RBCC Red Blood Cell Collection

PIK3R1 (GRB1) [Confidence: low (only semi-automatic identification from reviews)]
Phosphatidylinositol 3-kinase regulatory subunit alpha; PI3-kinase regulatory subunit alpha; PI3K regulatory subunit alpha; PtdIns-3-kinase regulatory subunit alpha (Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha; PI3-kinase subunit p85-alpha; PtdIns-3-kinase regulatory subunit p85-alpha)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P27986
ID P85A_HUMAN Reviewed; 724 AA.
AC P27986; B3KT19; D3DWA0; E7EX19; Q15747; Q4VBZ7; Q53EM6; Q8IXA2;
read moreAC Q8N1C5;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2006, sequence version 2.
DT 22-JAN-2014, entry version 173.
DE RecName: Full=Phosphatidylinositol 3-kinase regulatory subunit alpha;
DE Short=PI3-kinase regulatory subunit alpha;
DE Short=PI3K regulatory subunit alpha;
DE Short=PtdIns-3-kinase regulatory subunit alpha;
DE AltName: Full=Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha;
DE Short=PI3-kinase subunit p85-alpha;
DE Short=PtdIns-3-kinase regulatory subunit p85-alpha;
GN Name=PIK3R1; Synonyms=GRB1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1849461; DOI=10.1016/0092-8674(91)90410-Z;
RA Skolnik E.Y., Margolis B., Mohammadi M., Lowenstein E., Fischer R.,
RA Drepps A., Ullrich A., Schlessinger J.;
RT "Cloning of PI3 kinase-associated p85 utilizing a novel method for
RT expression/cloning of target proteins for receptor tyrosine kinases.";
RL Cell 65:83-90(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 4), INTERACTION WITH IRS1,
RP AND TISSUE SPECIFICITY.
RC TISSUE=Skeletal muscle;
RX PubMed=8628286;
RA Antonetti D.A., Algenstaedt P., Kahn C.R.;
RT "Insulin receptor substrate 1 binds two novel splice variants of the
RT regulatory subunit of phosphatidylinositol 3-kinase in muscle and
RT brain.";
RL Mol. Cell. Biol. 16:2195-2203(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Skeletal muscle;
RA Udelhoven M., Kotzka J., Knebel B., Klein E., Krone W.,
RA Mueller-Wieland D.;
RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP ILE-326.
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP LYS-451.
RC TISSUE=Placenta, and Skeletal muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP INTERACTION WITH PDGFRB.
RX PubMed=7692233;
RA Nishimura R., Li W., Kashishian A., Mondino A., Zhou M., Cooper J.,
RA Schlessinger J.;
RT "Two signaling molecules share a phosphotyrosine-containing binding
RT site in the platelet-derived growth factor receptor.";
RL Mol. Cell. Biol. 13:6889-6896(1993).
RN [10]
RP INTERACTION WITH INSR.
RX PubMed=8276809;
RA Van Horn D.J., Myers M.G. Jr., Backer J.M.;
RT "Direct activation of the phosphatidylinositol 3'-kinase by the
RT insulin receptor.";
RL J. Biol. Chem. 269:29-32(1994).
RN [11]
RP FUNCTION IN FGFR4 SIGNALING.
RX PubMed=7518429;
RA Vainikka S., Joukov V., Wennstrom S., Bergman M., Pelicci P.G.,
RA Alitalo K.;
RT "Signal transduction by fibroblast growth factor receptor-4 (FGFR-4).
RT Comparison with FGFR-1.";
RL J. Biol. Chem. 269:18320-18326(1994).
RN [12]
RP INTERACTION WITH IGF1R.
RX PubMed=7541045; DOI=10.1074/jbc.270.26.15639;
RA Craparo A., O'Neill T.J., Gustafson T.A.;
RT "Non-SH2 domains within insulin receptor substrate-1 and SHC mediate
RT their phosphotyrosine-dependent interaction with the NPEY motif of the
RT insulin-like growth factor I receptor.";
RL J. Biol. Chem. 270:15639-15643(1995).
RN [13]
RP INTERACTION WITH INSR.
RX PubMed=7537849;
RA Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.;
RT "Phosphotyrosine-dependent interaction of SHC and insulin receptor
RT substrate 1 with the NPEY motif of the insulin receptor via a novel
RT non-SH2 domain.";
RL Mol. Cell. Biol. 15:2500-2508(1995).
RN [14]
RP INTERACTION WITH PDGFRA.
RX PubMed=8940081; DOI=10.1074/jbc.271.48.30942;
RA Yokote K., Margolis B., Heldin C.H., Claesson-Welsh L.;
RT "Grb7 is a downstream signaling component of platelet-derived growth
RT factor alpha- and beta-receptors.";
RL J. Biol. Chem. 271:30942-30949(1996).
RN [15]
RP INTERACTION WITH KIT.
RX PubMed=9038210; DOI=10.1074/jbc.272.9.5915;
RA Price D.J., Rivnay B., Fu Y., Jiang S., Avraham S., Avraham H.;
RT "Direct association of Csk homologous kinase (CHK) with the
RT diphosphorylated site Tyr568/570 of the activated c-KIT in
RT megakaryocytes.";
RL J. Biol. Chem. 272:5915-5920(1997).
RN [16]
RP INTERACTION WITH AXL.
RX PubMed=9178760; DOI=10.1038/sj.onc.1201123;
RA Braunger J., Schleithoff L., Schulz A.S., Kessler H., Lammers R.,
RA Ullrich A., Bartram C.R., Janssen J.W.;
RT "Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is
RT mediated mainly by a multi-substrate docking-site.";
RL Oncogene 14:2619-2631(1997).
RN [17]
RP INTERACTION WITH LAT.
RX PubMed=9489702; DOI=10.1016/S0092-8674(00)80901-0;
RA Zhang W., Sloan-Lancaster J., Kitchen J., Trible R.P., Samelson L.E.;
RT "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor
RT to cellular activation.";
RL Cell 92:83-92(1998).
RN [18]
RP INTERACTION WITH IRS4.
RX PubMed=9553137; DOI=10.1074/jbc.273.17.10726;
RA Fantin V.R., Sparling J.D., Slot J.W., Keller S.R., Lienhard G.E.,
RA Lavan B.E.;
RT "Characterization of insulin receptor substrate 4 in human embryonic
RT kidney 293 cells.";
RL J. Biol. Chem. 273:10726-10732(1998).
RN [19]
RP INTERACTION WITH TRAT1.
RX PubMed=9687533; DOI=10.1084/jem.188.3.561;
RA Bruyns E., Marie-Cardine A., Kirchgessner H., Sagolla K.,
RA Shevchenko A., Mann M., Autschbach F., Bensussan A., Meuer S.,
RA Schraven B.;
RT "T cell receptor (TCR) interacting molecule (TRIM), a novel disulfide-
RT linked dimer associated with the TCR-CD3-zeta complex, recruits
RT intracellular signaling proteins to the plasma membrane.";
RL J. Exp. Med. 188:561-575(1998).
RN [20]
RP INTERACTION WITH HCST.
RX PubMed=10528161;
RA Chang C., Dietrich J., Harpur A.G., Lindquist J.A., Haude A.,
RA Loke Y.W., King A., Colonna M., Trowsdale J., Wilson M.J.;
RT "KAP10, a novel transmembrane adapter protein genetically linked to
RT DAP12 but with unique signaling properties.";
RL J. Immunol. 163:4651-4654(1999).
RN [21]
RP INTERACTION WITH CBLB.
RX PubMed=10086340; DOI=10.1038/sj.onc.1202499;
RA Ettenberg S.A., Keane M.M., Nau M.M., Frankel M., Wang L.-M.,
RA Pierce J.H., Lipkowitz S.;
RT "cbl-b inhibits epidermal growth factor receptor signaling.";
RL Oncogene 18:1855-1866(1999).
RN [22]
RP INTERACTION WITH FGR AND HCK.
RX PubMed=10739672; DOI=10.1006/excr.2000.4816;
RA Axelsson L., Hellberg C., Melander F., Smith D., Zheng L.,
RA Andersson T.;
RT "Clustering of beta(2)-integrins on human neutrophils activates dual
RT signaling pathways to PtdIns 3-kinase.";
RL Exp. Cell Res. 256:257-263(2000).
RN [23]
RP INTERACTION WITH ERBB4.
RX PubMed=10867024; DOI=10.1074/jbc.C901015199;
RA Sweeney C., Lai C., Riese D.J. II, Diamonti A.J., Cantley L.C.,
RA Carraway K.L. III;
RT "Ligand discrimination in signaling through an ErbB4 receptor
RT homodimer.";
RL J. Biol. Chem. 275:19803-19807(2000).
RN [24]
RP INTERACTION WITH CBLB, AND UBIQUITINATION.
RX PubMed=11087752; DOI=10.1074/jbc.M008901200;
RA Fang D., Wang H.-Y., Fang N., Altman Y., Elly C., Liu Y.-C.;
RT "Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol
RT 3-kinase for ubiquitination in T cells.";
RL J. Biol. Chem. 276:4872-4878(2001).
RN [25]
RP INTERACTION WITH CD3Z AND CD28, AND UBIQUITINATION.
RX PubMed=11526404; DOI=10.1038/ni0901-870;
RA Fang D., Liu Y.-C.;
RT "Proteolysis-independent regulation of PI3K by Cbl-b-mediated
RT ubiquitination in T cells.";
RL Nat. Immunol. 2:870-875(2001).
RN [26]
RP INTERACTION WITH NISCH.
RX PubMed=11912194; DOI=10.1074/jbc.M111838200;
RA Sano H., Liu S.C.H., Lane W.S., Piletz J.E., Lienhard G.E.;
RT "Insulin receptor substrate 4 associates with the protein IRAS.";
RL J. Biol. Chem. 277:19439-19447(2002).
RN [27]
RP INTERACTION WITH LAX1.
RX PubMed=12359715; DOI=10.1074/jbc.M208946200;
RA Zhu M., Janssen E., Leung K., Zhang W.;
RT "Molecular cloning of a novel gene encoding a membrane-associated
RT adaptor protein (LAX) in lymphocyte signaling.";
RL J. Biol. Chem. 277:46151-46158(2002).
RN [28]
RP INTERACTION WITH HIV-1 NEF.
RX PubMed=12009866; DOI=10.1006/viro.2002.1365;
RA Linnemann T., Zheng Y.-H., Mandic R., Peterlin B.M.;
RT "Interaction between Nef and phosphatidylinositol-3-kinase leads to
RT activation of p21-activated kinase and increased production of HIV.";
RL Virology 294:246-255(2002).
RN [29]
RP INTERACTION WITH HCV NS5A.
RX PubMed=12186904; DOI=10.1128/JVI.76.18.9207-9217.2002;
RA He Y., Nakao H., Tan S.-L., Polyak S.J., Neddermann P., Vijaysri S.,
RA Jacobs B.L., Katze M.G.;
RT "Subversion of cell signaling pathways by hepatitis C virus
RT nonstructural 5A protein via interaction with Grb2 and P85
RT phosphatidylinositol 3-kinase.";
RL J. Virol. 76:9207-9217(2002).
RN [30]
RP INTERACTION WITH NTRK1.
RX PubMed=15488758; DOI=10.1016/j.ccr.2004.09.011;
RA Tacconelli A., Farina A.R., Cappabianca L., Desantis G., Tessitore A.,
RA Vetuschi A., Sferra R., Rucci N., Argenti B., Screpanti I., Gulino A.,
RA Mackay A.R.;
RT "TrkA alternative splicing: a regulated tumor-promoting switch in
RT human neuroblastoma.";
RL Cancer Cell 6:347-360(2004).
RN [31]
RP REVIEW ON INTERACTION WITH KIT AND ROLE IN KIT SIGNALING.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [32]
RP INTERACTION WITH BCR.
RX PubMed=15302586; DOI=10.1016/j.yexcr.2004.05.010;
RA Laurent C.E., Smithgall T.E.;
RT "The c-Fes tyrosine kinase cooperates with the breakpoint cluster
RT region protein (Bcr) to induce neurite extension in a Rac- and Cdc42-
RT dependent manner.";
RL Exp. Cell Res. 299:188-198(2004).
RN [33]
RP PHOSPHORYLATION BY FGR.
RX PubMed=15561106; DOI=10.1016/j.yexcr.2004.09.005;
RA Continolo S., Baruzzi A., Majeed M., Caveggion E., Fumagalli L.,
RA Lowell C.A., Berton G.;
RT "The proto-oncogene Fgr regulates cell migration and this requires its
RT plasma membrane localization.";
RL Exp. Cell Res. 302:253-269(2005).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [35]
RP PHOSPHORYLATION, AND DEPHOSPHORYLATION BY PTPRJ.
RX PubMed=18348712; DOI=10.1042/BJ20071317;
RA Tsuboi N., Utsunomiya T., Roberts R.L., Ito H., Takahashi K., Noda M.,
RA Takahashi T.;
RT "The tyrosine phosphatase CD148 interacts with the p85 regulatory
RT subunit of phosphoinositide 3-kinase.";
RL Biochem. J. 413:193-200(2008).
RN [36]
RP INTERACTION WITH ERBB4.
RX PubMed=18721752; DOI=10.1016/j.chembiol.2008.07.006;
RA Kaushansky A., Gordus A., Budnik B.A., Lane W.S., Rush J.,
RA MacBeath G.;
RT "System-wide investigation of ErbB4 reveals 19 sites of Tyr
RT phosphorylation that are unusually selective in their recruitment
RT properties.";
RL Chem. Biol. 15:808-817(2008).
RN [37]
RP INTERACTION WITH FASLG.
RX PubMed=19807924; DOI=10.1186/1471-2172-10-53;
RA Voss M., Lettau M., Janssen O.;
RT "Identification of SH3 domain interaction partners of human FasL
RT (CD178) by phage display screening.";
RL BMC Immunol. 10:53-53(2009).
RN [38]
RP INTERACTION WITH FGFR3.
RX PubMed=19286672; DOI=10.1093/hmg/ddp116;
RA Salazar L., Kashiwada T., Krejci P., Muchowski P., Donoghue D.,
RA Wilcox W.R., Thompson L.M.;
RT "A novel interaction between fibroblast growth factor receptor 3 and
RT the p85 subunit of phosphoinositide 3-kinase: activation-dependent
RT regulation of ERK by p85 in multiple myeloma cells.";
RL Hum. Mol. Genet. 18:1951-1961(2009).
RN [39]
RP REVIEW ON ROLE IN FGFR1 SIGNALING AND PHOSPHORYLATION.
RX PubMed=15863030; DOI=10.1016/j.cytogfr.2005.01.001;
RA Eswarakumar V.P., Lax I., Schlessinger J.;
RT "Cellular signaling by fibroblast growth factor receptors.";
RL Cytokine Growth Factor Rev. 16:139-149(2005).
RN [40]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-580, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [41]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [42]
