RBCC Red Blood Cell Collection

C3 (CPAMD1) [Confidence: high (present in two of the MS resources)]
Complement C3 (C3 and PZP-like alpha-2-macroglobulin domain-containing protein 1; Complement C3 beta chain; Complement C3 alpha chain; C3a anaphylatoxin; Acylation stimulating protein; ASP; C3adesArg; Complement C3b alpha' chain; Complement C3c alpha' chain fragment 1; Complement C3dg fragment; Complement C3g fragment; Complement C3d fragment; Complement C3f fragment; Complement C3c alpha' chain fragment 2; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00164623
IPI00164623 Complement C3b Complement C3b membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 13 extracellular binds RBC n/a expected molecular weight found in band at molecular weight and > 188 kDa

UniProt P01024
ID CO3_HUMAN Reviewed; 1663 AA.
AC P01024; A7E236;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 12-DEC-2006, sequence version 2.
DT 22-JAN-2014, entry version 179.
DE RecName: Full=Complement C3;
DE AltName: Full=C3 and PZP-like alpha-2-macroglobulin domain-containing protein 1;
DE Contains:
DE RecName: Full=Complement C3 beta chain;
DE Contains:
DE RecName: Full=Complement C3 alpha chain;
DE Contains:
DE RecName: Full=C3a anaphylatoxin;
DE Contains:
DE RecName: Full=Acylation stimulating protein;
DE Short=ASP;
DE AltName: Full=C3adesArg;
DE Contains:
DE RecName: Full=Complement C3b alpha' chain;
DE Contains:
DE RecName: Full=Complement C3c alpha' chain fragment 1;
DE Contains:
DE RecName: Full=Complement C3dg fragment;
DE Contains:
DE RecName: Full=Complement C3g fragment;
DE Contains:
DE RecName: Full=Complement C3d fragment;
DE Contains:
DE RecName: Full=Complement C3f fragment;
DE Contains:
DE RecName: Full=Complement C3c alpha' chain fragment 2;
DE Flags: Precursor;
GN Name=C3; Synonyms=CPAMD1;
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], AND VARIANT LEU-314.
RX PubMed=2579379; DOI=10.1073/pnas.82.3.708;
RA de Bruijn M.H.L., Fey G.H.;
RT "Human complement component C3: cDNA coding sequence and derived
RT primary structure.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:708-712(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-102; LEU-314;
RP LYS-863; ASP-1224 AND THR-1367.
RG SeattleSNPs variation discovery resource;
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [5]
RP PROTEIN SEQUENCE OF N-TERMINUS, MASS SPECTROMETRY, AND FUNCTION OF
RP ACYLATION STIMULATING PROTEIN.
RX PubMed=8376604; DOI=10.1172/JCI116733;
RA Baldo A., Sniderman A.D., St-Luce S., Avramoglu R.K., Maslowska M.,
RA Hoang B., Monge J.C., Bell A., Mulay S., Cianflone K.;
RT "The adipsin-acylation stimulating protein system and regulation of
RT intracellular triglyceride synthesis.";
RL J. Clin. Invest. 92:1543-1547(1993).
RN [6]
RP PROTEIN SEQUENCE OF 672-748.
RX PubMed=1238393;
RA Hugli T.E.;
RT "Human anaphylatoxin (C3a) from the third component of complement.
RT Primary structure.";
RL J. Biol. Chem. 250:8293-8301(1975).
RN [7]
RP PROTEIN SEQUENCE OF 955-966, AND SUBUNIT.
RC TISSUE=Serum;
RX PubMed=7539791; DOI=10.1074/jbc.270.23.13645;
RA Oxvig C., Haaning J., Kristensen L., Wagner J.M., Rubin I.,
RA Stigbrand T., Gleich G.J., Sottrup-Jensen L.;
RT "Identification of angiotensinogen and complement C3dg as novel
RT proteins binding the proform of eosinophil major basic protein in
RT human pregnancy serum and plasma.";
RL J. Biol. Chem. 270:13645-13651(1995).
RN [8]
RP PROTEIN SEQUENCE OF 988-1036.
RX PubMed=6175959; DOI=10.1073/pnas.79.4.1054;
RA Thomas M.L., Janatova J., Gray W.R., Tack B.F.;
RT "Third component of human complement: localization of the internal
RT thiolester bond.";
RL Proc. Natl. Acad. Sci. U.S.A. 79:1054-1058(1982).
RN [9]
RP PROTEIN SEQUENCE OF 1409-1563.
RX PubMed=3279119;
RA Daoudaki M.E., Becherer J.D., Lambris J.D.;
RT "A 34-amino acid peptide of the third component of complement mediates
RT properdin binding.";
RL J. Immunol. 140:1577-1580(1988).
RN [10]
RP INTERACTION WITH HERPES SIMPLEX VIRUS HHV-1 AND HHV-2 GYCOPROTEIN C.
RX PubMed=2849025; DOI=10.1016/0882-4010(87)90012-X;
RA Eisenberg R.J., Ponce de Leon M., Friedman H.M., Fries L.F.,
RA Frank M.M., Hastings J.C., Cohen G.H.;
RT "Complement component C3b binds directly to purified glycoprotein C of
RT herpes simplex virus types 1 and 2.";
RL Microb. Pathog. 3:423-435(1987).
RN [11]
RP FUNCTION OF ACYLATION STIMULATING PROTEIN.
RX PubMed=2909530;
RA Cianflone K.M., Sniderman A.D., Walsh M.J., Vu H.T., Gagnon J.,
RA Rodriguez M.A.;
RT "Purification and characterization of acylation stimulating protein.";
RL J. Biol. Chem. 264:426-430(1989).
RN [12]
RP MUTAGENESIS OF THE THIOESTER BOND REGION.
RX PubMed=1577777;
RA Isaac L., Isenman D.E.;
RT "Structural requirements for thioester bond formation in human
RT complement component C3. Reassessment of the role of thioester bond
RT integrity on the conformation of C3.";
RL J. Biol. Chem. 267:10062-10069(1992).
RN [13]
RP DISULFIDE BONDS.
RX PubMed=8416818; DOI=10.1016/0014-5793(93)81139-Q;
RA Dolmer K., Sottrup-Jensen L.;
RT "Disulfide bridges in human complement component C3b.";
RL FEBS Lett. 315:85-90(1993).
RN [14]
RP FUNCTION OF ACYLATION STIMULATING PROTEIN.
RX PubMed=9059512; DOI=10.1016/S0005-2760(96)00144-0;
RA Tao Y., Cianflone K., Sniderman A.D., Colby-Germinario S.P.,
RA Germinario R.J.;
RT "Acylation-stimulating protein (ASP) regulates glucose transport in
RT the rat L6 muscle cell line.";
RL Biochim. Biophys. Acta 1344:221-229(1997).
RN [15]
RP IDENTIFICATION OF ACYLATION STIMULATING PROTEIN BY MASS SPECTROMETRY,
RP TISSUE SPECIFICITY, AND FUNCTION.
RX PubMed=9555951;
RA Saleh J., Summers L.K., Cianflone K., Fielding B.A., Sniderman A.D.,
RA Frayn K.N.;
RT "Coordinated release of acylation stimulating protein (ASP) and
RT triacylglycerol clearance by human adipose tissue in vivo in the
RT postprandial period.";
RL J. Lipid Res. 39:884-891(1998).
RN [16]
RP FUNCTION OF ACYLATION STIMULATING PROTEIN.
RX PubMed=10432298; DOI=10.1042/0264-6021:3420041;
RA Murray I., Kohl J., Cianflone K.;
RT "Acylation-stimulating protein (ASP): structure-function determinants
RT of cell surface binding and triacylglycerol synthetic activity.";
RL Biochem. J. 342:41-48(1999).
RN [17]
RP INTERACTION WITH C5AR2.
RX PubMed=11773063; DOI=10.1074/jbc.C100714200;
RA Cain S.A., Monk P.N.;
RT "The orphan receptor C5L2 has high affinity binding sites for
RT complement fragments C5a and C5a des Arg(74).";
RL J. Biol. Chem. 277:7165-7169(2002).
RN [18]
RP INTERACTION OF ACYLATION STIMULATING PROTEIN WITH C5AR2.
RX PubMed=12540846; DOI=10.1074/jbc.M206169200;
RA Kalant D., Cain S.A., Maslowska M., Sniderman A.D., Cianflone K.,
RA Monk P.N.;
RT "The chemoattractant receptor-like protein C5L2 binds the C3a des-
RT Arg77/acylation-stimulating protein.";
RL J. Biol. Chem. 278:11123-11129(2003).
RN [19]
RP GLYCOSYLATION AT ASN-85.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-939, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [21]
RP EFFECTS OF EXERCISE ON ACYLATION STIMULATING PROTEIN PRODUCTION.
RX PubMed=15809665; DOI=10.1038/sj.ijo.0802949;
RA Schrauwen P., Hesselink M.K., Jain M., Cianflone K.;
RT "Acylation-stimulating protein: effect of acute exercise and endurance
RT training.";
RL Int. J. Obes. Relat. Metab. Disord. 29:632-638(2005).
RN [22]
RP FUNCTION OF ACYLATION STIMULATING PROTEIN AS LIGAND FOR C5AR2, AND
RP TISSUE SPECIFICITY.
RX PubMed=15833747; DOI=10.1074/jbc.M406921200;
RA Kalant D., MacLaren R., Cui W., Samanta R., Monk P.N., Laporte S.A.,
RA Cianflone K.;
RT "C5L2 is a functional receptor for acylation-stimulating protein.";
RL J. Biol. Chem. 280:23936-23944(2005).
RN [23]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85; ASN-939 AND ASN-1617,
RP AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [24]
RP ASSOCIATION WITH TYPE 2 DIABETES.
RX PubMed=16302015; DOI=10.1038/sj.ijo.0803173;
RA Yang Y., Lu H.L., Zhang J., Yu H.Y., Wang H.W., Zhang M.X.,
RA Cianflone K.;
RT "Relationships among acylation stimulating protein, adiponectin and
RT complement C3 in lean vs obese type 2 diabetes.";
RL Int. J. Obes. Relat. Metab. Disord. 30:439-446(2006).
RN [25]
RP IDENTIFICATION OF ACYLATION STIMULATING PROTEIN BY MASS SPECTROMETRY,
RP AND FUNCTION OF ACYLATION STIMULATING PROTEIN.
RX PubMed=16333141; DOI=10.1194/jlr.M500500-JLR200;
RA Maslowska M., Legakis H., Assadi F., Cianflone K.;
RT "Targeting the signaling pathway of acylation stimulating protein.";
RL J. Lipid Res. 47:643-652(2006).
RN [26]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [27]
RP ASSOCIATION OF ACYLATION STIMULATING PROTEIN WITH OBESITY.
RX PubMed=18805911; DOI=10.1530/EJE-08-0467;
RA Wamba P.C., Mi J., Zhao X.Y., Zhang M.X., Wen Y., Cheng H., Hou D.Q.,
RA Cianflone K.;
RT "Acylation stimulating protein but not complement C3 associates with
RT metabolic syndrome components in Chinese children and adolescents.";
RL Eur. J. Endocrinol. 159:781-790(2008).
RN [28]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-85, AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [29]
RP FUNCTION OF ACYLATION STIMULATING PROTEIN AS LIGAND FOR C5AR2.
RX PubMed=19615750; DOI=10.1016/j.molimm.2009.06.007;
RA Cui W., Simaan M., Laporte S., Lodge R., Cianflone K.;
RT "C5a- and ASP-mediated C5L2 activation, endocytosis and recycling are
RT lost in S323I-C5L2 mutation.";
RL Mol. Immunol. 46:3086-3098(2009).
RN [30]
RP MUTAGENESIS OF ASP-1029; GLU-1030; GLU-1032; GLU-1035; ARG-1042;
RP ASP-1140; GLU-1153; ASP-1156; GLU-1159; GLU-1160; ASN-1163 AND
RP LYS-1284, AND INTERACTION WITH CR2 AND S.AUREUS SBI.
RX PubMed=20083651; DOI=10.4049/jimmunol.0902919;
RA Isenman D.E., Leung E., Mackay J.D., Bagby S., van den Elsen J.M.;
RT "Mutational analyses reveal that the staphylococcal immune evasion
RT molecule Sbi and complement receptor 2 (CR2) share overlapping contact
RT residues on C3d: implications for the controversy regarding the
RT CR2/C3d cocrystal structure.";
RL J. Immunol. 184:1946-1955(2010).
RN [31]
RP MUTAGENESIS OF ASP-1029; GLU-1030; GLU-1032; GLU-1110; ASP-1115;
RP ASP-1121; ASP-1140; GLU-1153; ASP-1156; GLU-1159; GLU-1160 AND
RP ASN-1163, AND INTERACTION WITH CR2.
RX PubMed=20951140; DOI=10.1016/j.jmb.2010.10.005;
RA Shaw C.D., Storek M.J., Young K.A., Kovacs J.M., Thurman J.M.,
RA Holers V.M., Hannan J.P.;
RT "Delineation of the complement receptor type 2-C3d complex by site-
RT directed mutagenesis and molecular docking.";
RL J. Mol. Biol. 404:697-710(2010).
RN [32]
RP ASSOCIATION WITH CORONARY HEART DISEASE.
