Full text data of APOC3
APOC3
[Confidence: low (only semi-automatic identification from reviews)]
Apolipoprotein C-III; Apo-CIII; ApoC-III (Apolipoprotein C3; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Apolipoprotein C-III; Apo-CIII; ApoC-III (Apolipoprotein C3; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P02656
ID APOC3_HUMAN Reviewed; 99 AA.
AC P02656; Q08E83; Q6Q786;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=Apolipoprotein C-III;
DE Short=Apo-CIII;
DE Short=ApoC-III;
DE AltName: Full=Apolipoprotein C3;
DE Flags: Precursor;
GN Name=APOC3;
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 [GENOMIC DNA / MRNA].
RX PubMed=6439535;
RA Protter A.A., Levy-Wilson B., Miller J., Bencen G., White T.,
RA Seilhamer J.J.;
RT "Isolation and sequence analysis of the human apolipoprotein CIII gene
RT and the intergenic region between the apo AI and apo CIII genes.";
RL DNA 3:449-456(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6548954;
RA Levy-Wilson B., Appleby V., Protter A.A., Auperin D., Seilhamer J.J.;
RT "Isolation and DNA sequence of full-length cDNA for human
RT preapolipoprotein CIII.";
RL DNA 3:359-364(1984).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=2989400;
RA Karathanasis S.K., Zannis V.I., Breslow J.L.;
RT "Isolation and characterization of cDNA clones corresponding to two
RT different human apoC-III alleles.";
RL J. Lipid Res. 26:451-456(1985).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6328445; DOI=10.1093/nar/12.9.3917;
RA Sharpe C.R., Sidoli A., Shelley C.S., Lucero M.A., Shoulders C.C.,
RA Baralle F.E.;
RT "Human apolipoproteins AI, AII, CII and CIII. cDNA sequences and mRNA
RT abundance.";
RL Nucleic Acids Res. 12:3917-3932(1984).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=15108119; DOI=10.1007/s00439-004-1106-x;
RA Fullerton S.M., Buchanan A.V., Sonpar V.A., Taylor S.L., Smith J.D.,
RA Carlson C.S., Salomaa V., Stengaard J.H., Boerwinkle E., Clark A.G.,
RA Nickerson D.A., Weiss K.M.;
RT "The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster.";
RL Hum. Genet. 115:36-56(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas, and Spleen;
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 [7]
RP PROTEIN SEQUENCE OF 21-99.
RX PubMed=3949020; DOI=10.1016/0014-5793(86)80300-3;
RA Hospattankar A.V., Brewer H.B. Jr., Ronan R., Fairwell T.;
RT "Amino acid sequence of human plasma apolipoprotein C-III from
RT normolipidemic subjects.";
RL FEBS Lett. 197:67-73(1986).
RN [8]
RP PROTEIN SEQUENCE OF 21-99.
RX PubMed=4846755;
RA Brewer H.B. Jr., Shulman R., Herbert P., Ronan R., Wehrly K.;
RT "The complete amino acid sequence of alanine apolipoprotein (apoC-3),
RT and apolipoprotein from human plasma very low density lipoproteins.";
RL J. Biol. Chem. 249:4975-4984(1974).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-94, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [10]
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 [11]
RP GLYCOSYLATION AT THR-94, STRUCTURE OF CARBOHYDRATES, AND MASS
RP SPECTROMETRY.
RX PubMed=23527852; DOI=10.1021/pr400136p;
RA Nicolardi S., van der Burgt Y.E., Dragan I., Hensbergen P.J.,
RA Deelder A.M.;
RT "Identification of new apolipoprotein-CIII glycoforms with ultrahigh
RT resolution MALDI-FTICR mass spectrometry of human sera.";
RL J. Proteome Res. 12:2260-2268(2013).
RN [12]
RP VARIANT C-III-0 ALA-94, AND GLYCOSYLATION AT THR-94.
RX PubMed=3123586;
RA Maeda H., Hashimoto R.K., Oguro T., Hiraga S., Uzawa H.;
RT "Molecular cloning of a human apoC-III variant: Thr 74-->Ala 74
RT mutation prevents O-glycosylation.";
RL J. Lipid Res. 28:1405-1409(1987).
RN [13]
RP VARIANT HALP2 GLU-78.
RX PubMed=2022742; DOI=10.1172/JCI115190;
RA von Eckardstein A., Holz H., Sandkamp M., Weng W., Funke H.,
RA Assmann G.;
RT "Apolipoprotein C-III(Lys-58-->Glu). Identification of an
RT apolipoprotein C-III variant in a family with
RT hyperalphalipoproteinemia.";
RL J. Clin. Invest. 87:1724-1731(1991).
CC -!- FUNCTION: Inhibits lipoprotein lipase and hepatic lipase and
CC decreases the uptake of lymph chylomicrons by hepatic cells. This
CC suggests that it delays the catabolism of triglyceride-rich
CC particles.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Constitutes 50% of the protein fraction of
CC VLDL and 2% of that of HDL. Synthesized predominantly in liver and
CC to a lesser degree in intestine.
CC -!- PTM: The most abundant glycoforms are characterized by an O-linked
CC disaccharide galactose linked to N-acetylgalactosamine (Gal-
CC GalNAc), further modified with up to 3 sialic acid residues. Less
CC abundant glycoforms are characterized by more complex and
CC fucosylated glycan moieties. O-glycosylated on Thr-94 with a core
CC 1 or possibly core 8 glycan.
CC -!- DISEASE: Hyperalphalipoproteinemia 2 (HALP2) [MIM:614028]: A
CC condition characterized by high levels of high density lipoprotein
CC (HDL) and increased HDL cholesterol levels. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the apolipoprotein C3 family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/APOC3";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J00098; AAB59515.1; -; Genomic_DNA.