RP INVOLVEMENT IN AGM7.
RX PubMed=22351933; DOI=10.1084/jem.20112533;
RA Conley M.E., Dobbs A.K., Quintana A.M., Bosompem A., Wang Y.D.,
RA Coustan-Smith E., Smith A.M., Perez E.E., Murray P.J.;
RT "Agammaglobulinemia and absent B lineage cells in a patient lacking
RT the p85? subunit of PI3K.";
RL J. Exp. Med. 209:463-470(2012).
RN [43]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-85.
RX PubMed=8648629; DOI=10.1006/jmbi.1996.0190;
RA Liang J., Chen J.K., Schreiber S.L., Clardy J.;
RT "Crystal structure of P13K SH3 domain at 2.0-A resolution.";
RL J. Mol. Biol. 257:632-643(1996).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 324-434.
RX PubMed=8599763; DOI=10.1038/nsb0496-364;
RA Nolte R.T., Eck M.J., Schlessinger J., Shoelson S.E., Harrison S.C.;
RT "Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain
RT and its phosphopeptide complexes.";
RL Nat. Struct. Biol. 3:364-373(1996).
RN [46]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 115-298.
RX PubMed=8962058; DOI=10.1073/pnas.93.25.14373;
RA Musacchio A., Cantley L.C., Harrison S.C.;
RT "Crystal structure of the breakpoint cluster region-homology domain
RT from phosphoinositide 3-kinase p85 alpha subunit.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:14373-14378(1996).
RN [47]
RP X-RAY CRYSTALLOGRAPHY (1.79 ANGSTROMS) OF 617-724 IN COMPLEX WITH
RP PDGFRB.
RX PubMed=11567151; DOI=10.1107/S0907444901012434;
RA Pauptit R.A., Dennis C.A., Derbyshire D.J., Breeze A.L., Weston S.A.,
RA Rowsell S., Murshudov G.N.;
RT "NMR trial models: experiences with the colicin immunity protein Im7
RT and the p85alpha C-terminal SH2-peptide complex.";
RL Acta Crystallogr. D 57:1397-1404(2001).
RN [48]
RP STRUCTURE BY NMR OF 1-79.
RX PubMed=7681364; DOI=10.1016/0092-8674(93)90582-B;
RA Koyama S., Yu H., Dalgarno D.C., Shin T.B., Zydowsky L.D.,
RA Schreiber S.L.;
RT "Structure of the PI3K SH3 domain and analysis of the SH3 family.";
RL Cell 72:945-952(1993).
RN [49]
RP STRUCTURE BY NMR OF 91-104.
RX PubMed=8961927; DOI=10.1021/bi9620969;
RA Renzoni D.A., Pugh D.J., Siligardi G., Das P., Morton C.J., Rossi C.,
RA Waterfield M.D., Campbell I.D., Ladbury J.E.;
RT "Structural and thermodynamic characterization of the interaction of
RT the SH3 domain from Fyn with the proline-rich binding site on the p85
RT subunit of PI3-kinase.";
RL Biochemistry 35:15646-15653(1996).
RN [50]
RP STRUCTURE BY NMR OF 617-724.
RX PubMed=8670861;
RA Breeze A.L., Kara B.V., Barratt D.G., Anderson M., Smith J.C.,
RA Luke R.W., Best J.R., Cartlidge S.A.;
RT "Structure of a specific peptide complex of the carboxy-terminal SH2
RT domain from the p85 alpha subunit of phosphatidylinositol 3-kinase.";
RL EMBO J. 15:3579-3589(1996).
RN [51]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 431-600, AND FUNCTION.
RX PubMed=17626883; DOI=10.1126/science.1135394;
RA Miled N., Yan Y., Hon W.C., Perisic O., Zvelebil M., Inbar Y.,
RA Schneidman-Duhovny D., Wolfson H.J., Backer J.M., Williams R.L.;
RT "Mechanism of two classes of cancer mutations in the phosphoinositide
RT 3-kinase catalytic subunit.";
RL Science 317:239-242(2007).
RN [52]
RP X-RAY CRYSTALLOGRAPHY (3.05 ANGSTROMS) OF 322-600.
RX PubMed=18079394; DOI=10.1126/science.1150799;
RA Huang C.-H., Mandelker D., Schmidt-Kittler O., Samuels Y.,
RA Velculescu V.E., Kinzler K.W., Vogelstein B., Gabelli S.B.,
RA Amzel L.M.;
RT "The structure of a human p110alpha/p85alpha complex elucidates the
RT effects of oncogenic PI3Kalpha mutations.";
RL Science 318:1744-1748(2007).
RN [53]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 322-694, FUNCTION, AND
RP SUBUNIT.
RX PubMed=19805105; DOI=10.1073/pnas.0908444106;
RA Mandelker D., Gabelli S.B., Schmidt-Kittler O., Zhu J., Cheong I.,
RA Huang C.H., Kinzler K.W., Vogelstein B., Amzel L.M.;
RT "A frequent kinase domain mutation that changes the interaction
RT between PI3Kalpha and the membrane.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:16996-17001(2009).
RN [54]
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1-83.
RX PubMed=19919182; DOI=10.1515/BC.2010.003;
RA Batra-Safferling R., Granzin J., Modder S., Hoffmann S., Willbold D.;
RT "Structural studies of the phosphatidylinositol 3-kinase (PI3K) SH3
RT domain in complex with a peptide ligand: role of the anchor residue in
RT ligand binding.";
RL Biol. Chem. 391:33-42(2010).
RN [55]
RP VARIANT ILE-326.
RX PubMed=9032108; DOI=10.2337/diab.46.3.494;
RA Hansen T., Andersen C.B., Echwald S.M., Urhammer S.A., Clausen J.O.,
RA Vestergaard H., Owens D., Hansen L., Pedersen O.;
RT "Identification of a common amino acid polymorphism in the p85alpha
RT regulatory subunit of phosphatidylinositol 3-kinase: effects on
RT glucose disappearance constant, glucose effectiveness, and the insulin
RT sensitivity index.";
RL Diabetes 46:494-501(1997).
RN [56]
RP VARIANTS ILE-326 AND GLN-409, AND CHARACTERIZATION OF VARIANTS ILE-326
RP AND GLN-409.
RX PubMed=10768093; DOI=10.1007/s001250050050;
RA Baynes K.C.R., Beeton C.A., Panayotou G., Stein R., Soos M.,
RA Hansen T., Simpson H., O'Rahilly S., Shepherd P.R., Whitehead J.P.;
RT "Natural variants of human p85 alpha phosphoinositide 3-kinase in
RT severe insulin resistance: a novel variant with impaired insulin-
RT stimulated lipid kinase activity.";
RL Diabetologia 43:321-331(2000).
RN [57]
RP VARIANTS SHORTS LYS-489 AND ILE-539 DEL.
RX PubMed=23810378; DOI=10.1016/j.ajhg.2013.05.019;
RA Thauvin-Robinet C., Auclair M., Duplomb L., Caron-Debarle M.,
RA Avila M., St-Onge J., Le Merrer M., Le Luyer B., Heron D.,
RA Mathieu-Dramard M., Bitoun P., Petit J.M., Odent S., Amiel J.,
RA Picot D., Carmignac V., Thevenon J., Callier P., Laville M.,
RA Reznik Y., Fagour C., Nunes M.L., Capeau J., Lascols O., Huet F.,
RA Faivre L., Vigouroux C., Riviere J.B.;
RT "PIK3R1 mutations cause syndromic insulin resistance with
RT lipoatrophy.";
RL Am. J. Hum. Genet. 93:141-149(2013).
RN [58]
RP VARIANT SHORTS TRP-649.
RX PubMed=23810379; DOI=10.1016/j.ajhg.2013.05.023;
RA Chudasama K.K., Winnay J., Johansson S., Claudi T., Konig R.,
RA Haldorsen I., Johansson B., Woo J.R., Aarskog D., Sagen J.V.,
RA Kahn C.R., Molven A., Njolstad P.R.;
RT "SHORT syndrome with partial lipodystrophy due to impaired
RT phosphatidylinositol 3 kinase signaling.";
RL Am. J. Hum. Genet. 93:150-157(2013).
CC -!- FUNCTION: Binds to activated (phosphorylated) protein-Tyr kinases,
CC through its SH2 domain, and acts as an adapter, mediating the
CC association of the p110 catalytic unit to the plasma membrane.
CC Necessary for the insulin-stimulated increase in glucose uptake
CC and glycogen synthesis in insulin-sensitive tissues. Plays an
CC important role in signaling in response to FGFR1, FGFR2, FGFR3,
CC FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role
CC in ITGB2 signaling.
CC -!- SUBUNIT: Heterodimer of a regulatory subunit PIK3R1 and a p110
CC catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts with FER.
CC Interacts (via SH2 domain) with TEK/TIE2 (tyrosine
CC phosphorylated). Interacts with PTK2/FAK1 (By similarity).
CC Interacts with phosphorylated TOM1L1. Interacts with
CC phosphorylated LIME1 upon TCR and/or BCR activation. Interacts
CC with SOCS7. Interacts with RUFY3. Interacts (via SH2 domain) with
CC CSF1R (tyrosine phosphorylated). Interacts with LYN (via SH3
CC domain); this enhances enzyme activity (By similarity). Interacts
CC with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation.
CC Interacts with CBLB. Interacts with HIV-1 Nef to activate the Nef
CC associated p21-activated kinase (PAK). This interaction depends on
CC the C-terminus of both proteins and leads to increased production
CC of HIV. Interacts with HCV NS5A. The SH2 domains interact with the
CC YTHM motif of phosphorylated INSR in vitro. Also interacts with
CC tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and
CC CD3Z upon T-cell activation. Interacts with IRS1 and
CC phosphorylated IRS4, as well as with NISCH and HCST. Interacts
CC with FASLG, KIT and BCR. Interacts with AXL, FGFR1, FGFR2, FGFR3
CC and FGFR4 (phosphorylated). Interacts with FGR and HCK. Interacts
CC with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine
CC phosphorylated). Interacts with ERBB4 (phosphorylated). Interacts
CC with NTRK1 (phosphorylated upon ligand-binding).
CC -!- INTERACTION:
CC Q8IZP0:ABI1; NbExp=8; IntAct=EBI-79464, EBI-375446;
CC P42684:ABL2; NbExp=2; IntAct=EBI-79464, EBI-1102694;
CC P22681:CBL; NbExp=5; IntAct=EBI-79464, EBI-518228;
CC P10747:CD28; NbExp=8; IntAct=EBI-79464, EBI-4314301;
CC Q8IY22:CMIP; NbExp=2; IntAct=EBI-79464, EBI-7689652;
CC P46109:CRKL; NbExp=2; IntAct=EBI-79464, EBI-910;
CC P16410:CTLA4; NbExp=3; IntAct=EBI-79464, EBI-1030991;
CC Q9Y2H0:DLGAP4; NbExp=2; IntAct=EBI-79464, EBI-722139;
CC P00533:EGFR; NbExp=4; IntAct=EBI-79464, EBI-297353;
CC P04626:ERBB2; NbExp=11; IntAct=EBI-79464, EBI-641062;
CC P21860:ERBB3; NbExp=40; IntAct=EBI-79464, EBI-720706;
CC P03372:ESR1; NbExp=6; IntAct=EBI-79464, EBI-78473;
CC P11362:FGFR1; NbExp=4; IntAct=EBI-79464, EBI-1028277;
CC P17948:FLT1; NbExp=2; IntAct=EBI-79464, EBI-1026718;
CC P36888:FLT3; NbExp=2; IntAct=EBI-79464, EBI-3946257;
CC Q13480:GAB1; NbExp=9; IntAct=EBI-79464, EBI-517684;
CC P62993:GRB2; NbExp=3; IntAct=EBI-79464, EBI-401755;
CC P08069:IGF1R; NbExp=3; IntAct=EBI-79464, EBI-475981;
CC P06213:INSR; NbExp=3; IntAct=EBI-79464, EBI-475899;
CC P35568:IRS1; NbExp=12; IntAct=EBI-79464, EBI-517592;
CC P35570:Irs1 (xeno); NbExp=2; IntAct=EBI-79464, EBI-520230;
CC Q9Y4H2:IRS2; NbExp=2; IntAct=EBI-79464, EBI-1049582;
CC Q86VI4-3:LAPTM4B; NbExp=2; IntAct=EBI-79464, EBI-3267286;
CC O43561:LAT; NbExp=4; IntAct=EBI-79464, EBI-1222766;
CC Q92918:MAP4K1; NbExp=2; IntAct=EBI-79464, EBI-881;
CC P45983:MAPK8; NbExp=2; IntAct=EBI-79464, EBI-286483;
CC Q8WX92:NELFB; NbExp=2; IntAct=EBI-79464, EBI-347721;
CC Q6PFX7:Nyap1 (xeno); NbExp=4; IntAct=EBI-79464, EBI-7447489;
CC Q8BM65-4:Nyap2 (xeno); NbExp=3; IntAct=EBI-79464, EBI-7447598;
CC P09619:PDGFRB; NbExp=18; IntAct=EBI-79464, EBI-641237;
CC P42336:PIK3CA; NbExp=13; IntAct=EBI-79464, EBI-2116585;
CC Q13905:RAPGEF1; NbExp=2; IntAct=EBI-79464, EBI-976876;
CC P26373:RPL13; NbExp=2; IntAct=EBI-79464, EBI-356849;
CC P19793:RXRA; NbExp=8; IntAct=EBI-79464, EBI-78598;
CC Q9UPX8:SHANK2; NbExp=2; IntAct=EBI-79464, EBI-1570571;
CC P29353:SHC1; NbExp=3; IntAct=EBI-79464, EBI-78835;
CC Q96EB6:SIRT1; NbExp=3; IntAct=EBI-79464, EBI-1802965;
CC Q07889:SOS1; NbExp=2; IntAct=EBI-79464, EBI-297487;
CC P12931:SRC; NbExp=5; IntAct=EBI-79464, EBI-621482;
CC P30874:SSTR2; NbExp=5; IntAct=EBI-79464, EBI-6266898;
CC P58753:TIRAP; NbExp=3; IntAct=EBI-79464, EBI-528644;
CC O15455:TLR3; NbExp=2; IntAct=EBI-79464, EBI-6289595;
CC Q15661:TPSAB1; NbExp=2; IntAct=EBI-79464, EBI-1761369;
CC Q9ULW0:TPX2; NbExp=2; IntAct=EBI-79464, EBI-1037322;
CC Q9UKW4:VAV3; NbExp=2; IntAct=EBI-79464, EBI-297568;
CC Q99152:VP3 (xeno); NbExp=3; IntAct=EBI-79464, EBI-1776808;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=P27986-1; Sequence=Displayed;
CC Name=2; Synonyms=AS53;
CC IsoId=P27986-2; Sequence=VSP_021842, VSP_021843;
CC Name=3; Synonyms=p46;
CC IsoId=P27986-3; Sequence=VSP_021841, VSP_021844;
CC Name=4; Synonyms=p85I;
CC IsoId=P27986-4; Sequence=VSP_021845;
CC Name=5;
CC IsoId=P27986-5; Sequence=VSP_045903;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Isoform 2 is expressed in skeletal muscle and
CC brain, and at lower levels in kidney and cardiac muscle. Isoform 2
CC and isoform 4 are present in skeletal muscle (at protein level).
CC -!- DOMAIN: The SH3 domain mediates the binding to CBLB, and to HIV-1
CC Nef.
CC -!- PTM: Polyubiquitinated in T-cells by CBLB; which does not promote
CC proteasomal degradation but impairs association with CD28 and CD3Z
CC upon T-cell activation.