RX PubMed=19913840; DOI=10.1016/j.metabol.2009.09.006;
RA Onat A., Hergenc G., Can G., Kaya Z., Yuksel H.;
RT "Serum complement C3: a determinant of cardiometabolic risk, additive
RT to the metabolic syndrome, in middle-aged population.";
RL Metabolism 59:628-634(2010).
RN [33]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [34]
RP STRUCTURE BY NMR OF C3A.
RX PubMed=3260670; DOI=10.1073/pnas.85.14.5036;
RA Nettesheim D.G., Edalji R.P., Mollison K.W., Greer J.,
RA Zuiderweg E.R.P.;
RT "Secondary structure of complement component C3a anaphylatoxin in
RT solution as determined by NMR spectroscopy: differences between
RT crystal and solution conformations.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:5036-5040(1988).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF C3D.
RX PubMed=9596584; DOI=10.1126/science.280.5367.1277;
RA Nagar B., Jones R.G., Diefenbach R.J., Isenman D.E., Rini J.M.;
RT "X-ray crystal structure of C3d: a C3 fragment and ligand for
RT complement receptor 2.";
RL Science 280:1277-1281(1998).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF C3D IN COMPLEX WITH CR2, AND
RP MUTAGENESIS OF 1108-ILE-LEU-1109 AND ASN-1163.
RX PubMed=11387479; DOI=10.1126/science.1059118;
RA Szakonyi G., Guthridge J.M., Li D., Young K., Holers V.M., Chen X.S.;
RT "Structure of complement receptor 2 in complex with its C3d ligand.";
RL Science 292:1725-1728(2001).
RN [37]
RP X-RAY SCATTERING SOLUTION STRUCTURE OF C3D IN COMPLEX WITH CR2.
RX PubMed=15713468; DOI=10.1016/j.jmb.2004.12.006;
RA Gilbert H.E., Eaton J.T., Hannan J.P., Holers V.M., Perkins S.J.;
RT "Solution structure of the complex between CR2 SCR 1-2 and C3d of
RT human complement: an X-ray scattering and sedimentation modelling
RT study.";
RL J. Mol. Biol. 346:859-873(2005).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF C3C, AND X-RAY
RP CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF C3.
RX PubMed=16177781; DOI=10.1038/nature04005;
RA Janssen B.J.C., Huizinga E.G., Raaijmakers H.C.A., Roos A., Daha M.R.,
RA Nilsson-Ekdahl K., Nilsson B., Gros P.;
RT "Structures of complement component C3 provide insights into the
RT function and evolution of immunity.";
RL Nature 437:505-511(2005).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (4.0 ANGSTROMS) OF C3B.
RX PubMed=17051160; DOI=10.1038/nature05172;
RA Janssen B.J.C., Christodoulidou A., McCarthy A., Lambris J.D.,
RA Gros P.;
RT "Structure of C3b reveals conformational changes that underlie
RT complement activity.";
RL Nature 444:213-216(2006).
RN [40]
RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF C3C IN COMPLEX WITH VSIG4,
RP X-RAY CRYSTALLOGRAPHY (4.1 ANGSTROMS) OF C3B IN COMPLEX WITH VSIG4,
RP AND GLYCOSYLATION AT ASN-85 AND ASN-939.
RX PubMed=17051150; DOI=10.1038/nature05263;
RA Wiesmann C., Katschke K.J., Yin J., Helmy K.Y., Steffek M.,
RA Fairbrother W.J., McCallum S.A., Embuscado L., DeForge L., Hass P.E.,
RA van Lookeren Campagne M.;
RT "Structure of C3b in complex with CRIg gives insights into regulation
RT of complement activation.";
RL Nature 444:217-220(2006).
RN [41]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 23-936 AND 1321-1663 IN
RP COMPLEX WITH INHIBITOR COMPSTATIN, DISULFIDE BONDS, AND GLYCOSYLATION
RP AT ASN-85.
RX PubMed=17684013; DOI=10.1074/jbc.M704587200;
RA Janssen B.J., Halff E.F., Lambris J.D., Gros P.;
RT "Structure of compstatin in complex with complement component C3c
RT reveals a new mechanism of complement inhibition.";
RL J. Biol. Chem. 282:29241-29247(2007).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 996-1287 IN COMPLEX WITH
RP S.AUREUS FIB.
RX PubMed=17351618; DOI=10.1038/ni1450;
RA Hammel M., Sfyroera G., Ricklin D., Magotti P., Lambris J.D.,
RA Geisbrecht B.V.;
RT "A structural basis for complement inhibition by Staphylococcus
RT aureus.";
RL Nat. Immunol. 8:430-437(2007).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 996-1303 IN COMPLEX WITH
RP S.AUREUS SBI, AND SUBUNIT.
RX PubMed=21055811; DOI=10.1016/j.molimm.2010.09.017;
RA Clark E.A., Crennell S., Upadhyay A., Zozulya A.V., Mackay J.D.,
RA Svergun D.I., Bagby S., van den Elsen J.M.;
RT "A structural basis for Staphylococcal complement subversion: X-ray
RT structure of the complement-binding domain of Staphylococcus aureus
RT protein Sbi in complex with ligand C3d.";
RL Mol. Immunol. 48:452-462(2011).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (3.16 ANGSTROMS) OF 996-1303 IN COMPLEX WITH
RP CR2, AND INTERACTION WITH CR2.
RX PubMed=21527715; DOI=10.1126/science.1201954;
RA van den Elsen J.M., Isenman D.E.;
RT "A crystal structure of the complex between human complement receptor
RT 2 and its ligand C3d.";
RL Science 332:608-611(2011).
RN [45]
RP VARIANT C3S ASN-1216.
RX PubMed=2473125;
RA Poznansky M.C., Clissold P.M., Lachmann P.J.;
RT "The difference between human C3F and C3S results from a single amino
RT acid change from an asparagine to an aspartate residue at position
RT 1216 on the alpha-chain of the complement component, C3.";
RL J. Immunol. 143:1254-1258(1989).
RN [46]
RP ERRATUM, AND RETRACTION.
RX PubMed=2584723;
RA Poznansky M.C., Clissold P.M., Lachmann P.J.;
RL J. Immunol. 143:3860-3862(1989).
RN [47]
RP VARIANTS GLY-102 AND LEU-314.
RX PubMed=1976733; DOI=10.1084/jem.172.4.1011;
RA Botto M., Yong Fong K., So A.K., Koch C., Walport M.J.;
RT "Molecular basis of polymorphisms of human complement component C3.";
RL J. Exp. Med. 172:1011-1017(1990).
RN [48]
RP VARIANT C3D ASN-549.
RX PubMed=7961791;
RA Singer L., Whitehead W.T., Akama H., Katz Y., Fishelson Z.,
RA Wetsel R.A.;
RT "Inherited human complement C3 deficiency. An amino acid substitution
RT in the beta-chain (Asp549 to Asn) impairs C3 secretion.";
RL J. Biol. Chem. 269:28494-28499(1994).
RN [49]
RP VARIANT C3D GLN-1320.
RA Watanabe Y., Matsui N., Yan K., Nishimukai H., Tokunaga K., Juji T.,
RA Kobayashi N., Kohsaka T.;
RT "A novel C3 allotype C3'F02'has an amino acid substitution that may
RT inhibit iC3b synthesis and cause C3-hypocomplementemia.";
RL Mol. Immunol. 30:62-62(1993).
RN [50]
RP ASSOCIATION OF VARIANT GLY-102 WITH ARMD9.
RX PubMed=17634448; DOI=10.1056/NEJMoa072618;
RA Yates J.R.W., Sepp T., Matharu B.K., Khan J.C., Thurlby D.A.,
RA Shahid H., Clayton D.G., Hayward C., Morgan J., Wright A.F.,
RA Armbrecht A.M., Dhillon B., Deary I.J., Redmond E., Bird A.C.,
RA Moore A.T.;
RT "Complement C3 variant and the risk of age-related macular
RT degeneration.";
RL N. Engl. J. Med. 357:553-561(2007).
RN [51]
RP VARIANTS AHUS5 GLN-592; TRP-592; TRP-735; VAL-1094; ASN-1115;
RP TRP-1158; LYS-1161 AND ASP-1464, AND CHARACTERIZATION OF VARIANTS
RP AHUS5 GLN-592; TRP-592; VAL-1094; ASN-1115 AND LYS-1161.
RX PubMed=18796626; DOI=10.1182/blood-2008-01-133702;
RA Fremeaux-Bacchi V., Miller E.C., Liszewski M.K., Strain L., Blouin J.,
RA Brown A.L., Moghal N., Kaplan B.S., Weiss R.A., Lhotta K., Kapur G.,
RA Mattoo T., Nivet H., Wong W., Gie S., Hurault de Ligny B.,
RA Fischbach M., Gupta R., Hauhart R., Meunier V., Loirat C.,
RA Dragon-Durey M.A., Fridman W.H., Janssen B.J., Goodship T.H.,
RA Atkinson J.P.;
RT "Mutations in complement C3 predispose to development of atypical
RT hemolytic uremic syndrome.";
RL Blood 112:4948-4952(2008).
RN [52]
RP VARIANTS AHUS5 VAL-603 AND LEU-1042.
RX PubMed=20513133; DOI=10.1002/humu.21256;
RA Maga T.K., Nishimura C.J., Weaver A.E., Frees K.L., Smith R.J.H.;
RT "Mutations in alternative pathway complement proteins in American
RT patients with atypical hemolytic uremic syndrome.";
RL Hum. Mutat. 31:E1445-E1460(2010).
RN [53]
RP VARIANT ASN-549, AND MASS SPECTROMETRY.
RX PubMed=22028381; DOI=10.1093/jmcb/mjr024;
RA Su Z.D., Sun L., Yu D.X., Li R.X., Li H.X., Yu Z.J., Sheng Q.H.,
RA Lin X., Zeng R., Wu J.R.;
RT "Quantitative detection of single amino acid polymorphisms by targeted
RT proteomics.";
RL J. Mol. Cell Biol. 3:309-315(2011).
CC -!- FUNCTION: C3 plays a central role in the activation of the
CC complement system. Its processing by C3 convertase is the central
CC reaction in both classical and alternative complement pathways.
CC After activation C3b can bind covalently, via its reactive
CC thioester, to cell surface carbohydrates or immune aggregates.
CC -!- FUNCTION: Derived from proteolytic degradation of complement C3,
CC C3a anaphylatoxin is a mediator of local inflammatory process. It
CC induces the contraction of smooth muscle, increases vascular
CC permeability and causes histamine release from mast cells and
CC basophilic leukocytes.
CC -!- FUNCTION: Acylation stimulating protein (ASP): adipogenic hormone
CC that stimulates triglyceride (TG) synthesis and glucose transport
CC in adipocytes, regulating fat storage and playing a role in
CC postprandial TG clearance. Appears to stimulate TG synthesis via
CC activation of the PLC, MAPK and AKT signaling pathways. Ligand for
CC C5AR2. Promotes the phosphorylation, ARRB2-mediated
CC internalization and recycling of C5AR2.
CC -!- SUBUNIT: C3 precursor is first processed by the removal of 4 Arg
CC residues, forming two chains, beta and alpha, linked by a
CC disulfide bond. C3 convertase activates C3 by cleaving the alpha
CC chain, releasing C3a anaphylatoxin and generating C3b (beta chain
CC + alpha' chain). C3dg interacts with CR2 (via the N-terminal Sushi
CC domains 1 and 2). During pregnancy, C3dg exists as a complex
CC (probably a 2:2:2 heterohexamer) with AGT and the proform of PRG2.
CC Interacts with VSIG4. C3b interacts with herpes simplex virus 1
CC (HHV-1) and herpes simplex virus 2 (HHV-2) envelope glycoprotein
CC C; this interaction inhibits the activation of the complement
CC system. Interacts with S.aureus immunoglobulin-binding protein
CC sbi, this prevents interaction between C3dg and CR2. Interacts
CC with S.aureus fib. Interacts (both C3a and ASP) with C5AR2; the
CC interaction occurs with higher affinity for ASP, enhancing the
CC phosphorylation and activation of C5AR2, recruitment of ARRB2 to
CC the cell surface and endocytosis of GRP77.
CC -!- INTERACTION:
CC P08603:CFH; NbExp=2; IntAct=EBI-6863106, EBI-1223708;
CC Q9Y279-1:VSIG4; NbExp=5; IntAct=EBI-905851, EBI-903144;
CC Q9Y279-2:VSIG4; NbExp=2; IntAct=EBI-905851, EBI-903148;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Plasma. The acylation stimulating protein
CC (ASP) is expressed in adipocytes and released into the plasma
CC during both the fasting and postprandial periods.
CC -!- PTM: C3b is rapidly split in two positions by factor I and a