DR EMBL; M33043; AAB59372.1; -; Genomic_DNA.
DR EMBL; M33041; AAB59372.1; JOINED; Genomic_DNA.
DR EMBL; M33042; AAB59372.1; JOINED; Genomic_DNA.
DR EMBL; X01392; CAA25648.1; -; Genomic_DNA.
DR EMBL; X01388; CAA25644.1; -; mRNA.
DR EMBL; X03120; CAA26895.1; -; Genomic_DNA.
DR EMBL; V01513; CAA24757.1; -; mRNA.
DR EMBL; M28613; AAA51760.1; -; mRNA.
DR EMBL; M28614; AAA51761.1; -; mRNA.
DR EMBL; X00567; CAA25233.1; -; mRNA.
DR EMBL; AY422951; AAQ91810.1; -; Genomic_DNA.
DR EMBL; AY555191; AAS68230.1; -; Genomic_DNA.
DR EMBL; BC027977; AAH27977.1; -; mRNA.
DR EMBL; BC121081; AAI21082.1; -; mRNA.
DR PIR; A90950; LPHUC3.
DR RefSeq; NP_000031.1; NM_000040.1.
DR UniGene; Hs.73849; -.
DR PDB; 2JQ3; NMR; -; A=21-99.
DR PDBsum; 2JQ3; -.
DR ProteinModelPortal; P02656; -.
DR SMR; P02656; 21-99.
DR IntAct; P02656; 3.
DR MINT; MINT-5000873; -.
DR STRING; 9606.ENSP00000227667; -.
DR PhosphoSite; P02656; -.
DR UniCarbKB; P02656; -.
DR DMDM; 114026; -.
DR DOSAC-COBS-2DPAGE; P02656; -.
DR SWISS-2DPAGE; P02656; -.
DR PaxDb; P02656; -.
DR PRIDE; P02656; -.
DR DNASU; 345; -.
DR Ensembl; ENST00000227667; ENSP00000227667; ENSG00000110245.
DR GeneID; 345; -.
DR KEGG; hsa:345; -.
DR UCSC; uc001ppt.1; human.
DR CTD; 345; -.
DR GeneCards; GC11P116700; -.
DR HGNC; HGNC:610; APOC3.
DR MIM; 107720; gene.
DR MIM; 614028; phenotype.
DR neXtProt; NX_P02656; -.
DR Orphanet; 79506; Cholesterol-ester transfer protein deficiency.
DR Orphanet; 33271; Non-alcoholic fatty liver disease.
DR PharmGKB; PA53; -.
DR eggNOG; NOG39866; -.
DR HOGENOM; HOG000247042; -.
DR HOVERGEN; HBG050549; -.
DR InParanoid; P02656; -.
DR KO; K08759; -.
DR PhylomeDB; P02656; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR EvolutionaryTrace; P02656; -.
DR GeneWiki; Apolipoprotein_C3; -.
DR GenomeRNAi; 345; -.
DR NextBio; 1423; -.
DR PRO; PR:P02656; -.
DR ArrayExpress; P02656; -.
DR Bgee; P02656; -.
DR CleanEx; HS_APOC3; -.
DR Genevestigator; P02656; -.
DR GO; GO:0042627; C:chylomicron; IDA:BHF-UCL.
DR GO; GO:0005769; C:early endosome; TAS:Reactome.
DR GO; GO:0034363; C:intermediate-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034366; C:spherical high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0015485; F:cholesterol binding; IC:BHF-UCL.
DR GO; GO:0055102; F:lipase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL.
DR GO; GO:0033344; P:cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0042632; P:cholesterol homeostasis; IMP:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:Ensembl.
DR GO; GO:0034382; P:chylomicron remnant clearance; IDA:BHF-UCL.
DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0034375; P:high-density lipoprotein particle remodeling; IMP:BHF-UCL.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0042953; P:lipoprotein transport; IEA:Ensembl.
DR GO; GO:0060621; P:negative regulation of cholesterol import; IMP:BHF-UCL.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0010987; P:negative regulation of high-density lipoprotein particle clearance; IMP:BHF-UCL.
DR GO; GO:0051005; P:negative regulation of lipoprotein lipase activity; IDA:BHF-UCL.
DR GO; GO:0010989; P:negative regulation of low-density lipoprotein particle clearance; IMP:BHF-UCL.
DR GO; GO:0048261; P:negative regulation of receptor-mediated endocytosis; IDA:BHF-UCL.
DR GO; GO:0010897; P:negative regulation of triglyceride catabolic process; IDA:BHF-UCL.
DR GO; GO:0010916; P:negative regulation of very-low-density lipoprotein particle clearance; IDA:BHF-UCL.
DR GO; GO:0010903; P:negative regulation of very-low-density lipoprotein particle remodeling; IDA:BHF-UCL.
DR GO; GO:0033700; P:phospholipid efflux; IDA:BHF-UCL.
DR GO; GO:0007603; P:phototransduction, visible light; TAS:Reactome.
DR GO; GO:0032489; P:regulation of Cdc42 protein signal transduction; IDA:BHF-UCL.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0043434; P:response to peptide hormone stimulus; IEA:Ensembl.
DR GO; GO:0001523; P:retinoid metabolic process; TAS:Reactome.
DR GO; GO:0043691; P:reverse cholesterol transport; IC:BHF-UCL.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0019433; P:triglyceride catabolic process; IDA:BHF-UCL.
DR GO; GO:0070328; P:triglyceride homeostasis; IMP:BHF-UCL.
DR GO; GO:0006642; P:triglyceride mobilization; IEA:Ensembl.
DR GO; GO:0034379; P:very-low-density lipoprotein particle assembly; TAS:BHF-UCL.