CC -!- PTM: Phosphorylated. Tyrosine phosphorylated in response to
CC signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated by
CC CSF1R. Phosphorylated by ERBB4. Phosphorylated on tyrosine
CC residues by TEK/TIE2. Dephosphorylated by PTPRJ. Phosphorylated by
CC PIK3CA at Ser-608; phosphorylation is stimulated by insulin and
CC PDGF. The relevance of phosphorylation by PIK3CA is however
CC unclear (By similarity). Phosphorylated in response to KIT and
CC KITLG/SCF. Phosphorylated by FGR.
CC -!- DISEASE: Agammaglobulinemia 7, autosomal recessive (AGM7)
CC [MIM:615214]: A primary immunodeficiency characterized by
CC profoundly low or absent serum antibodies and low or absent
CC circulating B cells due to an early block of B-cell development.
CC Affected individuals develop severe infections in the first years
CC of life. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: SHORT syndrome (SHORTS) [MIM:269880]: A rare, multisystem
CC disease characterized by short stature, anomalies of the anterior
CC chamber of the eye, characteristic facial features such as
CC triangular facies, lack of facial fat, and hypoplastic nasal alae
CC with overhanging columella, partial lipodystrophy, hernias,
CC hyperextensibility, and delayed dentition. The clinical phenotype
CC can include insulin resistance, nephrocalcinosis, and hearing
CC deficits. Developmental milestones and cognition are normal.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the PI3K p85 subunit family.
CC -!- SIMILARITY: Contains 1 Rho-GAP domain.
CC -!- SIMILARITY: Contains 2 SH2 domains.
CC -!- SIMILARITY: Contains 1 SH3 domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PIK3R1ID41717ch5q13.html";
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DR EMBL; M61906; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; U49349; AAB04140.1; -; mRNA.
DR EMBL; AF279367; AAO15359.1; -; mRNA.
DR EMBL; AK094785; BAG52931.1; -; mRNA.
DR EMBL; AK223613; BAD97333.1; -; mRNA.
DR EMBL; AC016564; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC104120; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471137; EAW51312.1; -; Genomic_DNA.
DR EMBL; CH471137; EAW51313.1; -; Genomic_DNA.
DR EMBL; BC030815; AAH30815.1; -; mRNA.
DR EMBL; BC094795; AAH94795.1; -; mRNA.
DR PIR; A38748; A38748.
DR RefSeq; NP_001229395.1; NM_001242466.1.
DR RefSeq; NP_852556.2; NM_181504.3.
DR RefSeq; NP_852664.1; NM_181523.2.
DR RefSeq; NP_852665.1; NM_181524.1.
DR RefSeq; XP_005248599.1; XM_005248542.1.
DR UniGene; Hs.132225; -.
DR UniGene; Hs.604502; -.
DR UniGene; Hs.734132; -.
DR PDB; 1A0N; NMR; -; A=91-104.
DR PDB; 1AZG; NMR; -; A=91-104.
DR PDB; 1H9O; X-ray; 1.79 A; A=617-724.
DR PDB; 1PBW; X-ray; 2.00 A; A/B=105-319.
DR PDB; 1PHT; X-ray; 2.00 A; A=1-85.
DR PDB; 1PIC; NMR; -; A=617-724.
DR PDB; 1PKS; NMR; -; A=1-79.
DR PDB; 1PKT; NMR; -; A=1-79.
DR PDB; 2IUG; X-ray; 1.89 A; A=321-440.
DR PDB; 2IUH; X-ray; 2.00 A; A=321-440.
DR PDB; 2IUI; X-ray; 2.40 A; A/B=321-440.
DR PDB; 2RD0; X-ray; 3.05 A; B=322-600.
DR PDB; 2V1Y; X-ray; 2.40 A; B=431-600.
DR PDB; 3HHM; X-ray; 2.80 A; B=322-694.
DR PDB; 3HIZ; X-ray; 3.30 A; B=322-694.
DR PDB; 3I5R; X-ray; 1.70 A; A=1-83.
DR PDB; 3I5S; X-ray; 3.00 A; A/B/C/D=1-83.
DR PDB; 4A55; X-ray; 3.50 A; B=322-600.
DR PDBsum; 1A0N; -.
DR PDBsum; 1AZG; -.
DR PDBsum; 1H9O; -.
DR PDBsum; 1PBW; -.
DR PDBsum; 1PHT; -.
DR PDBsum; 1PIC; -.
DR PDBsum; 1PKS; -.
DR PDBsum; 1PKT; -.
DR PDBsum; 2IUG; -.
DR PDBsum; 2IUH; -.
DR PDBsum; 2IUI; -.
DR PDBsum; 2RD0; -.
DR PDBsum; 2V1Y; -.
DR PDBsum; 3HHM; -.
DR PDBsum; 3HIZ; -.
DR PDBsum; 3I5R; -.
DR PDBsum; 3I5S; -.
DR PDBsum; 4A55; -.
DR ProteinModelPortal; P27986; -.
DR SMR; P27986; 3-85, 115-309, 324-724.
DR DIP; DIP-119N; -.
DR IntAct; P27986; 187.
DR MINT; MINT-93751; -.
DR STRING; 9606.ENSP00000274335; -.
DR BindingDB; P27986; -.
DR ChEMBL; CHEMBL2506; -.
DR DrugBank; DB01064; Isoproterenol.
DR PhosphoSite; P27986; -.
DR DMDM; 118572681; -.
DR PaxDb; P27986; -.
DR PRIDE; P27986; -.
DR DNASU; 5295; -.
DR Ensembl; ENST00000274335; ENSP00000274335; ENSG00000145675.
DR Ensembl; ENST00000320694; ENSP00000323512; ENSG00000145675.
DR Ensembl; ENST00000336483; ENSP00000338554; ENSG00000145675.
DR Ensembl; ENST00000396611; ENSP00000379855; ENSG00000145675.
DR Ensembl; ENST00000521381; ENSP00000428056; ENSG00000145675.
DR Ensembl; ENST00000521657; ENSP00000429277; ENSG00000145675.
DR Ensembl; ENST00000523872; ENSP00000430098; ENSG00000145675.
DR GeneID; 5295; -.
DR KEGG; hsa:5295; -.
DR UCSC; uc021xzn.1; human.
DR CTD; 5295; -.
DR GeneCards; GC05P067511; -.
DR HGNC; HGNC:8979; PIK3R1.
DR HPA; CAB004268; -.
DR HPA; HPA001216; -.
DR MIM; 171833; gene.
DR MIM; 269880; phenotype.
DR MIM; 615214; phenotype.
DR neXtProt; NX_P27986; -.
DR Orphanet; 33110; Autosomal agammaglobulinemia.
DR Orphanet; 3163; SHORT syndrome.
DR PharmGKB; PA33312; -.
DR eggNOG; NOG263689; -.
DR HOVERGEN; HBG082100; -.
DR KO; K02649; -.
DR OMA; GYNETTG; -.
DR OrthoDB; EOG7BP831; -.
DR PhylomeDB; P27986; -.
DR BioCyc; MetaCyc:ENSG00000145675-MONOMER; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P27986; -.
DR ChiTaRS; PIK3R1; human.
DR EvolutionaryTrace; P27986; -.
DR GeneWiki; PIK3R1; -.
DR GenomeRNAi; 5295; -.
DR NextBio; 20462; -.
DR PRO; PR:P27986; -.
DR ArrayExpress; P27986; -.
DR Bgee; P27986; -.
DR CleanEx; HS_PIK3R1; -.
DR Genevestigator; P27986; -.
DR GO; GO:0005943; C:1-phosphatidylinositol-4-phosphate 3-kinase, class IA complex; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005545; F:1-phosphatidylinositol binding; NAS:UniProtKB.
DR GO; GO:0043125; F:ErbB-3 class receptor binding; IDA:UniProtKB.
DR GO; GO:0043559; F:insulin binding; IDA:UniProtKB.
DR GO; GO:0043560; F:insulin receptor substrate binding; ISS:BHF-UCL.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; ISS:BHF-UCL.
DR GO; GO:0035014; F:phosphatidylinositol 3-kinase regulator activity; ISS:UniProtKB.
DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; ISS:BHF-UCL.
DR GO; GO:0030183; P:B cell differentiation; IEA:Ensembl.
DR GO; GO:0034644; P:cellular response to UV; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0060396; P:growth hormone receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IPI:UniProtKB.
DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; IPI:UniProtKB.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0001953; P:negative regulation of cell-matrix adhesion; IEA:Ensembl.
DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0051531; P:NFAT protein import into nucleus; IEA:Ensembl.
DR GO; GO:0014065; P:phosphatidylinositol 3-kinase cascade; IDA:BHF-UCL.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
DR GO; GO:0046854; P:phosphatidylinositol phosphorylation; ISS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0090004; P:positive regulation of establishment of protein localization to plasma membrane; ISS:BHF-UCL.
DR GO; GO:0046326; P:positive regulation of glucose import; ISS:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome.
DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.555.10; -; 1.
DR Gene3D; 3.30.505.10; -; 2.
DR InterPro; IPR001720; PI3kinase_P85.
DR InterPro; IPR008936; Rho_GTPase_activation_prot.
DR InterPro; IPR000198; RhoGAP_dom.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR011511; SH3_2.
DR InterPro; IPR001452; SH3_domain.
DR PANTHER; PTHR10155; PTHR10155; 1.
DR Pfam; PF00620; RhoGAP; 1.
DR Pfam; PF00017; SH2; 2.
DR Pfam; PF07653; SH3_2; 1.
DR PRINTS; PR00678; PI3KINASEP85.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00324; RhoGAP; 1.
DR SMART; SM00252; SH2; 2.
DR SMART; SM00326; SH3; 1.
DR SUPFAM; SSF48350; SSF48350; 1.
DR SUPFAM; SSF50044; SSF50044; 1.
DR PROSITE; PS50238; RHOGAP; 1.
DR PROSITE; PS50001; SH2; 2.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Disease mutation; Dwarfism; Host-virus interaction; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat; SH2 domain; SH3 domain;
KW Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 724 Phosphatidylinositol 3-kinase regulatory
FT subunit alpha.
FT /FTId=PRO_0000080758.
FT DOMAIN 3 79 SH3.
FT DOMAIN 113 301 Rho-GAP.
FT DOMAIN 333 428 SH2 1.
FT DOMAIN 624 718 SH2 2.
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 467 467 Phosphotyrosine (By similarity).
FT MOD_RES 580 580 Phosphotyrosine.
FT MOD_RES 608 608 Phosphoserine (By similarity).
FT VAR_SEQ 1 363 Missing (in isoform 5).
FT /FTId=VSP_045903.
FT VAR_SEQ 1 300 Missing (in isoform 3).
FT /FTId=VSP_021841.
FT VAR_SEQ 1 270 Missing (in isoform 2).
FT /FTId=VSP_021842.
FT VAR_SEQ 271 304 MLFRFSAASSDNTENLIKVIEILISTEWNERQPA -> MYN
FT TVWNMEDLDLEYAKTDINCGTDLMFYIEMDP (in
FT isoform 2).
FT /FTId=VSP_021843.
FT VAR_SEQ 301 306 RQPAPA -> MHNLQT (in isoform 3).
FT /FTId=VSP_021844.
FT VAR_SEQ 605 605 D -> ENFLSCLPS (in isoform 4).
FT /FTId=VSP_021845.
FT VARIANT 326 326 M -> I (does not affect insulin-
FT stimulated lipid kinase activity;
FT dbSNP:rs3730089).
FT /FTId=VAR_010023.
FT VARIANT 409 409 R -> Q (in a patient with severe insulin
FT resistance; lower insulin-stimulated
FT lipid kinase activity compared with wild-
FT type).
FT /FTId=VAR_010024.
FT VARIANT 451 451 E -> K (in dbSNP:rs17852841).
FT /FTId=VAR_029562.
FT VARIANT 489 489 E -> K (in SHORTS; there is 70 to 90%
FT reduction in the effect of insulin on
FT AKT1 activation, glycogen synthesis and
FT glucose uptake, indicating severe insulin
FT resistance for both proximal and distal
FT PI3K-dependent signaling).
FT /FTId=VAR_070221.
FT VARIANT 539 539 Missing (in SHORTS; there is 70 to 90%
FT reduction in the effect of insulin on
FT AKT1 activation, glycogen synthesis and
FT glucose uptake, indicating severe insulin
FT resistance for both proximal and distal
FT PI3K-dependent signaling).
FT /FTId=VAR_070222.
FT VARIANT 649 649 R -> W (in SHORTS; impairs interaction
FT between PIK3R1 and IRS1 and reduces AKT1-
FT mediated insulin signaling).
FT /FTId=VAR_070223.
FT CONFLICT 330 330 D -> N (in Ref. 1; M61906).
FT CONFLICT 460 460 S -> G (in Ref. 4; BAG52931).
FT STRAND 4 10
FT STRAND 29 33
FT HELIX 34 40
FT TURN 43 45
FT HELIX 46 48
FT HELIX 50 53
FT STRAND 55 60
FT TURN 61 64
FT STRAND 65 70
FT HELIX 71 73
FT STRAND 74 81
FT TURN 100 102
FT HELIX 118 121
FT HELIX 130 143
FT TURN 147 150
FT HELIX 160 164
FT STRAND 167 170
FT HELIX 174 176
FT HELIX 179 191
FT STRAND 193 195
FT HELIX 200 209
FT HELIX 210 212
FT HELIX 216 227
FT HELIX 234 252
FT HELIX 254 257
FT HELIX 261 273
FT HELIX 280 295
FT HELIX 326 329
FT STRAND 334 337
FT HELIX 340 347
FT STRAND 354 359
FT HELIX 363 365
FT STRAND 367 374
FT STRAND 377 386
FT STRAND 389 395
FT STRAND 398 400
FT HELIX 401 410
FT HELIX 413 415
FT HELIX 418 420
FT TURN 430 432
FT HELIX 439 512
FT TURN 513 516
FT HELIX 518 586
FT HELIX 591 598
FT HELIX 617 619
FT HELIX 621 623
FT STRAND 625 629
FT HELIX 631 638
FT STRAND 645 650
FT STRAND 652 655
FT STRAND 657 663
FT STRAND 666 675
FT STRAND 678 682
FT STRAND 688 690
FT HELIX 691 700
FT HELIX 703 705
FT TURN 708 710
FT STRAND 716 719
SQ SEQUENCE 724 AA; 83598 MW; B9DAD8416C33140F CRC64;
MSAEGYQYRA LYDYKKEREE DIDLHLGDIL TVNKGSLVAL GFSDGQEARP EEIGWLNGYN
ETTGERGDFP GTYVEYIGRK KISPPTPKPR PPRPLPVAPG SSKTEADVEQ QALTLPDLAE
QFAPPDIAPP LLIKLVEAIE KKGLECSTLY RTQSSSNLAE LRQLLDCDTP SVDLEMIDVH
VLADAFKRYL LDLPNPVIPA AVYSEMISLA PEVQSSEEYI QLLKKLIRSP SIPHQYWLTL
QYLLKHFFKL SQTSSKNLLN ARVLSEIFSP MLFRFSAASS DNTENLIKVI EILISTEWNE
RQPAPALPPK PPKPTTVANN GMNNNMSLQD AEWYWGDISR EEVNEKLRDT ADGTFLVRDA
STKMHGDYTL TLRKGGNNKL IKIFHRDGKY GFSDPLTFSS VVELINHYRN ESLAQYNPKL
DVKLLYPVSK YQQDQVVKED NIEAVGKKLH EYNTQFQEKS REYDRLYEEY TRTSQEIQMK
RTAIEAFNET IKIFEEQCQT QERYSKEYIE KFKREGNEKE IQRIMHNYDK LKSRISEIID
SRRRLEEDLK KQAAEYREID KRMNSIKPDL IQLRKTRDQY LMWLTQKGVR QKKLNEWLGN
ENTEDQYSLV EDDEDLPHHD EKTWNVGSSN RNKAENLLRG KRDGTFLVRE SSKQGCYACS
VVVDGEVKHC VINKTATGYG FAEPYNLYSS LKELVLHYQH TSLVQHNDSL NVTLAYPVYA
QQRR
//