CC cofactor to form iC3b (inactivated C3b) and C3f which is released.
CC Then iC3b is slowly cleaved (possibly by factor I) to form C3c
CC (beta chain + alpha' chain fragment 1 + alpha' chain fragment 2),
CC C3dg and C3f. Other proteases produce other fragments such as C3d
CC or C3g. C3a is further processed by carboxypeptidases to release
CC the C-terminal arginine residue generating the acylation
CC stimulating protein (ASP). Levels of ASP are increased in
CC adipocytes in the postprandial period and by insulin and dietary
CC chylomicrons.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- POLYMORPHISM: There are two alleles: C3S (C3 slow), the most
CC common allele in all races and C3F (C3 fast), relatively frequent
CC in Caucasians, less common in Black Americans, extremely rare in
CC Orientals.
CC -!- DISEASE: Complement component 3 deficiency (C3D) [MIM:613779]: A
CC rare defect of the complement classical pathway. Patients develop
CC recurrent, severe, pyogenic infections because of ineffective
CC opsonization of pathogens. Some patients may also develop
CC autoimmune disorders, such as arthralgia and vasculitic rashes,
CC lupus-like syndrome and membranoproliferative glomerulonephritis.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Macular degeneration, age-related, 9 (ARMD9)
CC [MIM:611378]: A form of age-related macular degeneration, a
CC multifactorial eye disease and the most common cause of
CC irreversible vision loss in the developed world. In most patients,
CC the disease is manifest as ophthalmoscopically visible yellowish
CC accumulations of protein and lipid that lie beneath the retinal
CC pigment epithelium and within an elastin-containing structure
CC known as Bruch membrane. Note=Disease susceptibility is associated
CC with variations affecting the gene represented in this entry.
CC -!- DISEASE: Hemolytic uremic syndrome atypical 5 (AHUS5)
CC [MIM:612925]: An atypical form of hemolytic uremic syndrome. It is
CC a complex genetic disease characterized by microangiopathic
CC hemolytic anemia, thrombocytopenia, renal failure and absence of
CC episodes of enterocolitis and diarrhea. In contrast to typical
CC hemolytic uremic syndrome, atypical forms have a poorer prognosis,
CC with higher death rates and frequent progression to end-stage
CC renal disease. Note=Disease susceptibility is associated with
CC variations affecting the gene represented in this entry. Other
CC genes may play a role in modifying the phenotype.
CC -!- DISEASE: Note=Increased levels of C3 and its cleavage product ASP,
CC are associated with obesity, diabetes and coronary heart disease.
CC Short-term endurance training reduces baseline ASP levels and
CC subsequently fat storage.
CC -!- SIMILARITY: Contains 1 anaphylatoxin-like domain.
CC -!- SIMILARITY: Contains 1 NTR domain.
CC -!- CAUTION: According to PubMed:21527715, the interaction surface
CC between C3 and CR2 reported in PubMed:11387479 is artifactual and
CC can be ascribed to the presence of zinc acetate in the buffer.
CC -!- WEB RESOURCE: Name=C3base; Note=C3 mutation db;
CC URL="http://bioinf.uta.fi/C3base/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/C3";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Complement C3 entry;
CC URL="http://en.wikipedia.org/wiki/Complement_c3";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/c3/";
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DR EMBL; K02765; AAA85332.1; -; mRNA.
DR EMBL; AY513239; AAR89906.1; -; Genomic_DNA.
DR EMBL; CH471139; EAW69071.1; -; Genomic_DNA.
DR EMBL; BC150179; AAI50180.1; -; mRNA.
DR EMBL; BC150200; AAI50201.1; -; mRNA.
DR PIR; A94065; C3HU.
DR RefSeq; NP_000055.2; NM_000064.2.
DR UniGene; Hs.529053; -.
DR PDB; 1C3D; X-ray; 1.80 A; A=996-1287.
DR PDB; 1GHQ; X-ray; 2.04 A; A=996-1300.
DR PDB; 1W2S; X-ray; -; A=996-1299.
DR PDB; 2A73; X-ray; 3.30 A; A=23-665, B=673-1663.
DR PDB; 2A74; X-ray; 2.40 A; A/D=23-665, B/E=749-936, C/F=1321-1663.
DR PDB; 2GOX; X-ray; 2.20 A; A/C=996-1287.
DR PDB; 2HR0; X-ray; 2.26 A; A=23-667, B=749-1663.
DR PDB; 2I07; X-ray; 4.00 A; A=23-667, B=749-1663.
DR PDB; 2ICE; X-ray; 3.10 A; A/D=23-664, B/E=749-954, C/F=1321-1663.
DR PDB; 2ICF; X-ray; 4.10 A; A=23-664, B=749-1663.
DR PDB; 2NOJ; X-ray; 2.70 A; A/C/E/G=996-1287.
DR PDB; 2QKI; X-ray; 2.40 A; A/D=23-665, B/E=749-936, C/F=1321-1663.
DR PDB; 2WII; X-ray; 2.70 A; A=23-667, B=749-1663.
DR PDB; 2WIN; X-ray; 3.90 A; A/C/E/G=23-667, B/D/F/H=749-1663.
DR PDB; 2WY7; X-ray; 1.70 A; A=996-1303.
DR PDB; 2WY8; X-ray; 1.70 A; A=996-1303.
DR PDB; 2XQW; X-ray; 2.31 A; A/B=996-1287.
DR PDB; 2XWB; X-ray; 3.49 A; A/C=23-664, B/D=752-1663.
DR PDB; 2XWJ; X-ray; 4.00 A; A/C/E/G=23-667, B/D/F/H=749-1663.
DR PDB; 3D5R; X-ray; 2.10 A; A/B=996-1287.
DR PDB; 3D5S; X-ray; 2.30 A; A/B=996-1287.
DR PDB; 3G6J; X-ray; 3.10 A; A/C=23-666, B/D=749-1663.
DR PDB; 3L3O; X-ray; 3.40 A; A/D=23-667, B/E=749-954, C/F=1321-1663.
DR PDB; 3L5N; X-ray; 7.54 A; A=23-667, B=749-1663.
DR PDB; 3NMS; X-ray; 4.10 A; A=23-667, B=749-954, C=1321-1663.
DR PDB; 3OED; X-ray; 3.16 A; A/B=996-1303.
DR PDB; 3OHX; X-ray; 3.50 A; A/D=23-667, B/E=749-954, C/F=1321-1663.
DR PDB; 3OXU; X-ray; 2.10 A; A/B/C=996-1303.
DR PDB; 3RJ3; X-ray; 2.35 A; A/B/C=996-1303.
DR PDB; 3T4A; X-ray; 3.40 A; A/D=23-667, B/E=749-954, C/F=1321-1663.
DR PDB; 4HW5; X-ray; 2.25 A; A/B=672-748.
DR PDB; 4HWJ; X-ray; 2.60 A; A=672-747.
DR PDB; 4I6O; X-ray; 2.14 A; A=672-748.
DR PDB; 4M76; X-ray; 2.80 A; A=994-1288.
DR PDBsum; 1C3D; -.
DR PDBsum; 1GHQ; -.
DR PDBsum; 1W2S; -.
DR PDBsum; 2A73; -.
DR PDBsum; 2A74; -.
DR PDBsum; 2GOX; -.
DR PDBsum; 2HR0; -.
DR PDBsum; 2I07; -.
DR PDBsum; 2ICE; -.
DR PDBsum; 2ICF; -.
DR PDBsum; 2NOJ; -.
DR PDBsum; 2QKI; -.
DR PDBsum; 2WII; -.
DR PDBsum; 2WIN; -.
DR PDBsum; 2WY7; -.
DR PDBsum; 2WY8; -.
DR PDBsum; 2XQW; -.
DR PDBsum; 2XWB; -.
DR PDBsum; 2XWJ; -.
DR PDBsum; 3D5R; -.
DR PDBsum; 3D5S; -.
DR PDBsum; 3G6J; -.
DR PDBsum; 3L3O; -.
DR PDBsum; 3L5N; -.
DR PDBsum; 3NMS; -.
DR PDBsum; 3OED; -.
DR PDBsum; 3OHX; -.
DR PDBsum; 3OXU; -.
DR PDBsum; 3RJ3; -.
DR PDBsum; 3T4A; -.
DR PDBsum; 4HW5; -.
DR PDBsum; 4HWJ; -.
DR PDBsum; 4I6O; -.
DR PDBsum; 4M76; -.
DR ProteinModelPortal; P01024; -.
DR SMR; P01024; 23-664, 673-1663.
DR DIP; DIP-35180N; -.
DR IntAct; P01024; 10.
DR MINT; MINT-5003988; -.
DR STRING; 9606.ENSP00000245907; -.
DR BindingDB; P01024; -.
DR ChEMBL; CHEMBL4917; -.
DR MEROPS; I39.950; -.
DR PhosphoSite; P01024; -.
DR UniCarbKB; P01024; -.
DR DMDM; 119370332; -.
DR DOSAC-COBS-2DPAGE; P01024; -.
DR SWISS-2DPAGE; P01024; -.
DR PaxDb; P01024; -.
DR PeptideAtlas; P01024; -.
DR PRIDE; P01024; -.
DR Ensembl; ENST00000245907; ENSP00000245907; ENSG00000125730.
DR GeneID; 718; -.
DR KEGG; hsa:718; -.
DR UCSC; uc002mfm.3; human.
DR CTD; 718; -.
DR GeneCards; GC19M006677; -.
DR H-InvDB; HIX0020036; -.
DR HGNC; HGNC:1318; C3.
DR HPA; CAB004209; -.
DR HPA; HPA003563; -.
DR HPA; HPA020432; -.
DR MIM; 120700; gene.
DR MIM; 611378; phenotype.
DR MIM; 612925; phenotype.
DR MIM; 613779; phenotype.
DR neXtProt; NX_P01024; -.
DR Orphanet; 279; Age-related macular degeneration.
DR Orphanet; 93575; Atypical hemolytic uremic syndrome with C3 anomaly.
DR Orphanet; 280133; Complement component 3 deficiency.
DR PharmGKB; PA25897; -.
DR eggNOG; NOG241555; -.
DR HOGENOM; HOG000286028; -.
DR HOVERGEN; HBG005110; -.
DR InParanoid; P01024; -.
DR KO; K03990; -.
DR OMA; PGMPFDL; -.
DR OrthoDB; EOG77HDCX; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; C3; human.
DR EvolutionaryTrace; P01024; -.
DR GeneWiki; Complement_component_3; -.
DR GenomeRNAi; 718; -.
DR NextBio; 2922; -.
DR PMAP-CutDB; P01024; -.
DR PRO; PR:P01024; -.
DR ArrayExpress; P01024; -.
DR Bgee; P01024; -.
DR CleanEx; HS_C3; -.
DR Genevestigator; P01024; -.
DR GO; GO:0005615; C:extracellular space; IEA:InterPro.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0031715; F:C5L2 anaphylatoxin chemotactic receptor binding; IDA:UniProtKB.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; IEA:InterPro.
DR GO; GO:0006957; P:complement activation, alternative pathway; TAS:Reactome.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0006631; P:fatty acid metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0010951; P:negative regulation of endopeptidase activity; IEA:GOC.
DR GO; GO:0001970; P:positive regulation of activation of membrane attack complex; IEA:Ensembl.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl.
DR GO; GO:0045745; P:positive regulation of G-protein coupled receptor protein signaling pathway; IDA:UniProtKB.
DR GO; GO:0010828; P:positive regulation of glucose transport; IDA:UniProtKB.
DR GO; GO:0010884; P:positive regulation of lipid storage; IDA:UniProtKB.
DR GO; GO:0050766; P:positive regulation of phagocytosis; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0001798; P:positive regulation of type IIa hypersensitivity; IEA:Ensembl.
DR GO; GO:0010575; P:positive regulation vascular endothelial growth factor production; IDA:BHF-UCL.
DR GO; GO:0030449; P:regulation of complement activation; TAS:Reactome.
DR GO; GO:0010866; P:regulation of triglyceride biosynthetic process; IDA:UniProtKB.
DR Gene3D; 1.20.91.20; -; 1.
DR Gene3D; 2.60.40.690; -; 1.
DR InterPro; IPR009048; A-macroglobulin_rcpt-bd.
DR InterPro; IPR011626; A2M_comp.
DR InterPro; IPR002890; A2M_N.
DR InterPro; IPR011625; A2M_N_2.
DR InterPro; IPR000020; Anaphylatoxin/fibulin.
DR InterPro; IPR018081; Anaphylatoxin_comp_syst.
DR InterPro; IPR001840; Anaphylatoxn_comp_syst_dom.
DR InterPro; IPR001599; Macroglobln_a2.
DR InterPro; IPR019742; MacrogloblnA2_CS.
DR InterPro; IPR019565; MacrogloblnA2_thiol-ester-bond.
DR InterPro; IPR001134; Netrin_domain.
DR InterPro; IPR018933; Netrin_module_non-TIMP.
DR InterPro; IPR008930; Terpenoid_cyclase/PrenylTrfase.
DR InterPro; IPR008993; TIMP-like_OB-fold.
DR Pfam; PF00207; A2M; 1.
DR Pfam; PF07678; A2M_comp; 1.
DR Pfam; PF01835; A2M_N; 1.
DR Pfam; PF07703; A2M_N_2; 1.
DR Pfam; PF07677; A2M_recep; 1.
DR Pfam; PF01821; ANATO; 1.
DR Pfam; PF01759; NTR; 1.
DR Pfam; PF10569; Thiol-ester_cl; 1.
DR PRINTS; PR00004; ANAPHYLATOXN.
DR SMART; SM00104; ANATO; 1.
DR SMART; SM00643; C345C; 1.
DR SUPFAM; SSF47686; SSF47686; 1.
DR SUPFAM; SSF48239; SSF48239; 1.
DR SUPFAM; SSF49410; SSF49410; 1.
DR SUPFAM; SSF50242; SSF50242; 1.
DR PROSITE; PS00477; ALPHA_2_MACROGLOBULIN; 1.
DR PROSITE; PS01177; ANAPHYLATOXIN_1; 1.
DR PROSITE; PS01178; ANAPHYLATOXIN_2; 1.
DR PROSITE; PS50189; NTR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Age-related macular degeneration;