DR InterPro; IPR008403; Apo-CIII.
DR PANTHER; PTHR14225; PTHR14225; 1.
DR Pfam; PF05778; Apo-CIII; 1.
DR ProDom; PD010414; Apo-CIII; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chylomicron; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycoprotein;
KW Lipid degradation; Lipid metabolism; Lipid transport; Polymorphism;
KW Reference proteome; Secreted; Sialic acid; Signal; Transport; VLDL.
FT SIGNAL 1 20
FT CHAIN 21 99 Apolipoprotein C-III.
FT /FTId=PRO_0000002031.
FT REGION 68 99 Lipid-binding.
FT CARBOHYD 94 94 O-linked (GalNAc...).
FT /FTId=CAR_000168.
FT VARIANT 78 78 K -> E (in HALP2).
FT /FTId=VAR_000643.
FT VARIANT 94 94 T -> A (in C-III-0; unglycosylated).
FT /FTId=VAR_000644.
FT CONFLICT 52 53 ES -> SQ (in Ref. 8; AA sequence).
FT CONFLICT 57 59 QQA -> AQQ (in Ref. 8; AA sequence).
FT HELIX 29 39
FT HELIX 40 42
FT HELIX 43 48
FT HELIX 49 55
FT HELIX 56 62
FT TURN 63 68
FT HELIX 69 80
FT HELIX 83 85
FT HELIX 93 98
SQ SEQUENCE 99 AA; 10852 MW; D4E806339FAE4DA7 CRC64;
MQPRVLLVVA LLALLASARA SEAEDASLLS FMQGYMKHAT KTAKDALSSV QESQVAQQAR
GWVTDGFSSL KDYWSTVKDK FSEFWDLDPE VRPTSAVAA
//
ID APOC3_HUMAN Reviewed; 99 AA.
AC P02656; Q08E83; Q6Q786;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=Apolipoprotein C-III;
DE Short=Apo-CIII;
DE Short=ApoC-III;
DE AltName: Full=Apolipoprotein C3;
DE Flags: Precursor;
GN Name=APOC3;
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 [GENOMIC DNA / MRNA].
RX PubMed=6439535;
RA Protter A.A., Levy-Wilson B., Miller J., Bencen G., White T.,
RA Seilhamer J.J.;
RT "Isolation and sequence analysis of the human apolipoprotein CIII gene
RT and the intergenic region between the apo AI and apo CIII genes.";
RL DNA 3:449-456(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6548954;
RA Levy-Wilson B., Appleby V., Protter A.A., Auperin D., Seilhamer J.J.;
RT "Isolation and DNA sequence of full-length cDNA for human
RT preapolipoprotein CIII.";
RL DNA 3:359-364(1984).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=2989400;
RA Karathanasis S.K., Zannis V.I., Breslow J.L.;
RT "Isolation and characterization of cDNA clones corresponding to two
RT different human apoC-III alleles.";
RL J. Lipid Res. 26:451-456(1985).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6328445; DOI=10.1093/nar/12.9.3917;
RA Sharpe C.R., Sidoli A., Shelley C.S., Lucero M.A., Shoulders C.C.,
RA Baralle F.E.;
RT "Human apolipoproteins AI, AII, CII and CIII. cDNA sequences and mRNA
RT abundance.";
RL Nucleic Acids Res. 12:3917-3932(1984).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=15108119; DOI=10.1007/s00439-004-1106-x;
RA Fullerton S.M., Buchanan A.V., Sonpar V.A., Taylor S.L., Smith J.D.,
RA Carlson C.S., Salomaa V., Stengaard J.H., Boerwinkle E., Clark A.G.,
RA Nickerson D.A., Weiss K.M.;
RT "The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster.";
RL Hum. Genet. 115:36-56(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas, and Spleen;
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 [7]
RP PROTEIN SEQUENCE OF 21-99.
RX PubMed=3949020; DOI=10.1016/0014-5793(86)80300-3;
RA Hospattankar A.V., Brewer H.B. Jr., Ronan R., Fairwell T.;
RT "Amino acid sequence of human plasma apolipoprotein C-III from
RT normolipidemic subjects.";
RL FEBS Lett. 197:67-73(1986).
RN [8]
RP PROTEIN SEQUENCE OF 21-99.
RX PubMed=4846755;
RA Brewer H.B. Jr., Shulman R., Herbert P., Ronan R., Wehrly K.;
RT "The complete amino acid sequence of alanine apolipoprotein (apoC-3),
RT and apolipoprotein from human plasma very low density lipoproteins.";
RL J. Biol. Chem. 249:4975-4984(1974).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-94, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [10]
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 [11]
RP GLYCOSYLATION AT THR-94, STRUCTURE OF CARBOHYDRATES, AND MASS
RP SPECTROMETRY.
RX PubMed=23527852; DOI=10.1021/pr400136p;
RA Nicolardi S., van der Burgt Y.E., Dragan I., Hensbergen P.J.,
RA Deelder A.M.;
RT "Identification of new apolipoprotein-CIII glycoforms with ultrahigh
RT resolution MALDI-FTICR mass spectrometry of human sera.";
RL J. Proteome Res. 12:2260-2268(2013).
RN [12]
RP VARIANT C-III-0 ALA-94, AND GLYCOSYLATION AT THR-94.
RX PubMed=3123586;
RA Maeda H., Hashimoto R.K., Oguro T., Hiraga S., Uzawa H.;
RT "Molecular cloning of a human apoC-III variant: Thr 74-->Ala 74
RT mutation prevents O-glycosylation.";
RL J. Lipid Res. 28:1405-1409(1987).
RN [13]
RP VARIANT HALP2 GLU-78.