MIM 171833
*RECORD*
*FIELD* NO
171833
*FIELD* TI
*171833 PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 1; PIK3R1
;;PHOSPHATIDYLINOSITOL 3-KINASE-ASSOCIATED p85-ALPHA; GRB1;;
read morePHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT, 85-KD, ALPHA;;
p85-ALPHA
*FIELD* TX

DESCRIPTION

Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that
phosphorylates the inositol ring of phosphatidylinositol and related
compounds at the 3-prime position. The products of these reactions are
thought to serve as second messengers in growth signaling pathways. The
kinase itself is made up of a catalytic subunit of molecular mass 110 kD
(p110; 171834) and a regulatory subunit of 85 kD (p85), 55 kD, or 50 kD.

CLONING

Otsu et al. (1991) showed that the bovine PI3K p85 subunit consists of 2
closely related proteins, p85-alpha and p85-beta (PIK3R2; 603157). They
cloned cDNAs encoding both p85 subunits, each of which is a 724-amino
acid polypeptide. The 2 subunits shared 62% amino acid sequence identity
across their entire length. Both sequences contained an N-terminal SH3
region, 2 SH2 regions, and a region of homology to the C-terminal region
of BCR (151410). Functional expression studies showed that both p85
subunits lacked PI3-kinase activity, but both bound to tyrosine kinase
receptors. Volinia et al. (1992) stated that human p85-alpha contains
all the peptide sequence found in bovine p85-alpha.

Skolnik et al. (1991) developed a novel method for expression cloning of
receptor tyrosine kinase target proteins (called CORT for 'cloning of
receptor targets') and illustrated the method by cloning cDNA for GRB1,
the gene encoding phosphatidylinositol 3-kinase-associated p85-alpha.

The PIK3R1 gene encodes 3 regulatory isoforms of PI3K: p85, p55, and
p50. The 9 3-prime exons are shared by all 3 isoforms with 2 distinct
promoters, and 2 exon 1 sequences upstream of these 9 exons control the
production of p55 and p50 (summary by Conley et al., 2012).

Conley et al. (2012) found variable expression of the 3 regulatory
isoforms in hematopoietic cells: normal T cells expressed almost equal
amounts of p85 and p50, and activated T cells also contained trace
amounts of p55. In contrast, normal B cells contained p85, but no
detectable p50 or p55; EBV-transformed B cells expressed low levels of
p50 and p55. NK cells and neutrophils contained p85 and low levels of
p50.

GENE FUNCTION

Skolnik et al. (1991) showed that the product of the GRB1 gene
associates with activated growth factor receptors. p85-alpha modulates
the interaction between PI3 kinase and platelet-derived growth factor
receptor.

Simoncini et al. (2000) showed that the estrogen receptor isoform
ER-alpha (133430) binds in a ligand-dependent manner to the p85-alpha
regulatory subunit of PI3K. Stimulation with estrogen increases
ER-alpha-associated PI3K activity, leading to the activation of protein
kinase B/AKT (164730) and endothelial nitric oxide synthase (eNOS;
163729). Recruitment and activation of PI3K by ligand-bound ER-alpha are
independent of gene transcription, do not involve phosphotyrosine
adaptor molecules or src-homology domains of p85-alpha, and extend to
other steroid hormone receptors. Mice treated with estrogen showed
increased eNOS activity and decreased vascular leukocyte accumulation
after ischemia and reperfusion injury. This vascular protective effect
of estrogen was abolished in the presence of PI3K or eNOS inhibitors.
Simoncini et al. (2000) concluded that their findings defined a
physiologically important nonnuclear estrogen-signaling pathway
involving the direct interaction of ER-alpha with PI3K.

Niswender et al. (2001) demonstrated that systemic administration of
leptin (164160) in rat activates the enzyme
phosphatidylinositol-3-hydroxykinase in the hypothalamus and that
intracerebroventricular infusion of inhibitors of this enzyme prevents
leptin-induced anorexia. They concluded that
phosphatidylinositol-3-hydroxykinase is a crucial enzyme in the signal
transduction pathway that links hypothalamic leptin to reduced food
intake.

He et al. (2002) determined that the hepatitis C virus nonstructural 5A
(NS5A) protein interacts directly with GRB2 (108355) and with the p85
subunit of PI3K following stimulation with epidermal growth factor (EGF;
131530). The in vivo association of NS5A with p85 PI3K increased
tyrosine phosphorylation of p85 PI3K. Downstream effects of the
EGF-induced interaction included tyrosine phosphorylation of AKT and
serine phosphorylation of BAD (603167). Both of these events would tend
to inhibit apoptosis and were consistent with the antiapoptotic
properties of NS5A.

Ectopic activation of fibroblast growth factor receptor-3 (FGFR3;
134934) is associated with several cancers, including multiple myeloma
(254500). Salazar et al. (2009) identified the PI3K regulatory subunit
PIK3R1 as a novel interactor of FGFR3 by yeast 2-hybrid screen and
confirmed an interaction between FGFR3 and PIK3R1 and PIK3R2 in
mammalian cells. The interaction of FGFR3 with PIK3R1 was dependent upon
receptor activation. In contrast to the Gab1 (604439)-mediated
association of FGFRs with PIK3R1, the FGFR3-PIK3R1 interaction required
FGFR3 tyr760, previously identified as a PLC-gamma (PLCG1;
172420)-binding site. Interaction of PIK3R1 with FGFR3 did not require
PLC-gamma, suggesting that PIK3R1 interaction was direct and independent
of PLC-gamma binding. FGFR3 and PIK3R1/PIK3R2 proteins also interacted
in multiple myeloma cell lines, which consistently express PIK3R1 p85
isoforms but not p50 or p55 isoforms, or PIK3R3 (606076). siRNA
knockdown of PIK3R2 in multiple myeloma cells caused an increased ERK
response to FGF2 stimulation. Salazar et al. (2009) suggested that an
endogenous negative regulatory role for the PIK3R-FGFR3 interaction on
the Ras/ERK/MAPK pathway may exist in response to FGFR3 activity.