KW Cleavage on pair of basic residues; Complement alternate pathway;
KW Complement pathway; Complete proteome; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Fatty acid metabolism; Glycoprotein;
KW Hemolytic uremic syndrome; Immunity; Inflammatory response;
KW Innate immunity; Lipid metabolism; Phosphoprotein; Polymorphism;
KW Reference proteome; Secreted; Signal; Thioester bond.
FT SIGNAL 1 22
FT CHAIN 23 1663 Complement C3.
FT /FTId=PRO_0000005907.
FT CHAIN 23 667 Complement C3 beta chain.
FT /FTId=PRO_0000005908.
FT CHAIN 672 1663 Complement C3 alpha chain.
FT /FTId=PRO_0000005909.
FT CHAIN 672 748 C3a anaphylatoxin.
FT /FTId=PRO_0000005910.
FT CHAIN 672 747 Acylation stimulating protein.
FT /FTId=PRO_0000419935.
FT CHAIN 749 1663 Complement C3b alpha' chain.
FT /FTId=PRO_0000005911.
FT CHAIN 749 954 Complement C3c alpha' chain fragment 1.
FT /FTId=PRO_0000005912.
FT CHAIN 955 1303 Complement C3dg fragment.
FT /FTId=PRO_0000005913.
FT CHAIN 955 1001 Complement C3g fragment.
FT /FTId=PRO_0000005914.
FT CHAIN 1002 1303 Complement C3d fragment.
FT /FTId=PRO_0000005915.
FT PEPTIDE 1304 1320 Complement C3f fragment.
FT /FTId=PRO_0000005916.
FT CHAIN 1321 1663 Complement C3c alpha' chain fragment 2.
FT /FTId=PRO_0000273948.
FT DOMAIN 693 728 Anaphylatoxin-like.
FT DOMAIN 1518 1661 NTR.
FT REGION 1424 1456 Properdin-binding.
FT SITE 747 748 Cleavage; by carboxypeptidases.
FT SITE 748 749 Cleavage; by C3 convertase.
FT SITE 954 955 Cleavage; by factor I (Potential).
FT SITE 1303 1304 Cleavage; by factor I.
FT SITE 1320 1321 Cleavage; by factor I.
FT CARBOHYD 85 85 N-linked (GlcNAc...).
FT CARBOHYD 939 939 N-linked (GlcNAc...).
FT CARBOHYD 1617 1617 N-linked (GlcNAc...).
FT DISULFID 559 816 Interchain (between beta and alpha
FT chains).
FT DISULFID 627 662
FT DISULFID 693 720
FT DISULFID 694 727
FT DISULFID 707 728
FT DISULFID 873 1513
FT DISULFID 1101 1158
FT DISULFID 1358 1489
FT DISULFID 1389 1458
FT DISULFID 1506 1511
FT DISULFID 1518 1590
FT DISULFID 1537 1661
FT DISULFID 1637 1646
FT CROSSLNK 1010 1013 Isoglutamyl cysteine thioester (Cys-Gln).
FT VARIANT 102 102 R -> G (in allele C3F; associated with
FT ARMD9; dbSNP:rs2230199).
FT /FTId=VAR_001983.
FT VARIANT 314 314 P -> L (in dbSNP:rs1047286).
FT /FTId=VAR_001984.
FT VARIANT 469 469 E -> D (in dbSNP:rs11569422).
FT /FTId=VAR_020262.
FT VARIANT 549 549 D -> N (in C3D; impairs secretion;
FT variant confirmed at protein level).
FT /FTId=VAR_001985.
FT VARIANT 592 592 R -> Q (in AHUS5; leads to impaired
FT binding to the regulator CD46/MCP and
FT resistance to cleavage by factor I).
FT /FTId=VAR_063213.
FT VARIANT 592 592 R -> W (in AHUS5; leads to impaired
FT binding to the regulator CD46/MCP and
FT resistance to cleavage by factor I).
FT /FTId=VAR_063214.
FT VARIANT 603 603 F -> V (in AHUS5).
FT /FTId=VAR_063654.
FT VARIANT 735 735 R -> W (in AHUS5; dbSNP:rs117793540).
FT /FTId=VAR_063215.
FT VARIANT 863 863 R -> K (in dbSNP:rs11569472).
FT /FTId=VAR_019206.
FT VARIANT 1042 1042 R -> L (in AHUS5).
FT /FTId=VAR_063655.
FT VARIANT 1094 1094 A -> V (in AHUS5; leads to impaired
FT binding to the regulator CD46/MCP and
FT resistance to cleavage by factor I).
FT /FTId=VAR_063216.
FT VARIANT 1115 1115 D -> N (in AHUS5; leads to impaired
FT binding to the regulator CD46/MCP and
FT resistance to cleavage by factor I).
FT /FTId=VAR_063217.
FT VARIANT 1158 1158 C -> W (in AHUS5).
FT /FTId=VAR_063218.
FT VARIANT 1161 1161 Q -> K (in AHUS5; leads to impaired
FT binding to the regulator CD46/MCP and
FT resistance to cleavage by factor I).
FT /FTId=VAR_063219.
FT VARIANT 1216 1216 D -> N (in C3S).
FT /FTId=VAR_022761.
FT VARIANT 1224 1224 G -> D (in dbSNP:rs11569534).
FT /FTId=VAR_019207.
FT VARIANT 1320 1320 R -> Q (in C3D; allotype C3'F02'; may
FT inhibit IC3B synthesis).
FT /FTId=VAR_001986.
FT VARIANT 1367 1367 I -> T (in dbSNP:rs11569541).
FT /FTId=VAR_019208.
FT VARIANT 1464 1464 H -> D (in AHUS5).
FT /FTId=VAR_063220.
FT VARIANT 1521 1521 Q -> R (in dbSNP:rs7256789).
FT /FTId=VAR_029792.
FT VARIANT 1601 1601 H -> N (in dbSNP:rs1803225).
FT /FTId=VAR_029793.
FT VARIANT 1619 1619 S -> R (in dbSNP:rs2230210).
FT /FTId=VAR_029326.
FT MUTAGEN 1029 1029 D->A: Minor effect on binding of C3d to
FT CR2.
FT MUTAGEN 1030 1030 E->A: Impaired binding of C3d to CR2.
FT MUTAGEN 1032 1032 E->A: Impaired binding of C3d to CR2.
FT MUTAGEN 1035 1035 E->A: No effect on binding of C3d to CR2.
FT MUTAGEN 1042 1042 R->M: Impaired binding of C3d to CR2.
FT MUTAGEN 1108 1109 IL->RR: Impaired binding of C3d to CR2;
FT when associated with A-1163.
FT MUTAGEN 1110 1110 E->A: No effect on binding of C3d to CR2.
FT MUTAGEN 1115 1115 D->A: No effect on binding of C3d to CR2.
FT MUTAGEN 1121 1121 D->A: No effect on binding of C3d to CR2.
FT MUTAGEN 1140 1140 D->A: No effect on binding of C3d to CR2.
FT MUTAGEN 1153 1153 E->A: Impaired binding of C3d to CR2.
FT MUTAGEN 1156 1156 D->A: Impaired binding of C3d to CR2.
FT MUTAGEN 1159 1159 E->A: Impaired binding of C3d to CR2.
FT MUTAGEN 1160 1160 E->A: Minor effect on binding of C3d to
FT CR2.
FT MUTAGEN 1163 1163 N->A: No effect on binding of C3d to CR2.
FT Impaired binding of C3d to CR2; when
FT associated with 1108-R-R-1109.
FT MUTAGEN 1163 1163 N->R: Impaired binding of C3d to CR2.
FT MUTAGEN 1284 1284 K->A: Impaired binding of C3d to CR2.
FT CONFLICT 681 681 D -> N (in Ref. 6; AA sequence).
FT CONFLICT 700 700 E -> Q (in Ref. 6; AA sequence).
FT CONFLICT 1026 1026 H -> S (in Ref. 8; AA sequence).
FT STRAND 28 35
FT STRAND 36 41
FT STRAND 43 47
FT STRAND 54 56
FT STRAND 59 61
FT TURN 62 64
FT STRAND 67 69
FT STRAND 73 75
FT HELIX 78 80
FT STRAND 87 89
FT HELIX 94 97
FT STRAND 105 112
FT STRAND 115 124
FT STRAND 129 135
FT STRAND 137 139
FT STRAND 143 152
FT STRAND 162 168
FT STRAND 174 181
FT TURN 183 187
FT STRAND 188 194
FT STRAND 202 210
FT STRAND 216 223
FT STRAND 233 244
FT STRAND 251 258
FT STRAND 267 277
FT STRAND 280 283
FT HELIX 285 287
FT STRAND 289 294
FT STRAND 297 302
FT HELIX 304 308
FT TURN 310 312
FT HELIX 316 319
FT STRAND 323 336
FT STRAND 338 350
FT STRAND 354 356
FT STRAND 358 360
FT STRAND 362 364
FT STRAND 368 377
FT STRAND 379 383
FT STRAND 389 394
FT HELIX 395 397
FT STRAND 398 400
FT STRAND 405 412
FT STRAND 420 426
FT TURN 429 431
FT TURN 433 435
FT STRAND 438 444
FT HELIX 449 451
FT STRAND 455 460
FT STRAND 469 478
FT TURN 481 483
FT TURN 484 486
FT STRAND 489 496
FT STRAND 499 507
FT STRAND 513 520
FT HELIX 523 525
FT STRAND 527 538
FT STRAND 540 554
FT STRAND 564 567
FT TURN 568 570
FT STRAND 571 573
FT STRAND 580 588
FT STRAND 592 598
FT HELIX 600 603
FT HELIX 613 621
FT STRAND 628 630
FT STRAND 633 636
FT HELIX 637 640
FT TURN 641 643
FT STRAND 644 647
FT STRAND 649 651
FT HELIX 675 684
FT HELIX 688 697
FT HELIX 707 710
FT TURN 712 714
FT HELIX 718 743
FT STRAND 753 755
FT HELIX 758 760
FT STRAND 769 771
FT STRAND 775 777
FT STRAND 786 794
FT STRAND 800 810
FT TURN 811 813
FT STRAND 814 817
FT STRAND 821 825
FT STRAND 828 834
FT STRAND 837 840
FT STRAND 845 853
FT STRAND 860 866
FT STRAND 872 875
FT STRAND 878 880
FT STRAND 882 888
FT STRAND 892 902
FT STRAND 906 919
FT STRAND 922 932
FT HELIX 942 947
FT HELIX 949 952
FT STRAND 956 962
FT STRAND 968 970
FT STRAND 983 988
FT HELIX 989 995
FT HELIX 997 999
FT HELIX 1001 1003
FT STRAND 1009 1012
FT HELIX 1013 1031
FT HELIX 1034 1037
FT HELIX 1041 1057
FT TURN 1062 1064
FT STRAND 1067 1072
FT HELIX 1076 1089
FT TURN 1090 1092
FT HELIX 1097 1111
FT TURN 1114 1116
FT HELIX 1127 1133
FT HELIX 1139 1158
FT TURN 1159 1161
FT HELIX 1165 1179
FT HELIX 1180 1182
FT HELIX 1186 1198
FT HELIX 1204 1213
FT TURN 1216 1218
FT STRAND 1223 1225
FT HELIX 1226 1243
FT TURN 1246 1248
FT HELIX 1249 1258
FT STRAND 1262 1265
FT HELIX 1269 1285
FT STRAND 1293 1299
FT STRAND 1303 1305
FT STRAND 1307 1312
FT STRAND 1313 1316
FT STRAND 1320 1326
FT STRAND 1331 1333
FT STRAND 1337 1339
FT STRAND 1340 1350
FT STRAND 1359 1369
FT STRAND 1381 1392
FT STRAND 1394 1396
FT STRAND 1400 1406
FT STRAND 1409 1413
FT HELIX 1415 1423
FT STRAND 1424 1426
FT STRAND 1430 1432
FT TURN 1438 1440
FT STRAND 1443 1449
FT STRAND 1453 1455
FT STRAND 1459 1467
FT STRAND 1469 1471
FT STRAND 1475 1481
FT STRAND 1484 1493
FT TURN 1495 1498
FT STRAND 1504 1507
FT STRAND 1510 1513
FT TURN 1515 1517
FT STRAND 1518 1520
FT TURN 1524 1526
FT HELIX 1529 1535
FT STRAND 1537 1540
FT STRAND 1541 1554
FT STRAND 1556 1570
FT STRAND 1581 1587
FT HELIX 1588 1590
FT HELIX 1591 1594
FT STRAND 1601 1607
FT HELIX 1608 1610
FT STRAND 1611 1613
FT STRAND 1615 1617
FT STRAND 1619 1621
FT STRAND 1627 1631
FT HELIX 1634 1636
FT STRAND 1637 1639
FT TURN 1640 1642
FT HELIX 1643 1657
SQ SEQUENCE 1663 AA; 187148 MW; 30C2832A9E75FFC4 CRC64;
MGPTSGPSLL LLLLTHLPLA LGSPMYSIIT PNILRLESEE TMVLEAHDAQ GDVPVTVTVH
DFPGKKLVLS SEKTVLTPAT NHMGNVTFTI PANREFKSEK GRNKFVTVQA TFGTQVVEKV
VLVSLQSGYL FIQTDKTIYT PGSTVLYRIF TVNHKLLPVG RTVMVNIENP EGIPVKQDSL
SSQNQLGVLP LSWDIPELVN MGQWKIRAYY ENSPQQVFST EFEVKEYVLP SFEVIVEPTE
KFYYIYNEKG LEVTITARFL YGKKVEGTAF VIFGIQDGEQ RISLPESLKR IPIEDGSGEV
VLSRKVLLDG VQNPRAEDLV GKSLYVSATV ILHSGSDMVQ AERSGIPIVT SPYQIHFTKT
PKYFKPGMPF DLMVFVTNPD GSPAYRVPVA VQGEDTVQSL TQGDGVAKLS INTHPSQKPL
SITVRTKKQE LSEAEQATRT MQALPYSTVG NSNNYLHLSV LRTELRPGET LNVNFLLRMD
RAHEAKIRYY TYLIMNKGRL LKAGRQVREP GQDLVVLPLS ITTDFIPSFR LVAYYTLIGA
SGQREVVADS VWVDVKDSCV GSLVVKSGQS EDRQPVPGQQ MTLKIEGDHG ARVVLVAVDK
GVFVLNKKNK LTQSKIWDVV EKADIGCTPG SGKDYAGVFS DAGLTFTSSS GQQTAQRAEL
QCPQPAARRR RSVQLTEKRM DKVGKYPKEL RKCCEDGMRE NPMRFSCQRR TRFISLGEAC
KKVFLDCCNY ITELRRQHAR ASHLGLARSN LDEDIIAEEN IVSRSEFPES WLWNVEDLKE
PPKNGISTKL MNIFLKDSIT TWEILAVSMS DKKGICVADP FEVTVMQDFF IDLRLPYSVV
RNEQVEIRAV LYNYRQNQEL KVRVELLHNP AFCSLATTKR RHQQTVTIPP KSSLSVPYVI
VPLKTGLQEV EVKAAVYHHF ISDGVRKSLK VVPEGIRMNK TVAVRTLDPE RLGREGVQKE
DIPPADLSDQ VPDTESETRI LLQGTPVAQM TEDAVDAERL KHLIVTPSGC GEQNMIGMTP
TVIAVHYLDE TEQWEKFGLE KRQGALELIK KGYTQQLAFR QPSSAFAAFV KRAPSTWLTA
YVVKVFSLAV NLIAIDSQVL CGAVKWLILE KQKPDGVFQE DAPVIHQEMI GGLRNNNEKD
MALTAFVLIS LQEAKDICEE QVNSLPGSIT KAGDFLEANY MNLQRSYTVA IAGYALAQMG
RLKGPLLNKF LTTAKDKNRW EDPGKQLYNV EATSYALLAL LQLKDFDFVP PVVRWLNEQR
YYGGGYGSTQ ATFMVFQALA QYQKDAPDHQ ELNLDVSLQL PSRSSKITHR IHWESASLLR
SEETKENEGF TVTAEGKGQG TLSVVTMYHA KAKDQLTCNK FDLKVTIKPA PETEKRPQDA
KNTMILEICT RYRGDQDATM SILDISMMTG FAPDTDDLKQ LANGVDRYIS KYELDKAFSD
RNTLIIYLDK VSHSEDDCLA FKVHQYFNVE LIQPGAVKVY AYYNLEESCT RFYHPEKEDG
KLNKLCRDEL CRCAEENCFI QKSDDKVTLE ERLDKACEPG VDYVYKTRLV KVQLSNDFDE
YIMAIEQTIK SGSDEVQVGQ QRTFISPIKC REALKLEEKK HYLMWGLSSD FWGEKPNLSY
IIGKDTWVEH WPEEDECQDE ENQKQCQDLG AFTESMVVFG CPN
//