RX PubMed=2022742; DOI=10.1172/JCI115190;
RA von Eckardstein A., Holz H., Sandkamp M., Weng W., Funke H.,
RA Assmann G.;
RT "Apolipoprotein C-III(Lys-58-->Glu). Identification of an
RT apolipoprotein C-III variant in a family with
RT hyperalphalipoproteinemia.";
RL J. Clin. Invest. 87:1724-1731(1991).
CC -!- FUNCTION: Inhibits lipoprotein lipase and hepatic lipase and
CC decreases the uptake of lymph chylomicrons by hepatic cells. This
CC suggests that it delays the catabolism of triglyceride-rich
CC particles.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Constitutes 50% of the protein fraction of
CC VLDL and 2% of that of HDL. Synthesized predominantly in liver and
CC to a lesser degree in intestine.
CC -!- PTM: The most abundant glycoforms are characterized by an O-linked
CC disaccharide galactose linked to N-acetylgalactosamine (Gal-
CC GalNAc), further modified with up to 3 sialic acid residues. Less
CC abundant glycoforms are characterized by more complex and
CC fucosylated glycan moieties. O-glycosylated on Thr-94 with a core
CC 1 or possibly core 8 glycan.
CC -!- DISEASE: Hyperalphalipoproteinemia 2 (HALP2) [MIM:614028]: A
CC condition characterized by high levels of high density lipoprotein
CC (HDL) and increased HDL cholesterol levels. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the apolipoprotein C3 family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/APOC3";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J00098; AAB59515.1; -; Genomic_DNA.
DR EMBL; M33043; AAB59372.1; -; Genomic_DNA.
DR EMBL; M33041; AAB59372.1; JOINED; Genomic_DNA.
DR EMBL; M33042; AAB59372.1; JOINED; Genomic_DNA.
DR EMBL; X01392; CAA25648.1; -; Genomic_DNA.
DR EMBL; X01388; CAA25644.1; -; mRNA.
DR EMBL; X03120; CAA26895.1; -; Genomic_DNA.
DR EMBL; V01513; CAA24757.1; -; mRNA.
DR EMBL; M28613; AAA51760.1; -; mRNA.
DR EMBL; M28614; AAA51761.1; -; mRNA.
DR EMBL; X00567; CAA25233.1; -; mRNA.
DR EMBL; AY422951; AAQ91810.1; -; Genomic_DNA.
DR EMBL; AY555191; AAS68230.1; -; Genomic_DNA.
DR EMBL; BC027977; AAH27977.1; -; mRNA.
DR EMBL; BC121081; AAI21082.1; -; mRNA.
DR PIR; A90950; LPHUC3.
DR RefSeq; NP_000031.1; NM_000040.1.
DR UniGene; Hs.73849; -.
DR PDB; 2JQ3; NMR; -; A=21-99.
DR PDBsum; 2JQ3; -.
DR ProteinModelPortal; P02656; -.
DR SMR; P02656; 21-99.
DR IntAct; P02656; 3.
DR MINT; MINT-5000873; -.
DR STRING; 9606.ENSP00000227667; -.
DR PhosphoSite; P02656; -.
DR UniCarbKB; P02656; -.
DR DMDM; 114026; -.
DR DOSAC-COBS-2DPAGE; P02656; -.
DR SWISS-2DPAGE; P02656; -.
DR PaxDb; P02656; -.
DR PRIDE; P02656; -.
DR DNASU; 345; -.
DR Ensembl; ENST00000227667; ENSP00000227667; ENSG00000110245.
DR GeneID; 345; -.
DR KEGG; hsa:345; -.
DR UCSC; uc001ppt.1; human.
DR CTD; 345; -.
DR GeneCards; GC11P116700; -.
DR HGNC; HGNC:610; APOC3.
DR MIM; 107720; gene.
DR MIM; 614028; phenotype.
DR neXtProt; NX_P02656; -.
DR Orphanet; 79506; Cholesterol-ester transfer protein deficiency.
DR Orphanet; 33271; Non-alcoholic fatty liver disease.
DR PharmGKB; PA53; -.
DR eggNOG; NOG39866; -.
DR HOGENOM; HOG000247042; -.
DR HOVERGEN; HBG050549; -.
DR InParanoid; P02656; -.
DR KO; K08759; -.
DR PhylomeDB; P02656; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR EvolutionaryTrace; P02656; -.
DR GeneWiki; Apolipoprotein_C3; -.
DR GenomeRNAi; 345; -.
DR NextBio; 1423; -.
DR PRO; PR:P02656; -.
DR ArrayExpress; P02656; -.
DR Bgee; P02656; -.
DR CleanEx; HS_APOC3; -.
DR Genevestigator; P02656; -.
DR GO; GO:0042627; C:chylomicron; IDA:BHF-UCL.
DR GO; GO:0005769; C:early endosome; TAS:Reactome.
DR GO; GO:0034363; C:intermediate-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034366; C:spherical high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0015485; F:cholesterol binding; IC:BHF-UCL.
DR GO; GO:0055102; F:lipase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL.
DR GO; GO:0033344; P:cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0042632; P:cholesterol homeostasis; IMP:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:Ensembl.
DR GO; GO:0034382; P:chylomicron remnant clearance; IDA:BHF-UCL.
DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0034375; P:high-density lipoprotein particle remodeling; IMP:BHF-UCL.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0042953; P:lipoprotein transport; IEA:Ensembl.
DR GO; GO:0060621; P:negative regulation of cholesterol import; IMP:BHF-UCL.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0010987; P:negative regulation of high-density lipoprotein particle clearance; IMP:BHF-UCL.
DR GO; GO:0051005; P:negative regulation of lipoprotein lipase activity; IDA:BHF-UCL.
DR GO; GO:0010989; P:negative regulation of low-density lipoprotein particle clearance; IMP:BHF-UCL.