Using mouse embryonic fibroblasts, Park et al. (2010) showed that, in
addition to regulating PI3K function, p85-alpha and p85-beta regulated
the function of Xbp1s (XBP1; 194355), a transcription factor that
orchestrates the unfolded protein response (UPR) following endoplasmic
reticulum (ER) stress. Both p85-alpha and p85-beta bound Xbp1s and
increased its nuclear translocation, and it appeared that the p110 PI3K
catalytic subunit and Xbp1s competed for binding of these regulatory
subunits. p85-alpha and p85-beta formed an inactive dimer that was
disrupted by insulin in a time-dependent manner, which promoted their
association with Xbp1s. Refeeding of wildtype mice after fasting induced
ER stress that was quickly resolved, as measured by Xbp1s levels. In
contrast, obese and insulin-resistant ob/ob (LEP; 164160) mice could not
resolve the ER stress induced during refeeding, and nuclear
translocation of Xbp1s was absent in ob/ob mice. Overexpression of
p85-alpha or p85-beta in livers of ob/ob mice increased glucose
tolerance and reduced blood glucose concentrations.

Independently, Winnay et al. (2010) found that p85-alpha interacted with
Xbp1 in an ER stress-dependent manner in mice and that this interaction
was essential in the ER stress response. Cells deficient in p85-alpha or
mouse livers with selective inactivation of p85-alpha showed reduced ER
stress-dependent accumulation of nuclear Xbp1s and attenuated induction
of UPR target genes.

BIOCHEMICAL FEATURES

- Crystal Structure

Miled et al. (2007) used crystallographic and biochemical approaches to
gain insight into activating mutations in 2 noncatalytic p100-alpha
domains--the adaptor-binding and the helical domains. A structure of the
adaptor-binding domain of p110-alpha (171834) in a complex with the
p85-alpha inter-Src homology 2 (inter-SH2) domains shows that the
oncogenic mutations in the adaptor-binding domain are not at the
inter-SH2 interface but in a polar surface patch that is a plausible
docking site for other domains in the holo p110/p85 complex. The authors
also examined helical domain mutations and found that the glu545-to-lys
(E545K) oncogenic mutant disrupts an inhibitory charge-charge
interaction with the p85 N-terminal SH2 domain. Miled et al. (2007)
concluded that their studies extended understanding of the architecture
of the phosphatidylinositol 3-kinases and provided insight into how 2
classes of mutations that cause a gain of function can lead to cancer.

MAPPING

Cannizzaro et al. (1991) demonstrated that the GRB1 gene is located at
5q13 by analysis of its segregation in rodent-human hybrids and by
chromosome in situ hybridization. Cannizzaro et al. (1991) observed that
the RASA gene (139150), encoding another receptor-associated signal
transducing protein, is also located in 5q13. Volinia et al. (1992)
confirmed the mapping of PIK3R1 to chromosome 5q12-q13. Hoyle et al.
(1994) demonstrated that the homologous gene in the mouse, Pik3r1, maps
to chromosome 13.

MOLECULAR GENETICS

Phosphatidylinositol 3-kinase is a key step in the metabolic actions of
insulin. Two amino acid polymorphisms have been identified in the
regulatory subunit of p85-alpha, met326 to ile and asn330 to asp. The
former is associated with alterations in glucose/insulin homeostasis.
Almind et al. (2002) presented observations indicating that the
met326-to-ile variant of p85-alpha is functional for intracellular
signaling and adipocyte differentiation but has small alterations in
protein expression and activity that could play a role in modifying
insulin action. These conclusions were based on studies where the 4
human p85-alpha proteins encoded by these 4 alleles were expressed in
yeast.

The Cancer Genome Atlas Research Network (2008) reported the interim
integrative analysis of DNA copy number, gene expression, and DNA
methylation aberrations in 206 glioblastomas and nucleotide sequence
alterations in 91 of the 206 glioblastomas. The authors observed that
the RTK/RAS/PI3K signaling pathway was altered in 88% of glioblastomas.
Somatic mutation in the PI3K complex was frequently identified. In
particular, novel somatic mutations were identified in the PIK3R1 gene
that resulted in disruption of the important C2-iSH2 interaction between
PIK3R1 and PIK3CA (171834).

- Agammaglobulinemia 7, Autosomal Recessive

In a patient with autosomal recessive agammaglobulinemia-7 (AGM7;
615214), Conley et al. (2012) identified a homozygous truncating variant
in the PIK3R1 gene (W298X; 171833.0001). The mutation, which was
identified by exome sequencing, segregated with the disorder and was not
found in 1,000 in-house control alleles. Screening of the PIK3R1 gene in
55 additional patients with defects in B-cell development did not
identify any other mutations.

- SHORT Syndrome

By whole-exome sequencing in 2 unrelated patients with SHORT syndrome
(269880), Thauvin-Robinet et al. (2013) identified de novo mutations in
the PIK3R1 gene (171833.0002 and 171833.0003). Screening PIK3R1 for
mutations in 4 more affected individuals from 3 families revealed a
recurrent substitution (R649W; 171833.0004) in all 4 patients.
Sequencing PIK3R1 in a heterogeneous clinical group of 14 additional
unrelated individuals with severe insulin resistance and/or generalized
lipoatrophy associated with dysmorphic features and growth retardation,
who had not previously been diagnosed with SHORT syndrome and who were
negative for mutation in known lipodystrophy-associated genes,
identified 3 with mutations in PIK3R1, including 1 with the recurrent
R649W substitution and another with a 1-bp duplication at R649
(171833.0005). Thauvin-Robinet et al. (2013) noted that the c.1945C-T
(R649W) mutation occurred within the context of a CpG dinucleotide,
which might explain its recurrence.

In a 3-generation Norwegian family and in a German mother and son with
SHORT syndrome, Chudasama et al. (2013) identified heterozygosity for
the R649W missense mutation in the PIK3R1 gene. Haplotype analysis
showed that the mutations resided on different backgrounds in the 2
families, indicating that they stemmed from 2 independent mutational
events.

Dyment et al. (2013) performed whole-exome sequencing in a girl with
SHORT syndrome and her unaffected parents and identified a frameshift
mutation in the PIK3R1 gene (171833.0006) that segregated with disease.
Analysis of PIK3R1 in 3 more SHORT probands revealed the presence of the
R649W mutation in an affected mother and 2 sons from an English family
and in another patient. A PIK3R1 nonsense mutation was identified in the
third patient.

ANIMAL MODEL

Phosphoinositide 3-kinase (PI3K) activation is implicated in many
responses, including fibroblast growth, transformation, survival, and
chemotaxis. Although PI3K is activated by several agents that stimulate
T and B cells, the role of PI3K in lymphocyte function remained to be
clarified. Fruman et al. (1999) disrupted the mouse gene encoding the
PI3K adaptor subunit p85-alpha and its splice variants p55-alpha and
p50-alpha. Most mice homozygous for disruption for all 3 variants died
within days after birth. Lymphocyte development and function were
studied with the use of the RAG2-deficient blastocyst complementation
system. Chimeric mice had reduced numbers of peripheral mature B cells
and decreased serum immunoglobulin. The B cells that developed had
diminished proliferative responses to antibody to immunoglobulin M,
antibody to CD40, and lipopolysaccharide stimulation, as well as
decreased survival after incubation with interleukin-4. In contrast,
T-cell development and proliferation were normal. This phenotype was
similar to defects observed in mice lacking the tyrosine kinase Btk and
in patients with Bruton X-linked agammaglobulinemia (300300).

Suzuki et al. (1999) found that mice with a targeted gene disruption of
p85-alpha had impaired B-cell development at the pro-B cell stage,
reduced numbers of mature B cells and peritoneal CD5+ Ly-1 B cells,
reduced B-cell proliferative responses, and no T cell-independent
antibody production. These phenotypes were nearly identical to those of
the mutant X-linked immunodeficiency (xid) mouse and of mice in whom the
Btk gene has been disrupted. These results provided evidence that
p85-alpha is functionally linked to the Btk pathway in antigen
receptor-mediated signal transduction and is pivotal in B-cell
development and functions.

Terauchi et al. (1999) reported that Pik3r1 -/- mice show increased
insulin sensitivity and hypoglycemia due to increased glucose transport
in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity
associated with insulin receptor substrates was mediated by full-length
p85-alpha in wildtype mice, but by the p50-alpha alternative splicing
isoform of the same gene in Pik3r1 -/- mice. This isoform switch was
associated with an increase in insulin-induced generation of
phosphatidylinositol(3,4,5)triphosphate in Pik3r1 -/- adipocytes and
facilitation of Glut4 (138190) translocation from the low density
microsome fraction to the plasma membrane. This mechanism seemed to be
responsible for the phenotype of the homozygous deficient mice, namely
increased glucose transport and hypoglycemia. This work provided the
first direct evidence that PI3K and its regulatory subunits have a role
in glucose homeostasis in vivo.

Taniguchi et al. (2006) found that mice with a liver-specific deletion
of Pik3r1 showed increased hepatic and peripheral insulin sensitivity.
Pik3r1 ablation resulted in improved Akt activation, in part, because of
decreased activity of the (3,4,5)-trisphosphate phosphatase Pten
(601728). The authors concluded that Pik3r1 is a critical modulator of
insulin sensitivity not only because of its effect on PI3K activation,
but also as a regulator of PTEN activity.

Fukao et al. (2002) found that mice lacking p85-alpha were severely
deficient in gastrointestinal and peritoneal mast cells, whereas dermal
mast cells were present in the skin. The p85-alpha -/- mice were
susceptible to acute septic peritonitis. However, they were also
susceptible to systemic anaphylaxis, reflecting the absence of
peritoneal mast cells but the presence of mast cells at other anatomic
sites. Reconstitution of the mutant mice with bone marrow-derived mast
cells (BMMCs) restored antibacterial immunity but not immunity to an
intestinal nematode. Treatment of the BMMCs with Th2 lymphocyte-derived
cytokines, i.e. IL4 (147780) and IL10 (124092), induced immunity to the
parasitic worm, probably because mesenteric lymph node cells from the
p85-alpha -/- mice produced reduced amounts of these cytokines. Fukao et
al. (2002) concluded that PI3K plays an essential role in the
development and induction of mast cells in normal and pathogenic immune
responses.

Fukao et al. (2002) found that Pik3r1-deficient mice showed enhanced
Th1-type responses after Leishmania major infection. Normal splenic
dendritic cells (DCs) responded to IL12 (see 161561) production-inducing
stimuli with concomitant Pi3k activation. Splenic DCs from mutant mice
or normal DCs treated with a Pi3k inhibitor showed increased IL12
production and reduced Th2 cytokine production. Because Pi3k inhibition
and Pik3r1 deficiency resulted in enhanced IL12 production, Fukao et al.
(2002) proposed that Pi3k is a negative regulator of IL12 production and
that Pi3k inhibition may prevent potential immunopathologic effects of
strong Th1 responses resulting from excessive IL12 production.

Oak et al. (2006) crossed mice with a floxed Pik3r1 allele and a null
Pik3r2 allele with Lck (153390)-Cre transgenic mice to generate a strain
in which class IA Pi3k expression and function were essentially
abrogated in T cells beginning at the double-negative stage.
Histopathologic analysis of these mice showed development of
organ-specific autoimmunity resembling Sjogren syndrome (SS; 270150). By
3 to 8 months of age, mutant mice developed corneal opacity and eye
lesions due to irritation and constant scratching. Mutant mice showed
marked lymphocytic infiltration of lacrimal glands and serum antinuclear
and anti-Ssa (SSA1; 109092) antibodies, but no kidney pathology.
Cd4-positive T cells, which were the predominant infiltrating cells in
lacrimal glands of mutant mice, exhibited aberrant differentiation in
vitro. Oak et al. (2006) concluded that impaired class IA PI3K signaling
in T cells can lead to organ-specific autoimmunity, and they proposed
that class IA Pi3k-deficient mice manifest the cardinal features of
human primary SS.

*FIELD* AV
.0001
AGAMMAGLOBULINEMIA 7, AUTOSOMAL RECESSIVE (1 family)
PIK3R1, TRP298TER

In a 19-year-old girl with agammaglobulinemia-7 (AGM7; 615214) and a
severe defect in early B-cell development, Conley et al. (2012)
identified a homozygous G-to-A transition in exon 6 of the PIK3R1 gene,
resulting in a trp298-to-ter (W298X) substitution in the Rac binding
domain. The patient was from a consanguineous family of Chinese/Peruvian
descent and had previously been reported by de la Morena et al. (1995)
as having an autosomal recessive immunodeficiency reminiscent of Bruton
agammaglobulinemia (300755). Each unaffected parent was heterozygous for
the mutation, which was found by whole-exome sequencing and was not
present in 1,000 in-house control alleles. The mutation resulted in
absence of p85 expression, but normal p55 and p50 expression. The
patient presented at 3.5 months of age with pneumonia and
gastroenteritis. Laboratory studies showed panhypogammaglobulinemia,
neutropenia, and decreased NK cells. T cells were essentially normal. As
a teenager, she developed erythema nodosum, juvenile idiopathic
arthritis, recurrent Campylobacter bacteremia, and inflammatory bowel
disease, suggesting disordered cytokine production. The family history
was positive for 2 older brothers and 2 maternal uncles who died of
acute infections between 9 and 18 months of age. Flow cytometric
analysis showed that the patient had near absence of B cells in
peripheral blood, and bone marrow aspiration showed normal cellularity
with almost complete absence of B lineage cells. However, there were
normal percentages of very early CD34+,CD19- B-cell precursors. The
patient had no p85 in T cells, neutrophils, or dendritic cells. There
was decreased expression of p110 (171834) in patient immune cells,
indicating that the N-terminal end of p85 contributes to binding and
stabilization of p110. Overall, the findings suggested that mutations in
the N-terminal region of p85 can result in failure of B-cell development
at a very early stage, even earlier than in mouse models. Screening of
the PIK3R1 gene in 55 additional patients with defects in B-cell
development did not identify any other mutations.