MIM 120700
*RECORD*
*FIELD* NO
120700
*FIELD* TI
*120700 COMPLEMENT COMPONENT 3; C3
C3a, INCLUDED;;
C3b, INCLUDED;;
C3c, INCLUDED;;
read moreC3d, INCLUDED;;
ACYLATION-STIMULATING PROTEIN, INCLUDED; ASP, INCLUDED
*FIELD* TX

DESCRIPTION

The complement system is an important mediator of natural and acquired
immunity. It consists of approximately 30 proteins that can exhibit
catalytic activity, function as regulators, or act as cellular surface
receptors. These components normally circulate in inactive forms and are
activated by the classical, alternative, or lectin pathways. Complement
component 3 plays a central role in all 3 activation pathways (summary
by Reis et al., 2006).

For a review of the complement system and its components, see Degn et
al. (2011).

CLONING

De Bruijn and Fey (1985) presented the complete coding sequence of the
C3 gene and the derived amino acid sequence. C3 is an acute phase
reactant; increased synthesis of C3 is induced during acute
inflammation. The liver is the main site of synthesis, although small
amounts are also produced by activated monocytes and macrophages. A
single chain precursor (pro-C3) of approximately 200 kD is found
intracellularly; the cDNA shows that it comprises 1,663 amino acids.
This is processed by proteolytic cleavage into alpha (C3a) and beta
(C3b) subunits which in the mature protein are linked by disulfide
bonds. Pro-C3 contains a signal peptide of 22 amino acid residues, the
beta chain (645 residues) and the alpha chain (992 residues). The 2
chains are joined by 4 arginine residues that are not present in the
mature protein. Human C3 has 79% identity to mouse C3 at the nucleotide
level and 77% at the amino acid level.

BIOCHEMICAL FEATURES

- Crystal Structure

Janssen et al. (2005) presented the crystal structures of native C3 and
its final major proteolytic fragment C3c. The structures revealed 13
domains, 9 of which were unpredicted, and suggested that the proteins of
the alpha-2-macroglobulin family evolved from a core of 8 homologous
domains. A double mechanism prevents hydrolysis of the thioester group,
essential for covalent attachment of activated C3 to target surfaces.
Marked conformational changes in the alpha chain, including movement of
a critical interaction site through a ring formed by the domains of the
beta chain, indicated an unprecedented, conformation-dependent mechanism
of activation, regulation, and biologic function of C3.

Janssen et al. (2006) presented the crystal structure at 4-angstrom
resolution of the activated complement protein C3b and described the
conformation rearrangements of the 12 domains that take place upon
proteolytic activation. In the activated form the thioester is fully
exposed for covalent attachment to target surfaces and is more than 85
angstroms away from the buried site in native C3. Marked domain
rearrangements in the alpha chain present an altered molecular surface,
exposing hidden and cryptic sites that are consistent with known
putative binding sites of factor B (CFB; 138470) and several complement
regulators. The structural data indicated that the large conformational
changes in the proteolytic activation and regulation of C3 take place
mainly in the first conversion step, from C3 to C3b.

Wiesmann et al. (2006) presented the crystal structure of C3b in complex
with CRIG (300353) and, using CRIG mutants, provided evidence that CRIG
acts as an inhibitor of the alternative pathway of complement. The
structure shows that activation of C3 induces major structural
rearrangements, including a dramatic movement (greater than 80
angstroms) of the thioester bond-containing domain through which C3b
attaches to pathogen surfaces. Wiesmann et al. (2006) showed that CRIG
is not only a phagocytic receptor, but also a potent inhibitor of the
alternative pathway convertases. Wiesmann et al. (2006) concluded that
the structure provides insights into the complex macromolecular
structural rearrangements that occur during complement activation and
inhibition.

Ajees et al. (2006) presented a structure of C3b that reveals a marked
loss of secondary structure in the CUB (complement C1r/Cls, Uegf, Bmp1)
domain, which together with the resulting translocation of the thioester
domain provides a molecular basis for conformational changes
accompanying the conversion of C3 to C3b. Ajees et al. (2006) suggested
that the total conformational changes make many proposed ligand-binding
sites more accessible and create a cavity that shields target peptide
bonds from access by factor I. A covalently bound N-acetyl-L-threonine
residue demonstrates the geometry of C3b attachment to surface hydroxyl
groups.

Forneris et al. (2010) presented crystal structures of the proconvertase
C3bB at 4-angstrom resolution and its complex with factor D at
3.5-angstrom resolution. Their data showed how factor B binding to C3b
forms an open 'activation' state of C3bB. Factor D specifically binds
the open conformation of factor B through a site distant from the
catalytic center and is activated by the substrate, which displaces
factor D's self-inhibitory loop. This concerted proteolytic mechanism,
which if cofactor-dependent and substrate-induced, restricts complement
amplification to C3b-tagged target cells.

GENE FUNCTION

Component C3 plays several important biologic roles in the classical,
alternative, and lectin activation pathways, e.g., (1) formation of C3-
and C5-convertases, both essential for the full activation of the
system; (2) production of opsonins that enhance phagocytosis of
microorganisms; (3) degranulation of mast cells and basophils medicated
by the fragments C3a and C5a; (4) solubilization and clearance of
C3b-bound immune complexes; (5) adjuvant function of fragments C3d and
C3dg; and (6) clearance of apoptotic cells (summary by Reis et al.,
2006).

Polymorphisms in complement factor H (CFH; 134370), the main regulator
of the activation of C3, have been associated with susceptibility to
age-related macular degeneration (see ARMD4, 610698). Sivaprasad et al.
(2007) noted that only the C3a des Arg form of C3a is present in human
plasma. They therefore studied the levels of C3a des Arg in 84 persons
with a clinical diagnosis of ARMD compared with those in age-matched
controls. The levels were significantly raised in the patient group
compared with those in the control group. Sivaprasad et al. (2007) also
found that the concentration of plasma C3a des Arg did not differ
significantly between those with different CFH genotypes. The authors
suggested that systemic activation of the complement system may
contribute to the pathogenesis of ARMD independent of CFH polymorphism.

By immunofluorescence microscopy, Rahpeymai et al. (2006) demonstrated
that mouse neural progenitor cells and immature neurons expressed C3ar
(605246) and C5ar (113995). Mice lacking C3 or C3ar, or treated with a
C3ar antagonist, show decreased basal neurogenesis and impaired
ischemia-induced neurogenesis in the subventricular zone and in the
ischemic region. Rahpeymai et al. (2006) concluded that, in the adult
mammalian CNS, complement activation products promote both basal and
ischemia-induced neurogenesis.

GENE STRUCTURE

Fong et al. (1990) reported that the complete C3 gene is 41 kb long,
comprising 41 exons. The beta chain spans 13 kb from exon 1 to exon 16.
Exon 16 encodes both alpha and beta chains. The alpha chain is 28 kb
long, with 26 exons, including exon 16.

MAPPING

Weitkamp et al. (1974) presented evidence that the Lewis blood group
locus and the C3 locus are linked. Three independent studies, by Ott et
al. (1974), Berg and Heiberg (1976) and Elston et al. (1976), strongly
suggested loose linkage between familial hypercholesterolemia and C3.

By the method of somatic cell hybridization, Whitehead et al. (1982)
assigned the gene for fibroblast-derived C3 to chromosome 19. It was at
first unclear whether fibroblast and serum C3 were identical; it was
known that fibroblast C1q (120560) and serum C1q (120550) are different
(Skok et al., 1981). Studies with a C3 probe (Davies et al., 1984)
suggested that there was only one C3 gene per haploid chromosome set; no
other hybridization was observed with relaxed stringency. Furthermore,
no recombination was observed between probe and serum C3 (Williamson,
1983). Thus, serum and fibroblast C3 almost certainly have the same
genetic basis. A specific antihuman C3 monoclonal antibody was used by
Whitehead et al. (1982) in their mapping studies. The assignment to
chromosome 19 was confirmed by use of a unique-sequence human genomic C3
DNA clone as a probe in DNA hybridization experiments with DNA prepared
from appropriate human-mouse somatic cell hybrids (Whitehead et al.,
1982).

Sanders et al. (1984) studied the linkage of polymorphic serum C3 to
Lewis (111100) and secretor (182100) and found low positive lod scores
for all 3 linkages. They favored the order SE--C3--LE. Eiberg et al.
(1983) found linkage of secretor with the serum C3 polymorphism (male
lod = 4.35, theta = 0.12). There was suggestive evidence of linkage of
secretor with PEPD (male and female lod = 2.41, theta = 0.00) and of C3
with PEPD (male lod = 0.95, theta = 0.17)--independent confirmation of
assignment to chromosome 19 where PEPD is known to be by somatic cell
studies. What they termed Lewis secretion (LES) was also linked to C3
(male lod = 3.63, theta = 0.04). They suggested that the most likely
sequence is LES--C3--DM--(Se-PEPD)--Lu.

Ball et al. (1984) regionalized C3 to 19pter-p13.2. Brook et al. (1984)
assigned the gene to 19pter-p13 and concluded that familial
hypercholesterolemia is probably distal to C3 in the pter-p13 segment.
Brook et al. (1985) later presented data suggesting that the LDL
receptor is proximal to C3.

Lusis et al. (1986) used a reciprocal whole arm translocation between
the long arm of 19 and the short arm of chromosome 1 to map APOC1,
APOC2, APOE, and GPI to the long arm and LDLR, C3, and PEPD to the short
arm. Furthermore, they isolated a single lambda phage that carried both
APOC1 and APOE separated by about 6 kb of genomic DNA. Since family
studies indicate close linkage of APOE and APOC2, the 3 must be in a
cluster on 19q. Judging by the sequence of loci suggested by linkage
data (pter--FHC--C3--APOE/APOC2), the location of LDLR is probably
19p13.2-p13.12 and of C3, 19p13.2-p13.11.

MOLECULAR GENETICS

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

In a grandmother, mother, and 2 sons, Wieme and Demeulenaere (1967)
found a double electrophoretic band corresponding apparently to
complement component C-prime-3 (as it was then called). By means of high
voltage starch gel electrophoresis, Azen and Smithies (1968) also found
electrophoretic polymorphism of the third component of complement. This
component has many important functions in immune mechanisms. Alper and
Propp (1968) independently found polymorphism of C3.

- Complement Component 3 Deficiency

Alper et al. (1972) described an Afrikaner patient with a striking
susceptibility to pyogenic infection who was apparently homozygous for
C3 deficiency (613779). Her C3 levels were one-thousandth or less of
normal. Many relatives, including both parents, had approximately
half-normal levels. In the patient reported by Alper et al. (1972),
Botto et al. (1992) demonstrated homozygosity for a partial deletion of
the C3 gene (120700.0004) as the molecular basis of the deficiency.

Nilsson et al. (1992) described 3 sisters who were compound
heterozygotes for a null allele inherited from the father and a
dysfunctional C3 allele inherited from the mother. Alternative pathway
complement function was absent, but classic pathway complement function
was partially intact. One of the sisters, the proband, had an SLE-like
disease. The proband's C3 proved normally susceptible to trypsin
proteolysis and partially resistant to classical pathways, but
completely resistant to alternative pathway, convertase-dependent
cleavage.

In a 22-year-old Japanese male patient with C3 deficiency and an
SLE-like, who was born of consanguineous parents, Tsukamoto et al.
(2005) identified a homozygous splice site mutation (120700.0009).

- Age-Related Macular Degeneration

Yates et al. (2007) genotyped SNPs spanning the complement genes C3 and
C5 in 603 Caucasian English patients with age-related macular
degeneration (ARMD9; 611378) and 350 controls and found that the common
functional R102G polymorphism in the C3 gene (dbSNP rs2230199;
120700.0001), was strongly associated with ARMD (p = 5.9 x 10(-5)). The
association was replicated in a Scottish group of 244 cases and 351
controls (p = 5.0 x 10(-5)).

Maller et al. (2007) identified a nonsynonymous coding change in C3 that
was strongly associated with risk of age-related macular degeneration in
a large case-control sample (p less than 10(-12)). The nonsynonymous
coding change (R102G) in the third exon of C3 was the same as that
identified by Yates et al. (2007).

Seddon et al. (2013) sequenced the exons of 681 genes within all
reported ARMD loci and related pathways in 2,493 cases. Seddon et al.
(2013) genotyped 5,115 independent samples and confirmed associations
with ARMD of an allele in C3 encoding a lys155-to-gln variant
(120700.0010).

- Susceptibility to Atypical Hemolytic Uremic Syndrome 5

In 11 probands with atypical hemolytic uremic syndrome (AHUS5; 612925),
Fremeaux-Bacchi et al. (2008) identified 9 different mutations in the C3
gene (see, e.g., 120700.0005-120700.0008). Five of the mutations
resulted in a gain of function with resistance to degradation by MCP
(120920) and CFI (217030), and 2 resulted in haploinsufficiency. Family
history, when available, showed decreased penetrance.