DR GO; GO:0048261; P:negative regulation of receptor-mediated endocytosis; IDA:BHF-UCL.
DR GO; GO:0010897; P:negative regulation of triglyceride catabolic process; IDA:BHF-UCL.
DR GO; GO:0010916; P:negative regulation of very-low-density lipoprotein particle clearance; IDA:BHF-UCL.
DR GO; GO:0010903; P:negative regulation of very-low-density lipoprotein particle remodeling; IDA:BHF-UCL.
DR GO; GO:0033700; P:phospholipid efflux; IDA:BHF-UCL.
DR GO; GO:0007603; P:phototransduction, visible light; TAS:Reactome.
DR GO; GO:0032489; P:regulation of Cdc42 protein signal transduction; IDA:BHF-UCL.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0043434; P:response to peptide hormone stimulus; IEA:Ensembl.
DR GO; GO:0001523; P:retinoid metabolic process; TAS:Reactome.
DR GO; GO:0043691; P:reverse cholesterol transport; IC:BHF-UCL.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0019433; P:triglyceride catabolic process; IDA:BHF-UCL.
DR GO; GO:0070328; P:triglyceride homeostasis; IMP:BHF-UCL.
DR GO; GO:0006642; P:triglyceride mobilization; IEA:Ensembl.
DR GO; GO:0034379; P:very-low-density lipoprotein particle assembly; TAS:BHF-UCL.
DR InterPro; IPR008403; Apo-CIII.
DR PANTHER; PTHR14225; PTHR14225; 1.
DR Pfam; PF05778; Apo-CIII; 1.
DR ProDom; PD010414; Apo-CIII; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chylomicron; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycoprotein;
KW Lipid degradation; Lipid metabolism; Lipid transport; Polymorphism;
KW Reference proteome; Secreted; Sialic acid; Signal; Transport; VLDL.
FT SIGNAL 1 20
FT CHAIN 21 99 Apolipoprotein C-III.
FT /FTId=PRO_0000002031.
FT REGION 68 99 Lipid-binding.
FT CARBOHYD 94 94 O-linked (GalNAc...).
FT /FTId=CAR_000168.
FT VARIANT 78 78 K -> E (in HALP2).
FT /FTId=VAR_000643.
FT VARIANT 94 94 T -> A (in C-III-0; unglycosylated).
FT /FTId=VAR_000644.
FT CONFLICT 52 53 ES -> SQ (in Ref. 8; AA sequence).
FT CONFLICT 57 59 QQA -> AQQ (in Ref. 8; AA sequence).
FT HELIX 29 39
FT HELIX 40 42
FT HELIX 43 48
FT HELIX 49 55
FT HELIX 56 62
FT TURN 63 68
FT HELIX 69 80
FT HELIX 83 85
FT HELIX 93 98
SQ SEQUENCE 99 AA; 10852 MW; D4E806339FAE4DA7 CRC64;
MQPRVLLVVA LLALLASARA SEAEDASLLS FMQGYMKHAT KTAKDALSSV QESQVAQQAR
GWVTDGFSSL KDYWSTVKDK FSEFWDLDPE VRPTSAVAA
//
MIM
107720
*RECORD*
*FIELD* NO
107720
*FIELD* TI
*107720 APOLIPOPROTEIN C-III; APOC3
APOC3/APOA1 FUSION GENE, INCLUDED
*FIELD* TX
DESCRIPTION
read more
Apolipoprotein C-III, secreted from the liver and to a lesser extent by
the intestines, is a component of both high density lipoprotein (HDL)
and apolipoprotein B (APOB; 107730)-containing lipoprotein particles,
impairs catabolism and hepatic uptake of apoB-containing lipoproteins,
appears to enhance the catabolism of HDL particles, enhances monocyte
adhesion to vascular endothelial cells, and activates inflammatory
signaling pathways (summary by Pollin et al., 2008).
For background information on apolipoproteins, see APOA1 (107680).
GENE FUNCTION
Hypertriglyceridemia is a metabolic complication of retinoid therapy.
Vu-Dac et al. (1998) analyzed whether retinoids increase the expression
of apoC-III, an antagonist of plasma triglyceride catabolism. In men,
isotretinoin treatment resulted in elevated plasma apoC-III, but not
apoE concentrations. In human hepatoma HepG2 cells, retinoids increased
apoC-III mRNA and protein production. Transient transfection experiments
indicated that retinoids increase apoC-III expression at the
transcriptional level. Vu-Dac et al. (1998) showed that apoC-III is a
target gene for retinoids acting via RXR (see 180245). Increased
apoC-III expression may contribute to the hypertriglyceridemia and
atherogenic lipoprotein profile observed after retinoid therapy.
The APOC3 gene contains a proximal promoter and a distal regulatory
region that acts as a common enhancer for the 3 genes of the
apolipoprotein cluster on 11q23 (APOC3, APOA1, and APOA4 (107690))
(Zannis et al., 2001). Coste and Rodriguez (2002) determined that the
nuclear receptor REV-ERB-alpha (NR1D1; 602408), when transfected and
expressed in human hepatic cells, specifically repressed APOC3 promoter
activity. By deletion and site-directed mutagenesis experiments, they
showed that REV-ERB-alpha bound to an element in the proximal promoter
of the APOC3 gene that is also a ROR-alpha-1 (600825) element. They
provided evidence for cross-talk between REV-ERB-alpha and ROR-alpha-1
in modulating the APOC3 promoter.