.0002
SHORT SYNDROME
PIK3R1, ILE539DEL

In a 7-year-old boy with SHORT syndrome (269880), Thauvin-Robinet et al.
(2013) identified heterozygosity for a de novo 3-bp deletion
(c.1615_1617delATT) at chr5:67,591,018 (GRCh37) in the PIK3R1 gene,
resulting in deletion of ile539 in the inter-Src homology 2 (iSH2)
domain. The mutation was not present in his unaffected parents and was
not found in approximately 6,500 exomes in the NHLBI Exome Variant
Server, dbSNP137, or the 1000 Genomes Project. Functional studies on
patient fibroblasts revealed a 70 to 90% reduction in the effect of
insulin on AKT (see 164730) activation, glycogen synthesis, and glucose
uptake, indicating severe insulin resistance for both proximal and
distal PI3K-dependent signaling.

.0003
SHORT SYNDROME
PIK3R1, GLU489LYS

In a 7-year-old boy with SHORT syndrome (269880), Thauvin-Robinet et al.
(2013) identified heterozygosity for a de novo c.1465G-A transition at
chr5:67,590,403 (GRCh37) in the PIK3R1 gene, resulting in a
glu489-to-lys (E489K) substitution at a highly conserved residue in the
inter-Src homology 2 (iSH2) domain. The mutation was not present in his
unaffected parents and was not found in approximately 6,500 exomes in
the NHLBI Exome Variant Server, dbSNP137, or the 1000 Genomes Project.
Functional studies on patient fibroblasts revealed a 70 to 90% reduction
in the effect of insulin on AKT (see 164730) activation, glycogen
synthesis, and glucose uptake, indicating severe insulin resistance for
both proximal and distal PI3K-dependent signaling.

.0004
SHORT SYNDROME
PIK3R1, ARG649TRP

In 5 patients from 4 families with SHORT syndrome (269880), including a
patient previously reported by Bonnel et al. (2000), Thauvin-Robinet et
al. (2013) identified heterozygosity for a c.1945C-T transition at
chr5:67,592,129 (GRCh37) in the PIK3R1 gene, resulting in an
arg649-to-trp (R649W) substitution at a highly conserved residue in the
cSH2 domain. In the 1 family for which parental DNA was available, the
mutation was shown to be de novo. Thauvin-Robinet et al. (2013) noted
that the c.1945C-T mutation occurred within the context of a CpG
dinucleotide, which might explain its recurrence.

In affected members of a 3-generation Norwegian family with SHORT
syndrome, originally described by Aarskog et al. (1983), and a German
mother and son with SHORT syndrome, originally reported by Koenig et al.
(2003), Chudasama et al. (2013) identified heterozygosity for the R649W
missense mutation in the PIK3R1 gene. The mutation was not found in 340
Norwegian controls. Haplotype analysis showed that the mutations resided
on different backgrounds in the 2 families, indicating that they stemmed
from 2 independent mutational events. Analysis of patient fibroblasts
and reconstituted Pik3r1-knockout preadipocytes demonstrated impaired
interaction between p85-alpha and IRS1 (147545) and reduced AKT (see
164730)-mediated insulin signaling.

In a mother and 2 sons from an English family with SHORT syndrome,
originally reported by Bankier et al. (1995) and restudied by Reardon
and Temple (2008), and in an unrelated male patient, Dyment et al.
(2013) identified heterozygosity for the R649W mutation in the PIK3R1
gene.

.0005
SHORT SYNDROME
PIK3R1, 1-BP DUP, 1943T

In a 60-year-old woman with severe insulin resistance, generalized
lipoatrophy, and facial dysmorphism consistent with SHORT syndrome
(269880), Thauvin-Robinet et al. (2013) identified heterozygosity for a
1-bp duplication (c.1943dupT) in the PIK3R1 gene, causing a frameshift
predicted to result in a premature termination codon (Arg649ProfsTer5).

.0006
SHORT SYNDROME
PIK3R1, 1-BP INS, 1906C

In a 2-year-old girl with SHORT syndrome (269880), Dyment et al. (2013)
identified heterozygosity for a de novo 1-bp insertion (c.1906_1907insC)
in exon 14 of the PIK3R1 gene, causing a frameshift predicted to
generate a premature termination codon (Asn636ThrfsTer18). The mutation
was not found in her unaffected parents. Functional analysis of patient
lymphoblastoid cells showed decreased phosphorylation of the downstream
S6 target of the PI3K-AKT (see 164730)-mTOR (601231) pathway.

*FIELD* RF
1. Aarskog, D.; Ose, L.; Pande, H.; Eide, N.: Autosomal dominant
partial lipodystrophy associated with Rieger anomaly, short stature,
and insulinopenic diabetes. Am. J. Med. Genet. 15: 29-38, 1983.

2. Almind, K.; Delahaye, L.; Hansen, T.; Van Obberghen, E.; Pedersen,
O.; Kahn, C. R.: Characterization of the Met326Ile variant of phosphatidylinositol
3-kinase p85-alpha. Proc. Nat. Acad. Sci. 99: 2124-2128, 2002.

3. Bankier, A.; Keith, C. G.; Temple, I. K.: Absent iris stroma,
narrow body build and small facial bones: a new association or variant
of SHORT syndrome? Clin. Dysmorph. 4: 304-312, 1995.

4. Bonnel, S.; Dureau, P.; LeMerrer, M.; Dufier, J. L.: SHORT syndrome:
a case with high hyperopia and astigmatism. Ophthal. Genet. 21:
235-238, 2000.

5. Cancer Genome Atlas Research Network: Comprehensive genomic
characterization defines human glioblastoma genes and core pathways. Nature 455:
1061-1068, 2008. Note: Erratum: Nature 494: 506 only, 2013.

6. Cannizzaro, L. A.; Skolnik, E. Y.; Margolis, B.; Croce, C. M.;
Schlesinger, J.; Huebner, K.: The human gene encoding phosphatidylinositol
3-kinase associated p85-alpha is at chromosome region 5q12-13. Cancer
Res. 51: 3818-3820, 1991.

7. 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.; Njolstad, P. R.: SHORT syndrome with
partial lipodystrophy due to impaired phosphatidylinositol 3 kinase
signaling. Am. J. Hum. Genet. 93: 150-157, 2013.

8. Conley, M. E.; Dobbs, A. K.; Quintana, A. M.; Bosompem, A.; Wang,
Y.-D.; Coustan-Smith, E.; Smith, A. M.; Perez, E. E.; Murray, P. J.
: Agammaglobulinemia and absent B lineage cells in a patient lacking
the p85-alpha subunit of PI3K. J. Exp. Med. 209: 463-470, 2012.

9. de la Morena, M.; Haire, R. N.; Ohta, Y.; Nelson, R. P.; Litman,
R. T.; Day, N. K.; Good, R. A.; Litman, G. W.: Predominance of sterile
immunoglobulin transcripts in a female phenotypically resembling Bruton's
agammaglobulinemia. Europ. J. Immun. 25: 809-815, 1995.

10. 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.; Innes, A. M.: Mutations in
PIK3R1 cause SHORT syndrome. Am. J. Hum. Genet. 93: 158-166, 2013.

11. Fruman, D. A.; Snapper, S. B.; Yballe, C. M.; Davidson, L.; Yu,
J. Y.; Alt, F. W.; Cantley, L. C.: Impaired B cell development and
proliferation in absence of phosphoinositide 3-kinase p85-alpha. Science 283:
393-397, 1999.

12. Fukao, T.; Tanabe, M.; Terauchi, Y.; Ota, T.; Matsuda, S.; Asano,
T.; Kadowaki, T.; Takeuchi, T.; Koyasu, S.: PI3K-mediated negative
feedback regulation of IL-12 production in DCs. Nature Immun. 3:
875-881, 2002.

13. Fukao, T.; Yamada, T.; Tanabe, M.; Terauchi, Y.; Ota, T.; Takayama,
T.; Asano, T.; Takeuchi, T.; Kadowaki, T.; Hata, J.; Koyasu, S.:
Selective loss of gastrointestinal mast cells and impaired immunity
in PI3K-deficient mice. Nature Immun. 3: 295-304, 2002.

14. He, Y.; Nakao, H.; Tan, S.-L.; Polyak, S. J.; Neddermann, P.;
Vijaysri, S.; Jacobs, B. L.; Katze, M. G.: Subversion of cell signaling
pathways by hepatitis C virus nonstructural 5A protein via interaction
with Grb2 and P85 phosphatidylinositol 3-kinase. J. Virol. 76: 9207-9217,
2002.

15. Hoyle, J.; Yulug, I. G.; Egan, S. E.; Fisher, E. M. C.: The gene
that encodes the phosphatidylinositol-3 kinase regulatory subunit
(p85-alpha) maps to chromosome 13 in the mouse. Genomics 24: 400-402,
1994.

16. Koenig, R.; Brendel, L.; Fuchs, S.: SHORT syndrome. Clin. Dysmorph. 12:
45-49, 2003.

17. Miled, N.; Yan, Y.; Hon, W.-C.; Perisic, O.; Zvelebil, M.; Inbar,
Y.; Schneidman-Duhovny, D.; Wolfson, H. J.; Backer, J. M.; Williams,
R. L.: Mechanism of two classes of cancer mutations in the phosphoinositide
3-kinase catalytic subunit. Science 317: 239-242, 2007.

18. Niswender, K. D.; Morton, G. J.; Stearns, W. H.; Rhodes, C. J.;
Myers, M. G., Jr.; Schwartz, M. W.: Key enzyme in leptin-induced
anorexia. Nature 413: 794-795, 2001.

19. Oak, J. S.; Deane, J. A.; Kharas, M. G.; Luo, J.; Lane, T. E.;
Cantley, L. C.; Fruman, D. A.: Sjogren's syndrome-like disease in
mice with T cells lacking class 1A phosphoinositide-3-kinase. Proc.
Nat. Acad. Sci. 103: 16882-16887, 2006. Note: Erratum: Proc. Nat.
Acad. Sci. 106: 10871 only, 2009.

20. Otsu, M.; Hiles, I.; Gout, I.; Fry, M. J.; Ruiz-Larrea, F.; Panayotou,
G.; Thompson, A.; Dhand, R.; Hsuan, J.; Totty, N.; Smith, A. D.; Morgan,
S. J.; Courtneidge, S. A.; Parker, P. J.; Waterfield, M. D.: Characterization
of two 85 kd proteins that associate with receptor tyrosine kinases,
middle-T/pp60(c-src) complexes, and PI3-kinase. Cell 65: 91-104,
1991.

21. Park, S. W.; Zhou, Y.; Lee, J.; Lu, A.; Sun, C.; Chung, J.; Ueki,
K.; Ozcan, U.: The regulatory subunits of PI3K, p85-alpha and p85-beta,
interact with XBP-1 and increase its nuclear translocation. Nature
Med. 16: 429-437, 2010.

22. Reardon, W.; Temple, I. K.: Nephrocalcinosis and disordered calcium
metabolism in two children with SHORT syndrome. Am. J. Med. Genet. 146A:
1296-1298, 2008.

23. Salazar, L.; Kashiwada, T.; Krejci, P.; Muchowski, P.; Donoghue,
D.; Wilcox, W. R.; Thompson, L. M.: A novel interaction between fibroblast
growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase:
activation-dependent regulation of ERK by p85 in multiple myeloma
cells. Hum. Molec. Genet. 18: 1951-1961, 2009.

24. Simoncini, T.; Hafezi-Moghadam, A.; Brazil, D. P.; Ley, K.; Chin,
W. W.; Liao, J. K.: Interaction of oestrogen receptor with the regulatory
subunit of phosphatidylinositol-3-OH kinase. Nature 407: 538-541,
2000.

25. Skolnik, E. Y.; Margolis, B.; Mohammadi, M.; Lowenstein, E.; Fischer,
R.; Drepps, A.; Ullrich, A.; Schlessinger, J.: Cloning of PI3-kinase
associated p85 utilizing a novel method for expression/cloning of
target proteins for receptor tyrosine kinases. Cell 65: 83-90, 1991.

26. Suzuki, H.; Terauchi, Y.; Fujiwara, M.; Aizawa, S.; Yazaki, Y.;
Kadowaki, T.; Koyasu, S.: Xid-like immunodeficiency in mice with
disruption of the p85-alpha subunit of phosphoinositide 3-kinase. Science 283:
390-392, 1999.

