Cause SHORT Syndrome. Am J Hum Genet. 93, 158-166.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Xue Zhong, Jin Huk Choi, and Bruce Beutler|