Using adenovirus-mediated gene transfer to deliver forkhead box O1A
(FOXO1; 136533) cDNA to cultured hepatocytes and enterocytes, Altomonte
et al. (2004) demonstrated that FOXO1 stimulated APOC3 expression and
that this correlated with FOXO1 binding to the APOC3 promoter. Deletion
or mutation of the FOXO1 binding site abolished the FOXO1-mediated
stimulation and the APOC3 response to insulin (INS; 176730). Transgenic
mice expressing a constitutively active Foxo1 allele exhibited
hypertriglyceridemia; in livers of diabetic NOD or db/db mice, Foxo1
expression was deregulated, culminating in significantly elevated
production and skewed nuclear distribution of Foxo1. Altomonte et al.
(2004) suggested that FOXO1 provides a molecular link between insulin
deficiency or resistance and aberrant apoC-III production in the
pathogenesis of diabetic hypertriglyceridemia.
MAPPING
Karathanasis (1985) determined that the APOC3 gene resides in an
apolipoprotein gene cluster on chromosome 11q23 between the APOA1 and
APOA4 genes.
The APOA1 and APOC3 genes are oriented 'foot-to-foot,' i.e., the 3-prime
end of APOA1 is followed after an interval of about 2.5 kb by the
3-prime end of APOC3 (Karathanasis et al., 1983).
CYTOGENETICS
In certain patients with premature atherosclerosis, Karathanasis et al.
(1987) demonstrated a DNA inversion containing portions of the 3-prime
ends of the APOA1 and APOC3 genes, including the DNA region between
these genes. The breakpoints of this DNA inversion were found to be
located between the fourth exon of the APOA1 gene and the first intron
of the APOC3 gene; thus, the inversion results in reciprocal fusion of
the 2 gene transcriptional units. The absence of transcripts with
correct mRNA sequences causes deficiency of both apolipoproteins in the
plasma of these patients, leading to atherosclerosis. See also
107680.0011.
MOLECULAR GENETICS
- Hyperalphalipoproteinemia
To identify genetic factors contributing to fasting triglycerides and
the postprandial triglyceride dietary response, Pollin et al. (2008)
performed a single high fat feeding intervention and genomewide
association study in 809 Old Order Amish individuals. They found a
loss-of-function mutation in exon 2 of the APOC3 gene, R19X
(107720.0003), that was tagged by a strongly associated
single-nucleotide polymorphism (SNP), dbSNP rs10892151, in an intron of
the DSCAML1 gene (611782). See HALP2, 614028.
- Association of SstI Polymorphism with Hypertriglyceridemia
Ferns et al. (1985) found an uncommon allelic variant (called S2) of the
apoA-I/C-III gene cluster in 10 of 48 postmyocardial infarction patients
(21%). In 47 control subjects it was present in only 2 and in none of
those who were normotriglyceridemic. (The S2 allele, a DNA polymorphism,
is characterized by SstI restriction fragments of 5.7 and 3.2 kb,
whereas the common S1 allele produces fragments of 5.7 and 4.2 kb.) In
the same group of patients, Ferns et al. (1985) found no difference in
the distribution of alleles in the highly polymorphic region of 11p near
the insulin gene.
Henderson et al. (1987) found an increased prevalence of an SstI RFLP,
localized to the APOC3 gene, in lipid clinic patients with a variety of
hyperlipidemic phenotypes.
- Association of Promoter Polymorphisms with Hypertriglyceridemia
Dammerman et al. (1993) detected 5 DNA polymorphisms in the promoter of
the APOC3 gene in a subject with type III hyperlipidemia and severe
hypertriglyceridemia. The sites were in strong linkage disequilibrium
with each other and with the polymorphic SstI site in the APOC3 3-prime
untranslated region whose presence (S2 allele) had been shown to be
associated with hypertriglyceridemia. Carriers of the haplotype
designated 211 were at decreased risk and carriers of the so-called 222
haplotype were at increased risk for hypertriglyceridemia.
The promoter of the APOC3 gene contains 5 sites of single basepair
sequence variation between -641 and -455. Li et al. (1995) stated that
one possible explanation for the association of the variant promoter
with elevated triglycerides is that one or more these changes increases
the transcriptional activity of the APOC3 gene, thereby causing an
increase in apoC-III levels and inducing the development of
hypertriglyceridemia. Overexpression of plasma apoC-III causes
hypertriglyceridemia in transgenic mice. In animals and in cultured
cells, the APOC3 gene is transcriptionally downregulated by insulin. Li
et al. (1995) found that, unlike the wildtype promoter, the variant
promoter is defective in its response to insulin treatment, remaining
constitutively active in all concentrations of insulin. The loss of
insulin regulation was mapped to the polymorphic sites -482C-T and
-455T-C, which fall within a previously identified insulin response
element. The authors stated that loss of insulin regulation could result
in overexpression of the APOC3 gene and contribute to the development of
hypertriglyceridemia. The variant promoter is common in the general
population and may represent a major contributing factor to the
development of hypertriglyceridemia.
Variation in the insulin-responsive element of the APOC3 promoter is
associated with insulin and glucose concentrations after an oral glucose
tolerance test in young healthy men. Waterworth et al. (2003) presented
evidence that men who carry the rare alleles of the insulin-responsive
element variants have disturbed glucose homeostasis and an unfavorable
lipid phenotype. They found elevated 30-minute nonesterified fatty acid
values on the oral glucose tolerance test and suggested that this may be
an important mechanistic link between triglyceride-rich lipoprotein
metabolism and glucose homeostasis.
In 2,808 healthy middle-aged men, Talmud et al. (2002) used association
studies to examine the relative influence of APOA5 (606368) variants on
plasma lipids compared to the impact of variation in APOC3 and APOA4,
which lie in the same cluster. The major triglyceride-raising alleles
were defined by trp19 in APOA5 (see 606368.0002) and -482T in APOC3. The
authors concluded that variation in APOA5 is associated with differences
in triglycerides in healthy men, independent of those for APOC3, whereas
association between APOA4 and triglycerides reflects linkage
disequilibrium with these sites.