EVOLUTION

Because C3, C4 (120810), and C5 (120900) are strikingly similar, a
common evolutionary origin has been supposed (Whitehead et al., 1982).
C4 is in the major histocompatibility complex on chromosome 6, but C3
and C5 are not. (In the mouse, both C3 and H2 are on chromosome 17, but
not in close proximity. In the chimpanzee, as in man, C2 (613927) and Bf
are closely linked to the MHC and neither C3 nor C8 (120950) is closely
linked to MHC. C6 deficiency was observed in the chimpanzee.) The
protease alpha-2-macroglobulin (103950) also shows considerable homology
to C3, suggesting a common evolutionary origin.

ANIMAL MODEL

Johnson et al. (1986) described C3 deficiency in Brittany spaniel dogs.
Like the human disorder, this appears to be due to a null gene which
apparently is not closely linked to the canine major histocompatibility
complex.

Circolo et al. (1999) generated C3-deficient mice by disrupting the
promoter region and exon 1 of the C3 gene. They detected C3 expression
in lung, kidney, heart, spleen, and adipose, but not liver tissue, in
these mice. Although pro-C3 could be found in lung tissue, there was no
detectable secretion of mature C3. The mutant mice had dramatically
decreased resistance to S. pneumoniae. Circolo et al. (1999) concluded
that this model could be useful for the study of complete C3 deficiency.

Functional impairment of ASP has been hypothesized to be a major cause
of hyperapobetalipoproteinemia. However, Wetsel et al. (1999) could not
detect significant differences in lipids or lipoproteins in sera of
Asp-deficient mice and wildtype mice. They concluded that Asp deficiency
does not cause hyperapobetalipoproteinemia in mice.

Using C3-deficient mice in an allergen-induced model of pulmonary
allergy, Drouin et al. (2001) showed that these mice had diminished
airway hyperresponsiveness and lung eosinophilia. ELISPOT analysis
demonstrated reduced numbers of interleukin-4 (IL4; 147780)-producing
cells and attenuated antigen-specific IgE and IgG responses. Drouin et
al. (2001) concluded that C3 contributes significantly to the
pathogenesis of asthma resulting from pulmonary allergy and that
complement has a role in the production of IL4, a Th2 cytokine that is
critical to the development of airway hyperresponsiveness and IgE
responses in asthma.

Pratt et al. (2002) noted that the role of local, as opposed to hepatic,
secretion of complement by epithelial and vascular cells is unclear.
Proximal tubular epithelial cells (PTECs) synthesize C3 in transplanted
kidneys and production by PTECs increases during transplant rejection.
Pratt et al. (2002) found that in mice, wildtype-donor transplanted
kidneys were rejected by recipients in 12 days, whereas C3 -/- donor
kidneys transplanted into immunocompetent recipients survived for over
100 days. When C3-deficient mice were the recipients, the grafts
survived only 16 days, suggesting that locally synthesized rather than
circulating C3 has a greater influence on graft rejection. RT-PCR and
immunohistochemical analysis indicated that the cortical tubular
epithelium is the principal site of C3 expression as well as being the
main site of graft inflammation. Stimulation ex vivo of T cells from
recipients of C3-null kidneys generated reduced responses in mixed
lymphocyte reactions. Interferon-gamma (IFNG; 147570) treatment of
wildtype PTECs enhanced C3 production, but the expression of CD80
(112203), CD86 (601020), or MHC class II was not different in treated
C3-deficient cells. IL2 (147680) production was also lower in response
to Ifng-treated PTECs from C3 -/- mice. Flow cytometric analysis
demonstrated an expanded population of CD4+ Th1-like cells expressing
complement receptors CR1 (120620) and CR2 (120650) in the spleens of the
recipients of wildtype kidneys. Immunofluorescence microscopy
demonstrated rejecting graft infiltrates containing a similar population
of T cells in the peritubular and perivascular regions. Pratt et al.
(2002) concluded that local tissue production of C3 is important in
renal graft survival and that rejection is most likely mediated by T
cell recognition of C3-tagged graft cells.

Acylation-stimulating protein (ASP) is an adipocyte-derived product of
C3 cleavage and modification. ASP acts as a paracrine anabolic regulator
toward adipose tissue by stimulating glucose uptake and nonesterified
fatty acid storage. Genetic deficiency of C3 in mice leads to reduced
body fat and decreased leptin (164160) levels. Some male mice also show
delayed triglyceride clearance. Xia et al. (2002) developed C3 and
leptin (ob/ob) double-knockout (2KO) mice. Compared with ob/ob mice, 2KO
mice had delayed postprandial triglyceride and fatty acid clearance that
was associated with decreased body weight and increased insulin
sensitivity. Food intake was increased over that of ob/ob mice, but this
was balanced by increased energy expenditure as measured by oxygen
consumption. Although several metabolic measures were improved relative
to ob/ob mice, they were not returned to normal. Xia et al. (2002)
concluded that the regulation of energy storage by ASP influences energy
expenditure and metabolic balance.

Huber-Lang et al. (2006) found that wildtype mice and C3 -/- mice
developed intense lung injury after immune complex deposition, whereas
injury was attenuated in C5 (120900) -/- mice. Wildtype and C3 -/- mice
had similar levels of C5a in bronchoalveolar lavage fluid, and lung
injury was attenuated by administration of anti-C5a. Treatment of C3 -/-
mice, but not wildtype mice, with antithrombin or the leech
anticoagulant hirudin also attenuated lung injury. C3 -/- mice had
3-fold more thrombin (F2; 176930) activity than wildtype mice, and
levels of prothrombin mRNA and protein and thrombin protein in liver
were higher than in wildtype mice. Incubation of human C5 with thrombin
generated biologically active C5a. Huber-Lang et al. (2006) concluded
that, in the absence of C3, thrombin substitutes for C3-dependent C5
convertase and that there is linkage between the complement and
coagulation pathways to activate complement.

*FIELD* AV
.0001
MACULAR DEGENERATION, AGE-RELATED, 9, SUSCEPTIBILITY TO
C3S/C3F POLYMORPHISM
C3, ARG102GLY

Botto et al. (1990) studied the molecular basis of the C3F versus C3S
polymorphism. The less common variant, C3F, occurs with appreciable
frequencies (gene frequency = 0.20) only in the Caucasoid populations.
Botto et al. (1990) found a single-nucleotide change, C to G, at
position 364 in exon 3, distinguishing C3S and C3F. This led to a
substitution of an arginine residue in C3S for a glycine residue in C3F
(R102G). The substitution resulted in a polymorphic restriction site for
the enzyme HhaI.

The 3 pathways of complement activation proceed through the cleavage of
C3, the most abundant and functionally diverse complement component. The
renal tubular epithelium is both an important extrahepatic source of C3
and a major target of immunologic injury during rejection of renal
grafts. The donor kidney contributes 5% of the total circulating C3 pool
when it is in its stable state but up to 16% during acute rejection.
Brown et al. (2006) determined the C3 allotypes of 662 pairs of adult
kidney donors and recipients and then related C3F/S polymorphism status
to demographic and clinical outcome data. Among white C3S/S recipients,
receipt of a C3F/F or C3F/S donor kidney, rather than a C3S/S donor
kidney, was associated with a significantly better long-term outcome.
These findings suggested that the 2 alleles have functional differences.

In a study of 603 Caucasian English patients with age-related macular
degeneration (ARMD9; 611378) and 350 controls, Yates et al. (2007) found
that the R102G polymorphism, which they referred to as R80G based on
numbering that eliminated the 22 residues of the signal peptide, was
strongly associated with ARMD (p = 5.9 x 10(-5)). The association was
replicated in a Scottish group of 244 cases and 351 controls (p = 5.0 x
10(-5)). The 102R and 102G alleles correspond to slow (C3S) and fast
(C3F) electrophoretic variants, respectively. The odds ratio for ARMD in
SF heterozygotes and FF homozygotes was 1.7 and 2.6, respectively,
compared to SS homozygotes. The estimated population attributable risk
for C3F was 22%.

Maller et al. (2007) also found association of ARMD with R102G in a
large case-control sample (P less than 10(-12)).

In a matched sample set from the Age-Related Eye Disease Study (AREDS)
cohort involving 424 patients with ARMD and 215 patients without ARMD
acting as controls, Bergeron-Sawitzke et al. (2009) confirmed
association between ARMD and dbSNP rs2230199, with both the CG (OR, 1.9;
p = 9.0 x 10(-4)) and GG (OR, 2.5; p = 0.03) genotypes.

Fritsche et al. (2013) identified association of the C allele of dbSNP
rs2230199 with increased risk of ARMD (OR 1.42, 95% CI 1.37-1.47,
combined p = 1 x 10(-41)).

.0002
C3 POLYMORPHISM, HAV 4-1 PLUS/MINUS TYPE
C3, LEU314PRO

Botto et al. (1990) identified the molecular basis of a structural
polymorphism of C3, identified by the monoclonal antibody HAV 4-1: codon
314 in exon 9 of the beta chain showed a change of a proline residue in
the HAV 4-1(-) form to a leucine residue in the HAV 4-1(+) form.

.0003
C3 DEFICIENCY
C3, 61-BP DEL, EX18

Botto et al. (1990) studied the DNA from a 10-year-old boy who had
suffered from recurrent attacks of otitis media during the first 3 years
of life. Between 5 and 8 years of age, he suffered from more than 20
episodes of rash which affected his face, forearms, and hands and
resembled the target lesions of erythema multiforme. Attacks were
normally preceded by an upper respiratory infection, and a group A
beta-hemolytic Streptococcus was isolated from his throat during 2
episodes. The parents were consanguineous ('share a common
great-grandparent'). C3 could not be detected by RIA of serum from the
patient (613779). Segregation of C3S and C3F allotypes within the family
confirmed the presence of a null allele, for which the patient was
homozygous. DNA studies showed a GT-to-AT mutation at the 5-prime donor
splice site of intron 18 of the C3 gene. Exons 17-21 were amplified by
PCR from first-strand cDNA synthesized from mRNA obtained from
peripheral blood monocytes. This revealed a 61-bp deletion in exon 18,
resulting from splicing of a cryptic 5-prime donor splice site in exon
18 with the normal 3-prime splice site in exon 19. The deletion led to a
disturbance of the reading frame of the mRNA with a stop codon 17 bp
downstream from the abnormal splice in exon 18. Both parents were
heterozygous for the C3*Q0 allele (Q0 = quantity zero, i.e., null
allele).

.0004
C3 DEFICIENCY
C3, 800-BP DEL

Botto et al. (1992) demonstrated partial gene deletion as the molecular
basis of C3 deficiency (613779) in an Afrikaner patient previously
described by Alper et al. (1972) as homozygous C3 deficient. By Southern
blot analysis, they demonstrated that the C3 null gene had an 800-bp
deletion in exons 22 and 23, resulting in a frameshift and a stop codon
19 bp downstream from the deletion. DNA sequence analysis showed that
the deletion probably arose from homologous recombination between 2 ALU
repeats flanking the deletion. This mutant allele was found to have a
gene frequency of 0.0057 in the South African Afrikaans-speaking
population.

.0005
HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 5
C3, ARG570GLN

In 2 sibs with atypical hemolytic uremic syndrome (AHUS5; 612925),
Fremeaux-Bacchi et al. (2008) identified a heterozygous 1775G-A
transition in exon 14 of the C3 gene, resulting in an arg570-to-gln
(R570Q) substitution. Both patients developed end-stage renal disease
and had a total of 5 renal transplants; disease recurred in 1 of the
patients after transplant. In vitro functional expression studies showed
that binding of the mutant C3 protein to MCP (120290) was decreased to
22% of wildtype, which would result in resistance to cleavage by factor
I (CFI; 217030). The mutant C3 also showed reduced binding to factor H
(CFH; 134370) and iC3. The findings indicated that a modification in
interactions with regulators results in a secondary gain of function of
mutant C3. A third unrelated patient also carried this mutation, which
was inherited from her unaffected mother.

.0006
HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 5
C3, ALA1072VAL

In a 2-year-old girl with atypical hemolytic uremic syndrome-5 (612925),
Fremeaux-Bacchi et al. (2008) identified a heterozygous 3281C-T
transition in exon 26 of the C3 gene, resulting in an ala1072-to-val
(A1072V) substitution. She recovered by age 15 years. Her unaffected
father also carried the mutation. In vitro functional expression studies
showed that binding of the mutant C3 protein to MCP (120290) was
decreased to 18% of wildtype, which would result in resistance to
cleavage by factor I (CFI; 217030). The mutant C3 also showed reduced
binding to factor H (CFH; 134370) and iC3. The findings indicated that a
modification in interactions with regulators results in a secondary gain
of function of mutant C3.

.0007
HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 5
C3, ASP1093ASN

In a 23-year-old woman with atypical hemolytic uremic syndrome (AHUS5;
612925), Fremeaux-Bacchi et al. (2008) identified a heterozygous 3343G-A
transition in exon 26 of the C3 gene, resulting in an asp1093-to-asn
(D1093N) substitution. She had end-stage renal disease and 2 kidney
transplants. In vitro functional expression studies showed that binding
of the mutant C3 protein to MCP (120290) was decreased to 17% of
wildtype, which would result in resistance to cleavage by factor I (CFI;
217030). The mutant C3 also showed reduced binding to factor H (CFH;
134370) and iC3. The findings indicated that a modification in
interactions with regulators results in a secondary gain of function of
mutant C3.

.0008
HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 5
C3, TYR832TER

In a 6-year-old boy with atypical hemolytic uremic syndrome-5 (612925),
Fremeaux-Bacchi et al. (2008) identified a heterozygous 2562C-G
transversion in exon 20 of the C3 gene, resulting in a tyr832-to-ter
(Y832X) substitution. The patient recovered by age 10 years. His
unaffected mother also carried the mutation. The mutation was predicted
to result in haploinsufficiency of C3. The authors noted that this
finding made the pathogenic mechanism difficult to explain relative to
the concept of increased complement activation as the predisposing event
in aHUS.