27. Taniguchi, C. M.; Tran, T. T.; Kondo, T.; Luo, J.; Ueki, K.; Cantley,
L. C.; Kahn, C. R.: Phosphoinositide 3-kinase regulatory subunit
p85-alpha suppresses insulin action via positive regulation of PTEN. Proc.
Nat. Acad. Sci. 103: 12093-12097, 2006.

28. Terauchi, Y.; Tsuji, Y.; Satoh, S.; Minoura, H.; Murakami, K.;
Okuno, A.; Inukai, K.; Asano, T.; Kaburagi, Y.; Ueki, K.; Nakajima,
H.; Hanafusa, T.; and 18 others: Increased insulin sensitivity
and hypoglycaemia in mice lacking the p85-alpha subunit of phosphoinositide
3-kinase. Nature Genet. 21: 230-235, 1999.

29. Thauvin-Robinet, C.; Auclair, M.; Duplomb, L.; Caron-Debarle,
M.; Avila, M.; St-Onge, J.; Le Merrer, M.; Le Luyer, B.; Heron, D.;
Mathieu-Dramard, M.; Bitoun, P.; Petit, J.-M.; and 16 others: PIK3R1
mutations cause syndromic insulin resistance with lipoatrophy. Am.
J. Hum. Genet. 93: 141-149, 2013.

30. Volinia, S.; Patracchini, P.; Otsu, M.; Hiles, I.; Gout, I.; Calzolari,
E.; Bernardi, F.; Rooke, L.; Waterfield, M. D.: Chromosomal localization
of human p85-alpha, a subunit of phosphatidylinositol 3-kinase, and
its homologue p85-beta. Oncogene 7: 789-793, 1992.

31. Winnay, J. N.; Boucher, J.; Mori, M. A.; Ueki, K.; Kahn, C. R.
: A regulatory subunit of phosphoinositide 3-kinase increases the
nuclear accumulation of X-box-binding protein-1 to modulate the unfolded
protein response. Nature Med. 16: 438-445, 2010.

*FIELD* CN
Marla J. F. O'Neill - updated: 8/23/2013
Cassandra L. Kniffin - updated: 4/30/2013
Patricia A. Hartz - updated: 6/7/2010
George E. Tiller - updated: 2/23/2010
Ada Hamosh - updated: 11/26/2008
Ada Hamosh - updated: 7/31/2007
Paul J. Converse - updated: 1/16/2007
Patricia A. Hartz - updated: 9/15/2006
Patricia A. Hartz - updated: 12/17/2002
Paul J. Converse - updated: 9/5/2002
Paul J. Converse - updated: 4/29/2002
Victor A. McKusick - updated: 3/5/2002
Ada Hamosh - updated: 10/18/2000
Victor A. McKusick - updated: 3/3/1999
Victor A. McKusick - updated: 1/14/1999

*FIELD* CD
Victor A. McKusick: 7/1/1992

*FIELD* ED
carol: 11/12/2013
alopez: 8/23/2013
carol: 5/1/2013
ckniffin: 5/1/2013
ckniffin: 4/30/2013
terry: 6/6/2012
mgross: 6/10/2010
terry: 6/7/2010
wwang: 3/2/2010
terry: 2/23/2010
alopez: 12/5/2008
terry: 11/26/2008
mgross: 8/13/2007
alopez: 8/3/2007
terry: 7/31/2007
mgross: 1/16/2007
wwang: 9/22/2006
terry: 9/15/2006
wwang: 5/20/2005
mgross: 1/6/2003
terry: 12/17/2002
alopez: 9/20/2002
mgross: 9/5/2002
mgross: 4/29/2002
mgross: 3/11/2002
terry: 3/5/2002
cwells: 10/24/2001
terry: 10/23/2001
carol: 9/13/2001
alopez: 10/18/2000
carol: 3/9/1999
terry: 3/3/1999
alopez: 1/14/1999
joanna: 1/14/1999
alopez: 10/19/1998
psherman: 6/29/1998
alopez: 6/2/1997
jamie: 11/8/1996
carol: 1/9/1995
terry: 12/20/1994
carol: 10/15/1992
carol: 7/1/1992

MIM 269880
*RECORD*
*FIELD* NO
269880
*FIELD* TI
#269880 SHORT SYNDROME
;;SHORT STATURE, HYPEREXTENSIBILITY, HERNIA, OCULAR DEPRESSION, RIEGER
read moreANOMALY, AND TEETHING DELAY;;
LIPODYSTROPHY, PARTIAL, WITH RIEGER ANOMALY AND SHORT STATURE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that SHORT
syndrome can be caused by heterozygous mutation in the PIK3R1 gene
(171833) on chromosome 5q31.

DESCRIPTION

'Short,' the mnemonic designation for this syndrome, is an acronym: S =
stature; H = hyperextensibility of joints or hernia (inguinal) or both;
O = ocular depression; R = Rieger anomaly; T = teething delay. The name
was given by Gorlin (1975), who described the syndrome in 2 brothers.

Dyment et al. (2013) noted that the features listed in the acronym for
SHORT syndrome do not capture the full range of the clinical phenotype,
which can include a recognizable facial gestalt consisting of triangular
facies, lack of facial fat, and hypoplastic nasal alae with overhanging
columella, as well as near-universal partial lipodystrophy, insulin
resistance, nephrocalcinosis, and hearing deficits. Notably, both
developmental milestones and cognition are normal for individuals with
SHORT syndrome.

CLINICAL FEATURES

Sensenbrenner et al. (1975) described a 6-year-old girl with Rieger
anomaly, short stature, and partial lipodystrophy of the face and upper
limbs. She also had delayed dental eruption, delayed bone age, and
hyperextensibility of the joints. Gorlin (1975) reported the same
condition in 2 brothers, aged 11 and 4 years. Gorlin (1975) suggested
autosomal recessive inheritance because of possible consanguinity in 1
set of parents.

Aarskog et al. (1983) described a family from the Lofoten Islands of
Norway in which 4 persons in 3 generations had nonprogressive
lipodystrophy present from infancy affecting primarily the face and
buttocks. Affected persons also had the Rieger anomaly, midface
hypoplasia, retarded bone age, and hypotrichosis. Of 2 sisters, 1 had
glucose intolerance at age 55 years, and the other had insulinopenic
diabetes mellitus at age 39 years. Aarskog et al. (1983) suggested that
the disorder in their family was distinct from SHORT syndrome because of
the absence of joint hypermobility and less extensive lipodystrophy in
their patients.

Toriello et al. (1985) reported a patient with SHORT syndrome
characterized by lipoatrophy, delayed speech development, clinodactyly,
and short stature. The boy also had deafness, which the authors noted
had not previously been reported in the SHORT syndrome. Stratton et al.
(1989) reported a brother and sister with short stature, delayed bone
age, developmental delay, congenital hip dislocation, and iridocorneal
abnormalities with onset of glaucoma at or soon after birth. Many of the
features resembled those of the SHORT syndrome, but triangular face and
lipoatrophy were not present.

Schwingshandl et al. (1993) described a girl with most of the typical
features of SHORT syndrome who, at age 14 years, developed nonketotic
hyperglycemia. At the age of 16.5 years, diabetes mellitus with severe
insulin resistance was diagnosed. From an early age, the patient had had
partial lipodystrophy, as well as megalocornea and a peculiar
progeria-like face. At age 6 years, bilateral sensorineural hearing loss
was detected.

Verge et al. (1994) also described insulin-resistant diabetes in SHORT
syndrome. They suggested that defective function of insulin receptors in
adipose tissue may explain the paucity of fat storage in this disorder.

Bankier et al. (1995) described the association of triangular face,
deep-set eyes, micrognathia, small facial bones, and narrow body build
in 3 members of an English family and in an unrelated Australian girl.
Absence of iridal stroma was found in the Australian girl and in the
English mother; the son of the English woman also had sensorineural
deafness. Bankier et al. (1995) noted that the symptom complex was
similar to the SHORT syndrome, although all 4 patients had low-normal
height and did not manifest joint hyperextensibility. Reardon and Temple
(2008) reported that 1 of the female patients reported by Bankier et al.
(1995) developed nephrocalcinosis as an adult. The affected son of this
patient, who was diagnosed with SHORT syndrome in the neonatal period,
had nephrocalcinosis and increased serum and urinary calcium at 2 months
of age.

Sorge et al. (1996) described a 9-year-old Italian boy with short
stature, partial lipodystrophy, minor facial anomalies, mild
hyperextensibility of joints, ocular depression, Rieger anomaly, and
delay in speech development and dental eruption. Because the father and
sister showed a striking similarity to the propositus, Sorge et al.
(1996) suggested an autosomal dominant gene with variable expression in
this family. The sister had bilateral and symmetrical lens opacities, a
feature that had not been reported previously in affected subjects or
their relatives. Sorge et al. (1996) suggested that the disorder
reported by Aarskog et al. (1983) was the same disorder.

Brodsky et al. (1996) added congenital glaucoma as a feature of the
SHORT syndrome. Their patient was a 9-year-old boy who had enlarged
cloudy corneas, Rieger anomaly, and elevated intraocular pressure at
birth. He also had bilateral sensorineural hearing loss, short stature,
and mild developmental delay. The face had a triangular configuration
with prominent forehead, deeply set eyes, thin nasal alae, and a
proportionately small middle and lower face. The face and chest showed
diminished subcutaneous fat, and the hands had thin, dry, wrinkled skin,
producing a progeroid appearance. A paternal uncle reportedly had a
similar appearance.

Koenig et al. (2003) described a mother and son with short stature,
progeroid facies, Rieger anomaly, teething delay, mild developmental
retardation, particularly speech delay, and a slight build with lack of
subcutaneous fat. Resistance to insulin was suggested by an oral glucose
tolerance test in the mother, whereas the test was normal in the son at
the age of 2 years. After reviewing the reported cases of SHORT
syndrome, Koenig et al. (2003) concluded that 5 familial cases in
different generations, equally affected male and female patients, and
male-to-male transmission support autosomal dominant inheritance,
possibly with germline mosaicism in the cases of affected sibs and
unaffected parents.

Reardon and Temple (2008) reported 3 patients, including a mother and
son previously reported by Bankier et al. (1995), with a clinical
diagnosis of SHORT syndrome who all developed nephrocalcinosis. Two of
the patients had nephrocalcinosis in infancy and also showed increased
serum and urinary calcium. Reardon and Temple (2008) postulated that
disordered calcium metabolism may be a previously unreported feature of
SHORT syndrome.

Reis et al. (2011) studied a 6-year-old Caucasian girl with a diagnosis
of SHORT syndrome, whose ocular features included Rieger anomaly,
congenital glaucoma, microcornea, and nystagmus. She had short stature,
poor weight gain, and macrocephaly, as well as hyperextensible joints,
delayed eruption of teeth, decreased subcutaneous fat in the upper trunk
and head, and dysmorphic facial features including prominent forehead,
sunken eyes, small chin, and hypoplastic nares. Her hearing was normal,
hands and feet were small with normal structure, and umbilicus was
described as 'a bit pouchy' with mildly increased skin. Brain MRI showed
normal structures.

CYTOGENETICS

In a mother with Rieger syndrome (180500) and polycystic ovaries (see
184700) and a son manifesting SHORT syndrome, Karadeniz et al. (2004)
identified a t(1;4)(q31.2;q25) translocation. Because Rieger syndrome
can be caused by mutation in the PITX2 gene (601542) on chromosome 4q25,
Karadeniz et al. (2004) suggested that the 2 syndromes may represent a
single condition reflecting variable expression of this gene.

In a 6-year-old Caucasian girl with the complete constellation of
features comprising SHORT syndrome, in whom screening of PITX2 showed
normal sequence and copy number, Reis et al. (2011) identified
heterozygosity for a 2.263-Mb deletion on chromosome 14q22.1-q22.2,
encompassing BMP4 (112262) and 13 other genes. The minimum deleted
interval was chr14:51,402,258-53,665,008 and the maximum interval was
chr14:51,400,039-53,667,259 (NCBI36). Quantitative PCR confirmed
deletion of 1 copy of BMP4 and the presence of both copies of the OTX2
gene (600037). The patient's mother, who had high myopia but otherwise
normal ocular and systemic features, showed no evidence of BMP4
deletion; the unaffected father was unavailable for testing. Reis et al.
(2011) suggested that SHORT syndrome might be a contiguous gene deletion
syndrome requiring deletion of 1 or more other genes in addition to
BMP4.

MOLECULAR GENETICS

By whole-exome sequencing in 2 unrelated patients with SHORT syndrome,
Thauvin-Robinet et al. (2013) identified de novo mutations in the PIK3R1
gene (171833.0002 and 171833.0003). Screening PIK3R1 for mutations in 4
more affected individuals from 3 families, including a patient
previously studied by Bonnel et al. (2000), revealed a recurrent
substitution (R649W; 171833.0004) in all 4 patients. Thauvin-Robinet et
al. (2013) then sequenced PIK3R1 in a heterogeneous clinical group of 14
additional unrelated individuals with severe insulin resistance and/or
generalized lipoatrophy associated with dysmorphic features and growth
retardation, who had not previously been diagnosed with SHORT syndrome
and who were negative for mutation in known lipodystrophy-associated
genes. Three of the 14 patients had mutations in PIK3R1, including 1
with the recurrent R649W substitution and another with a 1-bp
duplication at R649 (171833.0005).