- Association of Promoter Polymorphisms with Nonalcoholic
Fatty Liver Disease
For a discussion of an association between variation in the APOC3 gene
and nonalcoholic fatty liver disease, see NAFLD2 (613387).
ANIMAL MODEL
To determine whether baboons, like humans, have particular haplotypes
associated with lipid phenotypes, Wang et al. (2004) genotyped 634 well
characterized baboons using 16 haplotype tagging SNPs within the
apolipoprotein gene cluster on chromosome 11q23, for which the human
orthologs have well established roles in influencing plasma HDL
cholesterol and triglyceride concentrations. Genetic analysis of single
SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3
variants with HDL cholesterol and triglyceride concentrations,
respectively. The authors concluded that independent variation in
orthologous genomic intervals associates with similar quantitative lipid
traits in both species, supporting the possibility of identifying human
quantitative trait loci genes in a highly controlled nonhuman primate
model.
*FIELD* AV
.0001
APOLIPOPROTEIN C-III, NONGLYCOSYLATED
APOC3, THR74ALA
In a subject whose serum contained unusually high amounts of apoC-III
lacking the carbohydrate moiety, Maeda et al. (1987) found that the
cloned APOC3 gene contained a single nucleotide substitution (A-to-G)
that encodes an alanine at position 74 instead of the normal threonine.
As a result of this amino acid replacement, the mutant apoC-III
polypeptide was not glycosylated. The mutation also created a novel AluI
site which permitted diagnosis of the change by Southern blotting of
genomic DNA. The family, first described by Maeda et al. (1981), showed
the unusual apolipoprotein (called apolipoprotein C-III-0) in an
autosomal dominant pedigree pattern. Three polymorphic forms of
apo-C-III, designated apolipoprotein C-III-0, apolipoprotein C-III-1,
and apolipoprotein C-III-2, depend on sialic acid content. The proband
of Maeda et al. (1981) was a mildly hypertensive 63-year-old woman whose
very low density lipoprotein and high density lipoprotein contained
unusually high amounts of apolipoprotein C-III-0. This lipoprotein was
inherited by 2 of her 4 children without clinical symptoms. Blood lipid
levels were normal.
.0002
HYPERALPHALIPOPROTEINEMIA 2
APOC3, LYS58GLU
In a family with hyperalphalipoproteinemia (HALP2; 614028), von
Eckardstein et al. (1991) identified a heterozygous carrier of an
apolipoprotein C-III variant by the presence of additional bands after
isoelectric focusing (IEF) of very low density lipoprotein (VLDL).
Structural analysis of the variant protein revealed a lysine-to-glutamic
acid change in position 58 (K58E). The underlying A-to-G exchange was
verified by direct sequencing subsequent to amplification by polymerase
chain reaction (PCR) of exon 4 of the APOC3 gene. Two variant carriers
exhibited plasma concentrations of HDL cholesterol and APOA1 above the
95th percentile for sex-matched controls. Their plasma concentrations of
apoC-III were 30 to 40% lower than those of 2 unaffected family members
and random controls.
.0003
HYPERALPHALIPOPROTEINEMIA 2
APOC3, ARG19TER
Pollin et al. (2008) found that 5% of the Lancaster Amish are
heterozygous carriers of a null mutation in exon 2 of the APOC3 gene
consisting of a C-to-T transition at nucleotide 55, resulting in an
arg19-to-ter (R19X) substitution. As the mutation occurs in the signal
peptide of the protein, a complete lack of production of apoC-III from
alleles carrying the mutation was predicted. Carriers had half the
amount of apoC-III present in noncarriers. Mutation carriers compared
with noncarriers had lower fasting and postprandial serum triglycerides,
higher levels of HDL cholesterol, and lower levels of LDL cholesterol.
Subclinical atherosclerosis, as measured by coronary artery
calcification, was less common in carriers than noncarriers, which
suggested that lifelong deficiency of apoC-III (614028) has a
cardioprotective effect.
*FIELD* SA
Oettgen et al. (1986)
*FIELD* RF
1. Altomonte, J.; Cong, L.; Harbaran, S.; Richter, A.; Xu, J.; Meseck,
M.; Dong, H. H.: Foxo1 mediates insulin action on apoC-III and triglyceride
metabolism. J. Clin. Invest. 114: 1493-1503, 2004.
2. Coste, H.; Rodriguez, J. C.: Orphan nuclear hormone receptor Rev-erb-alpha
regulates the human apolipoprotein C-III promoter. J. Biol. Chem. 277:
27120-27129, 2002.
3. Dammerman, M.; Sandkuijl, L. A.; Halaas, J. L.; Chung, W.; Breslow,
J. L.: An apolipoprotein CIII haplotype protective against hypertriglyceridemia
is specified by promoter and 3-prime untranslated region polymorphisms. Proc.
Nat. Acad. Sci. 90: 4562-4566, 1993.
4. Ferns, G. A. A.; Stocks, J.; Ritchie, C.; Galton, D. J.: Genetic
polymorphisms of apolipoprotein C-III and insulin in survivors of
myocardial infarction. Lancet 326: 300-303, 1985. Note: Originally
Volume II.
5. Henderson, H. E.; Landon, S. V.; Michie, J.; Berger, G. M. B.:
Association of a DNA polymorphism in the apolipoprotein C-III gene
with diverse hyperlipidaemic phenotypes. Hum. Genet. 75: 62-65,
1987.
6. Karathanasis, S. K.: Apolipoprotein multigene family: tandem organization
of human apolipoprotein AI, CIII, and AIV genes. Proc. Nat. Acad.
Sci. 82: 6374-6378, 1985.