.0009
C3 DEFICIENCY
C3, IVS38AS, A-G

In a 22-year-old Japanese male patient with C3 deficiency (613779) and
systemic lupus erythematosus, born of consanguineous parents, Tsukamoto
et al. (2005) identified a homozygous A-to-G transition in the acceptor
site of intron 38 of the C3 gene, resulting in skipping of exon 39.
Complement assay detected no C3 in serum and only a trace amount of C3
hemolytic activity. Both parents and 2 sibs were heterozygous for the
mutation, and all had reduced levels of C3 hemolytic activity. The
patient had suffered from photosensitivity, recurrent fever, and facial
erythema from childhood. Expression of the mutant cDNA in COS-7 cells
resulted retention of the molecule in the ER-Golgi intermediate
compartment due to defective secretion. Tsukamoto et al. (2005)
concluded that SLE or an SLE-like disease is a complication of
hereditary homozygous C3 deficiency in Japan.

.0010
MACULAR DEGENERATION, AGE-RELATED, 9, SUSCEPTIBILITY TO
C3, LYS155GLN (dbSNP rs147859257)

Seddon et al. (2013) identified an increased risk of age-related macular
degeneration (ARMD9; 611378) in individuals with a lys155-to-gln (K155Q)
variant (dbSNP rs147859257) with a joint p value of 5.2 x 10(-9) and an
odds ratio of 3.8. Seddon et al. (2013) showed that substitution of gln
for lys at codon 155 results in resistance to proteolytic inactivation
by CFH (134370) and CFI (217030). They concluded that their results
implicated loss of C3 protein regulation and excessive alternative
complement activation in ARMD pathogenesis.

Through whole-genome sequencing of 2,230 Icelanders, Helgason et al.
(2013) detected a rare nonsynonymous SNP with a minor allele frequency
of 0.55% in the C3 gene encoding a K155Q substitution which, following
imputation into a set of Icelandic cases with ARMD and controls,
associated with disease (odds ratio = 3.45; p = 1.1 x 10(-7)). This
signal was independent of the common SNPs in C3 encoding P314L
(120700.0002) and R102G (120700.0001) that associate with ARMD. The
association of the K155Q variant was replicated in ARMD case-control
samples of European ancestry with an odds ratio of 4.22 and a p value of
1.6 x 10(-10), resulting in an odds ratio of 3.65 and a p value of 8.8 x
10(-16) for all studies combined. In vitro studies suggested that the
K155Q substitution reduces C3 binding to CFH, potentially creating
resistance to inhibition by this factor. This resistance to inhibition
in turn was predicted to result in enhanced complement activation.

Zhan et al. (2013) sequenced 2,335 cases and 789 controls in 10
candidate loci (57 genes) and then augmented their control set with
ancestry-matched exome-sequenced controls. An analysis of coding
variation in 2,268 ARMD cases and 2,268 ancestry-matched controls
identified 2 large-effect rare variants: K155Q encoded in the C3 gene,
with a case frequency of 1.06%, control frequency of 0.39%, and odds
ratio of 2.68; and R1210C (134370.0017) encoded in the CFH gene, with a
case frequency of 0.51%, control frequency of 0.02%, and odds ratio of
23.11. The variants suggested decreased inhibition of C3 by CFH,
resulting in increased activation of the alternative complement pathway,
as a key component of disease biology.

*FIELD* SA
Alper et al. (1976); Alper et al. (1969); Alper and Rosen (1971);
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Koch and Behrendt (1986); McLean et al. (1985); Muller-Eberhard (1968);
Raum et al. (1980); Raum et al. (1980); Teisberg (1971); Teisberg
(1970); Walport (2001); Whitehead et al. (1981); Winkelstein et al.
(1981)
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59. Teisberg, P.: New variants in the C3 system. Hum. Hered. 20:
631-637, 1970.

60. Tsukamoto, H.; Horiuchi, T.; Kokuba, H.; Nagae, S.; Nishizaka,
H.; Sawabe, T.; Harashima, S.; Himeji, D.; Koyama, T.; Otsuka, J.;
Mitoma. H.; Kimoto, Y.; Hashimura, C.; Kitano, E.; Kitamura, H.; Furue,
M.; Harada, M.: Molecular analysis of a novel hereditary C3 deficiency
with systemic lupus erythematosus. Biochem. Biophys. Res. Commun. 330:
298-304, 2005.

61. Walport, M. J.: Complement (first of two parts). New Eng. J.
Med. 344: 1058-1066, 2001.

62. Weitkamp, L. R.; Johnston, E.; Guttormsen, S. A.: Probable genetic
linkage between the loci for the Lewis blood group and complement
C3. Cytogenet. Cell Genet. 13: 183-184, 1974.

63. Wetsel, R. A.; Kildsgaard, J.; Zsigmond E.; Liao, W.; Chan, L.
: Genetic deficiency of acylation stimulating protein (ASP(C3ades-Arg))
does not cause hyperapobetalipoproteinemia in mice. J. Biol. Chem. 274:
19429-19433, 1999.

64. Whitehead, A. S.; Sim, R. B.; Bodmer, W. F.: A monoclonal antibody
against human complement component C3: the production of C3 by human
cells in vitro. Europ. J. Immun. 11: 140-146, 1981.

65. Whitehead, A. S.; Solomon, E.; Chambers, S.; Bodmer, W. F.; Povey,
S.; Fey, G.: Assignment of the structural gene for the third component
of human complement to chromosome 19. Proc. Nat. Acad. Sci. 79:
5021-5025, 1982.

66. Wieme, R. J.; Demeulenaere, L.: Genetically determined electrophoretic
variant of the human complement component C-prime-3. Nature 214:
1042-1043, 1967.

67. Wiesmann, C.; Katschke, K. J., Jr.; Yin, J.; Helmy, K. Y.; Steffek,
M.; Fairbrother, W. J.; McCallum, S. A.; Embuscado, L.; DeForge, L.;
Hass, P. E.; van Lookeren Campagne, M.: Structure of C3b in complex
with CRIg gives insights into regulation of complement activation. Nature 444:
217-220, 2006.

68. Williamson, R.: Personal Communication. London, England 8/25/1983.

69. Winkelstein, J. A.; Cork, L. C.; Griffin, D. E.; Griffin, J. W.;
Adams, R. J.; Price, D. L.: Genetically determined deficiency of
the third component of complement in the dog. Science 212: 1169-1170,
1981.

70. Xia, Z.; Sniderman, A. D.; Cianflone, K.: Acylation-stimulating
protein (ASP) deficiency induces obesity resistance and increased
energy expenditure in ob/ob mice. J. Biol. Chem. 277: 45874-45879,
2002.

71. Yates, J. R. W.; Sepp, T.; Matharu, B. K.; Khan, J. C.; Thurlby,
D. A.; Shahid, H.; Clayton, D. G.; Hayward, C.; Morgan, J.; Wright,
A. F.; Armbrecht, A. M.; Dhillon, B.; Deary, I. J.; Redmond, E.; Bird,
A. C.; Moore, A. T.: Complement C3 variant and the risk of age-related
macular degeneration. New Eng. J. Med. 357: 553-561, 2007.

72. Zhan, X.; Larson, D. E.; Wang, C.; Koboldt, D. C.; Sergeev, Y.
V.; Fulton, R. S.; Fulton, L. L.; Fronick, C. C.; Branham, K. E.;
Bragg-Gresham, J.; Jun, G.; Hu, Y; and 48 others: Identification
of a rare coding variant in complement 3 associated with age-related
macular degeneration. Nature Genet. 45: 1375-1379, 2013.

*FIELD* CN
Ada Hamosh - updated: 01/08/2014
Ada Hamosh - updated: 10/22/2013
Ada Hamosh - updated: 1/28/2011
Paul J. Converse - updated: 6/11/2010
Paul J. Converse - updated: 5/25/2010
Marla J. F. O'Neill - updated: 1/27/2010
Jane Kelly - updated: 10/30/2007
Victor A. McKusick - updated: 10/18/2007
Marla J. F. O'Neill - updated: 8/21/2007
Ada Hamosh - updated: 11/28/2006
Paul J. Converse - updated: 7/20/2006
Victor A. McKusick - updated: 6/22/2006
Ada Hamosh - updated: 11/3/2005
Patricia A. Hartz - updated: 4/28/2003
Paul J. Converse - updated: 5/31/2002
Paul J. Converse - updated: 12/11/2001
Victor A. McKusick - updated: 4/25/2001

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

*FIELD* ED
alopez: 01/08/2014
alopez: 10/22/2013
alopez: 8/7/2013
carol: 7/6/2012
carol: 11/28/2011
terry: 5/17/2011
carol: 4/25/2011
terry: 3/22/2011
terry: 3/10/2011
carol: 3/1/2011
alopez: 2/3/2011
terry: 1/28/2011
mgross: 6/14/2010
terry: 6/11/2010
wwang: 5/25/2010
wwang: 1/29/2010
terry: 1/27/2010
carol: 7/30/2009
ckniffin: 7/27/2009
terry: 1/13/2009
terry: 1/12/2009
wwang: 12/27/2007
carol: 10/30/2007
alopez: 10/23/2007
terry: 10/18/2007
alopez: 10/4/2007
wwang: 8/27/2007
terry: 8/21/2007
ckniffin: 5/1/2007
alopez: 12/7/2006
terry: 11/28/2006
mgross: 8/7/2006
terry: 7/20/2006
terry: 6/22/2006
alopez: 11/7/2005
terry: 11/3/2005
terry: 5/17/2005
carol: 3/17/2004
mgross: 2/4/2004
terry: 4/28/2003
alopez: 5/31/2002
mgross: 1/9/2002
terry: 12/11/2001
carol: 4/30/2001
mcapotos: 4/26/2001
terry: 4/25/2001
carol: 8/4/1998
dkim: 6/30/1998
terry: 11/10/1997
mark: 7/30/1995
davew: 7/5/1994
mimadm: 6/25/1994
warfield: 4/8/1994
carol: 10/28/1992
carol: 8/17/1992

MIM 611378
*RECORD*
*FIELD* NO
611378
*FIELD* TI
#611378 MACULAR DEGENERATION, AGE-RELATED, 9; ARMD9
*FIELD* TX
A number sign (#) is used with this entry because there is a significant
read moreassociation between a polymorphism in the C3 gene (120700) and
susceptibility to age-related macular degeneration.

For a phenotypic description and a discussion of genetic heterogeneity
of age-related macular degeneration, see 603075.

MOLECULAR GENETICS

Yates et al. (2007) genotyped SNPs spanning the complement genes C3
(120700) and C5 (120900) in 603 Caucasian English patients with
age-related macular degeneration and 350 controls. They found that the
common functional arg102-to-gly (R102G) polymorphism in the C3 gene
(dbSNP rs2230199; 120700.0001), which they referred to as R80G based on
numbering that eliminated the 22 residues of the signal peptide, was
strongly associated with ARMD (p = 5.9 x 10(-5)). The association was
replicated in a Scottish group of 244 cases and 351 controls (p = 5.0 x
10(-5)). The 102R and 102G variants correspond to slow (C3S) and fast
(C3F) electrophoretic allotypes, respectively. The odds ratio for ARMD
in SF heterozygotes and FF homozygotes was 1.7 and 2.6, respectively,
compared to SS homozygotes. The estimated population attributable risk
for C3F was 22%.

Maller et al. (2007) likewise found association between the 102G variant
and age-related macular degeneration.

Fritsche et al. (2013) identified association of the C allele of dbSNP
rs2230199 with increased risk of ARMD (OR 1.42, 95% CI 1.37-1.47,
combined p = 1 x 10(-41)).

Seddon et al. (2013) sequenced the exons of 681 genes within all
reported ARMD loci and related pathways in 2,493 cases. They genotyped
5,115 independent samples and confirmed association with ARMD of an
allele in C3 encoding a lys155-to-gln variant (K155Q; 120700.0010)
(dbSNP rs147859257). Helgason et al. (2013) and Zhan et al. (2013) also
found association of the K155Q variant in C3 with ARMD.

*FIELD* RF
1. Fritsche, L. G.; Chen, W.; Schu, M.; Yaspan, B. L.; Yu, Y.; Thorleifsson,
G.; Zack, D. J.; Arakawa, S.; Cipriani, V.; Ripke, S.; Igo, R. P.,
Jr.; Buitendijk, G. H. S.; and 144 others: Seven new loci associated
with age-related macular degeneration. Nature Genet. 45: 433-439,
2013.

2. Helgason, H.; Sulem, P.; Duvvari, M. R.; Luo, H.; Thorleifsson,
G.; Stefansson, H.; Jonsdottir, I.; Masson, G.; Gudbjartsson, D. F.;
Walters, G. B.; Magnusson, O. T.; Kong, A.; and 25 others: A rare
nonsynonymous sequence variant in C3 is associated with high risk
of age-related macular degeneration. Nature Genet. 45: 1371-1374,
2013.

3. Maller, J. B.; Fagerness, J. A.; Reynolds, R. C.; Neale, B. M.;
Daly, M. J.; Seddon, J. M.: Variation in complement factor 3 is associated
with risk of age-related macular degeneration. Nature Genet. 39:
1200-1201, 2007.

4. Seddon, J. M.; Yu, Y.; Miller, E. C.; Reynolds, R.; Tan, P. L.;
Gowrisankar, S.; Goldstein, J. I.; Triebwasser, M.; Anderson, H. E.;
Zerbib, J.; Kavanagh, D.; Souied, E.; Katsanis, N.; Daly, M. J.; Atkinson,
J. P.; Raychaudhuri, S.: Rare variants in CFI, C3 and C9 are associated
with high risk of advanced age-related macular degeneration. Nature
Genet. 45: 1366-1370, 2013.