In a 3-generation Norwegian family with SHORT syndrome originally
described by Aarskog et al. (1983), Chudasama et al. (2013) performed
whole-exome sequencing and identified a heterozygous missense mutation
in the PIK3R1 gene (R649W) that segregated with disease in the family
and was not found in 340 Norwegian controls. Sanger sequencing of DNA
from a German mother and son with SHORT syndrome, originally reported by
Koenig et al. (2003), revealed that they were also heterozygous for the
PIK3R1 R649W mutation. Haplotype analysis showed that the mutations
resided on different backgrounds in the 2 families, indicating that they
stemmed from 2 independent mutational events.

Dyment et al. (2013) performed whole-exome sequencing in a girl with
SHORT syndrome and her unaffected parents and identified a frameshift
mutation in the PIK3R1 gene (171833.0006) that segregated with disease.
Analysis of PIK3R1 in 3 more SHORT probands revealed the R649W mutation
in an affected mother and 2 sons from an English family, originally
reported by Bankier et al. (1995) and restudied by Reardon and Temple
(2008), and in another patient. A PIK3R1 nonsense mutation was
identified in the third patient. In a 10-year-old boy diagnosed with
SHORT syndrome, previously studied by Reardon and Temple (2008), no
disease-causing variant was detected by whole-exome sequencing; coverage
for PIK3R1 was excellent, and there was no evidence of any structural
variant. Dyment et al. (2013) noted that although the boy showed several
core features of SHORT syndrome, his facial features appeared to be
distinct from those of mutation-positive individuals. The authors
suggested that SHORT syndrome is a highly specific diagnosis that relies
heavily on the facial gestalt.

*FIELD* RF
1. Aarskog, D.; Ose, L.; Pande, H.; Eide, N.: Autosomal dominant
partial lipodystrophy associated with Rieger anomaly, short stature,
and insulinopenic diabetes. Am. J. Med. Genet. 15: 29-38, 1983.

2. Bankier, A.; Keith, C. G.; Temple, I. K.: Absent iris stroma,
narrow body build and small facial bones: a new association or variant
of SHORT syndrome? Clin. Dysmorph. 4: 304-312, 1995.

3. Bonnel, S.; Dureau, P.; LeMerrer, M.; Dufier, J. L.: SHORT syndrome:
a case with high hyperopia and astigmatism. Ophthal. Genet. 21:
235-238, 2000.

4. Brodsky, M. C.; Whiteside-Michel, J.; Merin, L. M.: Rieger anomaly
and congenital glaucoma in the SHORT syndrome. Arch. Ophthal. 114:
1146-1147, 1996.

5. 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.; Njolstad, P. R.: SHORT syndrome with
partial lipodystrophy due to impaired phosphatidylinositol 3 kinase
signaling. Am. J. Hum. Genet. 93: 150-157, 2013.

6. 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.; Innes, A. M.: Mutations in
PIK3R1 cause SHORT syndrome. Am. J. Hum. Genet. 93: 158-166, 2013.

7. Gorlin, R. J.: A selected miscellany. Birth Defects Orig. Art.
Ser. XI(2): 46-48, 1975.

8. Karadeniz, N. N.; Kocak-Midillioglu, I.; Erdogan, D.; Bokesoy,
I.: Is SHORT syndrome another phenotypic variation of PITX2? Am.
J. Med. Genet. 130A: 406-409, 2004.

9. Koenig, R.; Brendel, L.; Fuchs, S.: SHORT syndrome. Clin. Dysmorph. 12:
45-49, 2003.

10. Reardon, W.; Temple, I. K.: Nephrocalcinosis and disordered calcium
metabolism in two children with SHORT syndrome. Am. J. Med. Genet. 146A:
1296-1298, 2008.

11. Reis, L. M.; Tyler, R. C.; Schilter, K. F.; Abdul-Rahman, O.;
Innis, J. W.; Kozel, B. A.; Schneider, A. S.; Bardakjian, T. M.; Lose,
E. J.; Martin, D. M.; Broeckel, U.; Semina, E. V.: BMP4 loss-of-function
mutations in developmental eye disorders including SHORT syndrome. Hum.
Genet. 130: 495-504, 2011.

12. Schwingshandl, J.; Mache, C. J.; Rath, K.; Borkenstein, M. H.
: SHORT syndrome and insulin resistance. Am. J. Med. Genet. 47:
907-909, 1993.

13. Sensenbrenner, J. A.; Hussels, I. E.; Levin, L. S.: A low birthweight
syndrome, ?Rieger syndrome. Birth Defects Orig. Art. Ser. XI(2):
423-426, 1975.

14. Sorge, G.; Ruggieri, M.; Polizzi, A.; Scuderi, A.; Di Pietro,
M.: SHORT syndrome: a new case with probable autosomal dominant inheritance. Am.
J. Med. Genet. 61: 178-181, 1996.

15. Stratton, R. F.; Parker, M. W.; McKeown, C. A.; Johnson, C. P.
: Sibs with growth deficiency, delayed bone age, congenital hip dislocation,
and iridocorneal abnormalities with glaucoma. Am. J. Med. Genet. 32:
330-332, 1989.

16. Thauvin-Robinet, C.; Auclair, M.; Duplomb, L.; Caron-Debarle,
M.; Avila, M.; St-Onge, J.; Le Merrer, M.; Le Luyer, B.; Heron, D.;
Mathieu-Dramard, M.; Bitoun, P.; Petit, J.-M.; and 16 others: PIK3R1
mutations cause syndromic insulin resistance with lipoatrophy. Am.
J. Hum. Genet. 93: 141-149, 2013.

17. Toriello, H. V.; Wakefield, S.; Komar, K.; Higgins, J. V.; Waterman,
D. F.: Report of a case and further delineation of the SHORT syndrome. Am.
J. Med. Genet. 22: 311-314, 1985.

18. Verge, C. F.; Donaghue, K. C.; Williams, P. F.; Cowell, C. T.;
Silink, M.: Insulin-resistant diabetes during growth hormone therapy
in a child with SHORT syndrome. Acta Pediat. 83: 786-788, 1994.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature;
Birth length less than 3rd percentile;
[Weight];
Birth weight less than 3rd percentile;
[Other];
Intrauterine growth retardation

HEAD AND NECK:
[Face];
Triangular face;
Chin dimple;
Micrognathia;
Prominent forehead;
[Ears];
Hearing loss, sensorineural;
Large ears;
[Eyes];
Deep-set eyes;
Rieger anomaly;
Telecanthus;
Glaucoma;
Megalocornea;
Cataracts;
Myopia;
[Nose];
Hypoplastic nasal alae;
Wide nasal bridge;
[Teeth];
Delayed dental eruption;
Hypodontia;
Malocclusion

GENITOURINARY:
[External genitalia, male];
Inguinal hernia

SKELETAL:
Joint laxity;
Delayed bone age;
[Limbs];
Large epiphyses;
Gracile diaphyses;
[Hands];
Clinodactyly

SKIN, NAILS, HAIR:
[Skin];
Dimples (chin, buttocks);
Thin, wrinkled skin

MUSCLE, SOFT TISSUE:
Lipoatrophy (lower face, upper limb, buttock)

NEUROLOGIC:
[Central nervous system];
Normal intelligence;
Speech delay

ENDOCRINE FEATURES:
Glucose intolerance;
Insulin resistant diabetes

IMMUNOLOGY:
Frequent illnesses

LABORATORY ABNORMALITIES:
Hyperglycemia

MISCELLANEOUS:
SHORT is an acronym for Short stature, Hyperextensibility of joints/hernia,
Ocular depression, Rieger anomaly, Teething delay

*FIELD* CN
Kelly A. Przylepa - revised: 4/2/2003

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 12/05/2008
joanna: 4/3/2003
joanna: 4/2/2003

*FIELD* CN
Marla J. F. O'Neill - updated: 8/23/2013
Marla J. F. O'Neill - updated: 11/11/2011
Cassandra L. Kniffin - updated: 6/16/2008
Marla J. F. O'Neill - updated: 1/4/2005
Siobhan M. Dolan - updated: 4/28/2004
Victor A. McKusick - updated: 2/25/1998
Iosif W. Lurie - updated: 1/14/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 08/26/2013
alopez: 8/23/2013
carol: 11/15/2011
carol: 11/14/2011
terry: 11/11/2011
wwang: 6/30/2008
ckniffin: 6/16/2008
carol: 1/6/2005
terry: 1/4/2005
carol: 5/14/2004
ckniffin: 5/11/2004
carol: 4/29/2004
terry: 4/28/2004
dholmes: 4/1/1998
alopez: 3/20/1998
terry: 2/25/1998
carol: 1/14/1997
mark: 2/27/1996
terry: 2/20/1996
mimadm: 3/12/1994
carol: 11/9/1993
supermim: 3/17/1992
carol: 3/2/1992
carol: 2/10/1992
carol: 10/4/1990

MIM 615214
*RECORD*
*FIELD* NO
615214
*FIELD* TI
#615214 AGAMMAGLOBULINEMIA 7, AUTOSOMAL RECESSIVE; AGM7
;;AGAMMAGLOBULINEMIA, AUTOSOMAL RECESSIVE, DUE TO PIK3R1 DEFECT
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
autosomal recessive agammaglobulinemia-7 (AGM7) is caused by homozygous
mutation in the PIK3R1 gene (171833) on chromosome 5q13. One such family
has been reported.

For a general phenotypic description and a discussion of genetic
heterogeneity of autosomal agammaglobulinemia, see AGM1 (601495).

CLINICAL FEATURES

De la Morena et al. (1995) reported a 6-month-old Hispanic girl of
Chinese and Peruvian Indian ancestry who presented at age 3.5 months
with interstitial pneumonia and gastroenteritis. Laboratory studies
showed agammaglobulinemia, neutropenia, and lack of mature B cells in
the peripheral blood and bone marrow. Lymph nodes showed lack of B
cells, plasma cells, and germinal center formation. T cells and T-cell
function were normal. Presence of CD10+ cells but absence of CD19+ cells
and a 10-fold decrease of mature V-D-J-C-mu transcripts suggested a
blockage at an earlier stage of B-cell development than that observed in
the X-linked form of agammaglobulinemia (300755); genetic analysis
excluded a defect in the BTK gene (300300).

Conley et al. (2012) provided follow-up of the patient reported by de la
Morena et al. (1995), who was 19 years old and showed a severe defect in
very early B-cell development. As a teenager, she developed erythema
nodosum, juvenile idiopathic arthritis, and recurrent Campylobacter
bacteremia and inflammatory bowel disease, suggesting disordered
cytokine production. The family history was positive for 2 older
brothers and 2 maternal uncles who died of acute infections between 9
and 18 months of age.

INHERITANCE

The transmission pattern in the family with AGM7 reported by Conley et
al. (2012) was consistent with autosomal recessive inheritance.

MOLECULAR GENETICS

In a patient with agammaglobulinemia-7, Conley et al. (2012) identified
a homozygous truncating variant in the PIK3R1 (W298X; 171833.0001). The
mutation, which was identified by exome sequencing, segregated with the
disorder and was not found in 1,000 in-house control alleles. Screening
of the PIK3R1 gene in 55 additional patients with defects in B-cell
development did not identify any other mutations.

*FIELD* RF
1. Conley, M. E.; Dobbs, A. K.; Quintana, A. M.; Bosompem, A.; Wang,
Y.-D.; Coustan-Smith, E.; Smith, A. M.; Perez, E. E.; Murray, P. J.
: Agammaglobulinemia and absent B lineage cells in a patient lacking
the p85-alpha subunit of PI3K. J. Exp. Med. 209: 463-470, 2012.

2. de la Morena, M.; Haire, R. N.; Ohta, Y.; Nelson, R. P.; Litman,
R. T.; Day, N. K.; Good, R. A.; Litman, G. W.: Predominance of sterile
immunoglobulin transcripts in a female phenotypically resembling Bruton's
agammaglobulinemia. Europ. J. Immun. 25: 809-815, 1995.

*FIELD* CS
INHERITANCE:
Autosomal recessive

RESPIRATORY:
Respiratory infections, recurrent

ABDOMEN:
[Gastrointestinal];
Gastroenteritis, recurrent

IMMUNOLOGY:
Agammaglobulinemia;
Recurrent infections;
Neutropenia;
Arrest of B cell development at very early stage;
Decreased NK cells;
Normal T cells

MISCELLANEOUS:
Onset in infancy;
Early death may occur due to infection;
One consanguineous family has been reported (last curated May 2013)

MOLECULAR BASIS:
Caused by mutation in the phosphatidylinositol 3-kinase, regulatory
subunit 1 gene (PIK3R1, 171833.0001)

*FIELD* CD
Cassandra L. Kniffin: 5/1/2013

*FIELD* ED
joanna: 05/03/2013
ckniffin: 5/1/2013

*FIELD* CD
Cassandra L. Kniffin: 5/1/2013

*FIELD* ED
carol: 05/03/2013
carol: 5/1/2013
ckniffin: 5/1/2013