5. Yates, J. R. W.; Sepp, T.; Matharu, B. K.; Khan, J. C.; Thurlby,
D. A.; Shahid, H.; Clayton, D. G.; Hayward, C.; Morgan, J.; Wright,
A. F.; Armbrecht, A. M.; Dhillon, B.; Deary, I. J.; Redmond, E.; Bird,
A. C.; Moore, A. T.: Complement C3 variant and the risk of age-related
macular degeneration. New Eng. J. Med. 357: 553-561, 2007.

6. Zhan, X.; Larson, D. E.; Wang, C.; Koboldt, D. C.; Sergeev, Y.
V.; Fulton, R. S.; Fulton, L. L.; Fronick, C. C.; Branham, K. E.;
Bragg-Gresham, J.; Jun, G.; Hu, Y; and 48 others: Identification
of a rare coding variant in complement 3 associated with age-related
macular degeneration. Nature Genet. 45: 1375-1379, 2013.

*FIELD* CN
Ada Hamosh - updated: 01/08/2014
Ada Hamosh - updated: 10/22/2013
Victor A. McKusick - updated: 10/18/2007

*FIELD* CD
Marla J. F. O'Neill: 8/27/2007

*FIELD* ED
alopez: 01/08/2014
alopez: 10/22/2013
alopez: 10/23/2007
terry: 10/18/2007
wwang: 8/27/2007

MIM 612925
*RECORD*
*FIELD* NO
612925
*FIELD* TI
#612925 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 5; AHUS5
;;AHUS, SUSCEPTIBILITY TO, 5
read more*FIELD* TX
A number sign (#) is used with this entry because susceptibility to the
development of atypical hemolytic uremic syndrome-5 (AHUS5) can be
conferred by mutation in the gene encoding complement component-3 (C3;
120700).

For a general phenotypic description and a discussion of genetic
heterogeneity of aHUS, see AHUS1 (235400).

CLINICAL FEATURES

Fremeaux-Bacchi et al. (2008) reported 11 probands with atypical HUS.
Further pedigree analysis showed that 1 proband had 2 additional
affected family members and another had 1 additional affected family
member. Age at onset ranged from 8 months to 40 years. Most developed
end-stage renal disease, and all had decreased serum C3. Six patients
had undergone renal transplantation, 3 of whom had recurrence of the
disease after transplantation.

MOLECULAR GENETICS

In 11 probands with atypical HUS, Fremeaux-Bacchi et al. (2008)
identified 9 different heterozygous mutations in the C3 gene (see, e.g.,
120700.0005-120700.0008). Five of the mutations resulted in a gain of
function with resistance to degradation by MCP (120920) and CFI
(217030), and 2 resulted in haploinsufficiency. Family history, when
available, showed decreased penetrance.

*FIELD* RF
1. Fremeaux-Bacchi, V.; Miller, E. C.; Liszewski, M. K.; Strain, L.;
Blouin, J.; Brown, A. L.; Moghal, N.; Kaplan, B. S.; Weiss, R. A.;
Lhotta, K.; Kapur, G.; Mattoo, T.; and 14 others: Mutations in
complement C3 predispose to development of atypical hemolytic uremic
syndrome. Blood 112: 4948-4952, 2008.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Vascular];
Hypertension (variable)

GENITOURINARY:
[Kidneys];
Acute renal failure;
Hematuria;
Proteinuria;
Anuria

HEMATOLOGY:
Microangiopathic hemolytic anemia;
Thrombocytopenia;
Thrombotic microangiopathy;
Fragmented erythrocytes;
Decreased hemoglobin

IMMUNOLOGY:
Defective complement regulation

LABORATORY ABNORMALITIES:
Increased blood urea nitrogen (BUN);
Increased creatinine;
Decreased or normal serum C3

MISCELLANEOUS:
Variable age of onset (childhood to young adulthood);
Recurrence is possible

MOLECULAR BASIS:
Susceptibility conferred by mutation in the complement component 3
gene (C3, 120700.0005)

*FIELD* CD
Cassandra L. Kniffin: 5/9/2012

*FIELD* ED
joanna: 05/10/2012
joanna: 5/9/2012
ckniffin: 5/9/2012

*FIELD* CD
Cassandra L. Kniffin: 7/23/2009

*FIELD* ED
joanna: 05/15/2012
carol: 7/30/2009
ckniffin: 7/27/2009

MIM 613779
*RECORD*
*FIELD* NO
613779
*FIELD* TI
#613779 COMPLEMENT COMPONENT 3 DEFICIENCY, AUTOSOMAL RECESSIVE; C3D
;;C3 DEFICIENCY, AUTOSOMAL RECESSIVE
read more*FIELD* TX
A number sign (#) is used with this entry because primary C3 deficiency
is caused by homozygous or compound heterozygous mutation in the C3 gene
(120700) on chromosome 19p13.

DESCRIPTION

The main clinical manifestation of primary C3 deficiency is
childhood-onset of recurrent bacterial infections, mainly caused by
gram-negative bacteria, such as Neisseria meningitidis, Enterobacter
aerogenes, Haemophilus influenzae, and Escherichia coli; infections with
gram-positive bacteria also occur. Infections in the upper and lower
respiratory tract, including pneumonia, episodes of sinusitis,
tonsillitis, and otitis, are the most frequent consequence of the C3
deficiency. Approximately 26% of patients with C3 deficiency develop
immune complex-mediated autoimmune diseases resembling systemic lupus
erythematosus (see 152700), and about 26% of patients develop
mesangiocapillary or membranoproliferative glomerulonephritis, resulting
in renal failure (summary by Reis et al., 2006).

CLINICAL FEATURES

Alper et al. (1972) described a patient with a striking susceptibility
to pyogenic infection who was apparently homozygous for C3 deficiency.
Her C3 levels were one-thousandth or less of normal. Many relatives,
including both parents, had approximately half-normal levels.

Pussell et al. (1980) described a family in which 3 children had
homozygous C3 deficiency and both parents and 2 other children were
heterozygous for a C3 null gene. The family was of Palestinian-Lebanese
origin, living in Kuwait; the parents were thought to be cousins. The
homozygous and heterozygous children were susceptible to infection.
Proteinuria and/or microscopic hematuria were present in all 3
homozygous children, and a heterozygous child had membranoproliferative
glomerulonephritis. The only child with normal complement had neither
nephritis nor increased susceptibility to infection.

Sano et al. (1981) reported 2 sisters with C3 deficiency and systemic
lupus erythematosus (SLE; 152700)-like symptoms.

Berger et al. (1983) and Borzy et al. (1988) observed C3-deficient
homozygotes who developed mesangiocapillary glomerulonephritis. The
association of C3 deficiency with nephritis was thought to be due to
failure of a second physiologic activity of the complement system, that
of promoting the disposal of immune complexes to the mononuclear
phagocytic system.

Nilsson et al. (1992) described 3 sisters who were compound
heterozygotes for a null allele inherited from the father and a
dysfunctional C3 allele inherited from the mother. Alternative pathway
complement function was absent, but classic pathway complement function
was partially intact. One of the sisters, the proband, had an SLE-like
disease. The proband's C3 proved normally susceptible to trypsin
proteolysis and partially resistant to classical pathways, but
completely resistant to alternative pathway, convertase-dependent
cleavage.

Botto et al. (1990) studied a 10-year-old boy who had recurrent attacks
of otitis media during the first 3 years of life. Between 5 and 8 years
of age, he had more than 20 episodes of rash which affected his face,
forearms, and hands and resembled the target lesions of erythema
multiforme. Attacks were normally preceded by an upper respiratory
infection, and a group A beta-hemolytic Streptococcus was isolated from
his throat during 2 episodes. The parents were consanguineous ('share a
common great-grandparent'). C3 could not be detected by RIA of serum
from the patient.

OTHER FEATURES

McLean and Hoefnagel (1980) observed an association between partial
lipodystrophy and familial C3 deficiency. A 16-year-old girl with
familial C3 deficiency developed partial lipodystrophy affecting the
face, arms and upper torso. The pattern was reminiscent of that observed
in patients with acquired partial lipodystrophy who do not have familial
C3 deficiency (608709).

MOLECULAR GENETICS

By segregation of C3S and C3F allotypes within a family in which a child
had C3 deficiency, Botto et al. (1990) confirmed the presence of a null
C3 allele (120700.0003), for which the patient was homozygous. Both
parents were heterozygous for the null allele.

In an Afrikaner patient with C3 deficiency described by Alper et al.
(1972), Botto et al. (1992) demonstrated homozygosity for a partial
deletion of the C3 gene (120700.0004) as the molecular basis of the
deficiency.

In a 22-year-old Japanese male patient with C3 deficiency and systemic
lupus erythematosus, born of consanguineous parents, Tsukamoto et al.
(2005) identified a homozygous splice site mutation in the C3 gene
(120700.0009). Complement assay detected no C3 in serum and only a trace
amount of C3 hemolytic activity. Both parents and 2 sibs were
heterozygous for the mutation, and all had reduced levels of C3
hemolytic activity. The patient had suffered from photosensitivity,
recurrent fever, and facial erythema from childhood.

*FIELD* SA
Grace et al. (1976); McLean et al. (1980); Osofsky et al. (1977)
*FIELD* RF
1. Alper, C. A.; Colten, H. R.; Rosen, S. F.; Rabson, A. R.; MacNab,
G. M.; Gear, J. S. S.: Homozygous deficiency of C3 in a patient with
repeated infections. Lancet 300: 1179-1181, 1972. Note: Originally
Volume II.

2. Berger, M.; Balow, J. E.; Wilson, C. B.; Frank, M. M.: Circulating
immune complexes and glomerulonephritis in a patient with congenital
absence of the third component of complement. New Eng. J. Med. 308:
1009-1012, 1983.

3. Borzy, M. S.; Gewurz, A.; Wolff, L.; Houghton, D.; Lovrien, E.
: Inherited C3 deficiency with recurrent infections and glomerulonephritis. Am.
J. Dis. Child. 142: 79-83, 1988.

4. Botto, M.; Fong, K. Y.; So, A. K.; Barlow, R.; Routier, R.; Morley,
B. J.; Walport, M. J.: Homozygous hereditary C3 deficiency due to
a partial gene deletion. Proc. Nat. Acad. Sci. 89: 4957-4961, 1992.

5. Botto, M.; Fong, K. Y.; So, A. K.; Koch, C.; Walport, M. J.: Molecular
basis of polymorphisms of human complement component C3. J. Exp.
Med. 172: 1011-1017, 1990.

6. Grace, H. J.; Brereton-Stiles, G. G.; Vos, G. H.; Schonland, M.
: A family with partial and total deficiency of complement C3. S.
Afr. Med. J. 50: 139-140, 1976.

7. McLean, R. H.; Hoefnagel, D.: Partial lipodystrophy and familial
C3 deficiency. Hum. Hered. 30: 149-154, 1980.

8. McLean, R. H.; Wienstein, A.; Chapitis, J.; Lowenstein, M.; Rothfield,
N. F.: Familial partial deficiency of the third component of complement
(C3) and the hypocomplementemic cutaneous vasculitis syndrome. Am.
J. Med. 68: 549-558, 1980.

9. Nilsson, U. R.; Nilsson, B.; Storm, K.-E.; Sjolin-Forsberg, G.;
Hallgren, R.: Hereditary dysfunction of the third component of complement
associated with a systemic lupus erythematosus-like syndrome and meningococcal
meningitis. Arthritis Rheum. 35: 580-586, 1992.

10. Osofsky, S. G.; Thompson, B. H.; Lint, T. F.; Gewurz, H.: Hereditary
deficiency of 3rd component of complement in a child with fever, skin
rash, and arthralgias--response to transfusion of whole blood. J.
Pediat. 90: 180-186, 1977.

11. Pussell, B. A.; Bourke, E.; Nayef, M.; Morris, S.; Peters, D.
K.: Complement deficiency and nephritis: a report of a family. Lancet 315:
675-677, 1980. Note: Originally Volume I.

12. Reis, E. S.; Falcao, D. A.; Isaac, L.: Clinical aspects and molecular
basis of primary deficiencies of complement component C3 and its regulatory
proteins factor I and factor H. Scand. J. Immunol. 63: 155-168,
2006.

13. Sano, Y.; Nishimukai, H.; Kitamura, H.; Nagaki, K.; Inai, S.;
Hamasaki, Y.; Maruyama, I.; Igata, A.: Hereditary deficiency of the
third component of complement in two sisters with systemic lupus erythematosus-like
symptoms. Arthritis Rheum. 24: 1255-1260, 1981.

14. Tsukamoto, H.; Horiuchi, T.; Kokuba, H.; Nagae, S.; Nishizaka,
H.; Sawabe, T.; Harashima, S.; Himeji, D.; Koyama, T.; Otsuka, J.;
Mitoma. H.; Kimoto, Y.; Hashimura, C.; Kitano, E.; Kitamura, H.; Furue,
M.; Harada, M.: Molecular analysis of a novel hereditary C3 deficiency
with systemic lupus erythematosus. Biochem. Biophys. Res. Commun. 330:
298-304, 2005.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GENITOURINARY:
[Kidneys];
Membranoproliferative glomerulonephritis (in about 26%);
Nephrotic syndrome;
Renal failure

IMMUNOLOGY:
Recurrent bacterial infections;
Autoimmune disease resembling systemic lupus erythematosis (SLE, 152700)
(in about 26%)

LABORATORY ABNORMALITIES:
Decreased C3 activity;
Decreased C3 antigen

MISCELLANEOUS:
Onset in infancy or early childhood

MOLECULAR BASIS:
Caused by mutation in the complement component 3 gene (C3, 120700.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 4/20/2011

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

*FIELD* ED
joanna: 05/15/2011
ckniffin: 4/20/2011

*FIELD* CN
Cassandra L. Kniffin - updated: 4/20/2011

*FIELD* CD
Carol A. Bocchini: 2/28/2011

*FIELD* ED
terry: 06/02/2011
carol: 4/22/2011
terry: 4/21/2011
ckniffin: 4/20/2011
terry: 3/10/2011
carol: 3/2/2011
carol: 3/1/2011