7. Karathanasis, S. K.; Ferris, E.; Haddad, I. A.: DNA inversion
within the apolipoproteins AI/CIII/AIV-encoding gene cluster of certain
patients with premature atherosclerosis. Proc. Nat. Acad. Sci. 84:
7198-7202, 1987.
8. Karathanasis, S. K.; McPherson, J.; Zannis, V. I.; Breslow, J.
L.: Linkage of human apolipoproteins A-I and C-III genes. Nature 304:
371-373, 1983.
9. Li, W. W.; Dammerman, M. M.; Smith, J. D.; Metzger, S.; Breslow,
J. L.; Leff, T.: Common genetic variation in the promoter of the
human apo CIII gene abolishes regulation by insulin and may contribute
to hypertriglyceridemia. J. Clin. Invest. 96: 2601-2605, 1995.
10. Maeda, H.; Hashimoto, R. K.; Oguro, T.; Hiraga, S.; Uzawa, H.
: Molecular cloning of a human apoC-III variant: thr 74-to-ala 74
mutation prevents O-glycosylation. J. Lipid Res. 28: 1405-1409,
1987.
11. Maeda, H.; Uzawa, H.; Kamei, R.: Unusual familial lipoprotein
C-III associated with apolipoprotein C-III-0 preponderance. Biochim.
Biophys. Acta 665: 578-585, 1981.
12. Oettgen, P.; Antonarakis, S. E.; Karathanasis, S. K.: PvuII polymorphic
site upstream to the human apoCIII gene. Nucleic Acids Res. 14:
5571, 1986.
13. Pollin, T. I.; Damcott, C. M.; Shen, H.; Ott, S. H.; Shelton,
J.; Horenstein, R. B.; Post, W.; McLenithan, J. C.; Bielak, L. F.;
Peyser, P. A.; Mitchell, B. D.; Miller, M.; O'Connell, J. R.; Shuldiner,
A. R.: A null mutation in human APOC3 confers a favorable plasmid
lipid profile and apparent cardioprotection. Science 322: 1702-1705,
2008. Note: Erratum: Science 323: 583 only, 2009.
14. Talmud, P. J.; Hawe, E.; Martin, S.; Olivier, M.; Miller, G. J.;
Rubin, E. M.; Pennacchio, L. A.; Humphries, S. E.: Relative contribution
of variation within the APOC3/A4/A5 gene cluster in determining plasma
triglycerides. Hum. Molec. Genet. 11: 3039-3046, 2002.
15. von Eckardstein, A.; Holz, H.; Sandkamp, M.; Weng, W.; Funke,
H.; Assmann, G.: Apolipoprotein C-III(lys58-to-glu): identification
of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia. J.
Clin. Invest. 87: 1724-1731, 1991.
16. Vu-Dac, N.; Gervois, P.; Torra, I. P.; Fruchart, J.-C.; Kosykh,
V.; Kooistra, T.; Princen, H. M. G.; Dallongeville, J.; Staels, B.
: Retinoids increase human Apo C-III expression at the transcriptional
level via the retinoid X receptor: contribution to the hypertriglyceridemic
action of retinoids. J. Clin. Invest. 102: 625-632, 1998.
17. Wang, Q.; Liu, X.; O'Connell, J.; Peng, Z.; Krauss, R. M.; Rainwater,
D. L.; VandeBerg, J. L.; Rubin, E. M.; Cheng, J.-F.; Pennachio, L.
A.: Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids
in both humans and baboons. Hum. Molec. Genet. 13: 1049-1056, 2004.
18. Waterworth, D. M.; Talmud, P. J.; Luan, J.; Flavell, D. M.; Byrne,
C. D.; Humphries, S. E.; Wareham, N. J.: Variants in the APOC3 promoter
insulin responsive element modulate insulin secretion and lipids in
middle-aged men. Biochim. Biophys. Acta 1637: 200-206, 2003.
19. Zannis, V. I.; Kan, H.-Y.; Kritis, A.; Zanni, E. E.; Kardassis,
D.: Transcriptional regulatory mechanisms of the human apolipoprotein
genes in vitro and in vivo. Curr. Opin. Lipid. 12: 181-207, 2001.
*FIELD* CN
Marla J. F. O'Neill - updated: 4/27/2010
Marla J. F. O'Neill - updated: 2/12/2009
Ada Hamosh - updated: 12/29/2008
Marla J. F. O'Neill - updated: 9/8/2006
George E. Tiller - updated: 9/5/2006
Marla J. F. O'Neill - updated: 1/19/2005
George E. Tiller - updated: 8/25/2004
Victor A. McKusick - updated: 7/2/2003
Patricia A. Hartz - updated: 10/29/2002
Victor A. McKusick - updated: 10/1/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
alopez: 06/08/2011
alopez: 6/8/2011
carol: 4/28/2010
carol: 4/27/2010
ckniffin: 4/7/2010
alopez: 2/17/2009
carol: 2/13/2009
carol: 2/12/2009
carol: 1/9/2009
terry: 1/7/2009
alopez: 12/30/2008
terry: 12/29/2008
wwang: 9/12/2006
terry: 9/8/2006
alopez: 9/5/2006
carol: 2/2/2005
carol: 1/31/2005
terry: 1/19/2005
tkritzer: 8/25/2004
cwells: 7/21/2003
terry: 7/2/2003
tkritzer: 11/19/2002
mgross: 10/29/2002
carol: 10/6/1998
terry: 10/1/1998
mark: 1/27/1996
carol: 6/17/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 1/27/1992
carol: 5/21/1991
carol: 12/6/1990
*RECORD*
*FIELD* NO
107720
*FIELD* TI
*107720 APOLIPOPROTEIN C-III; APOC3
APOC3/APOA1 FUSION GENE, INCLUDED
*FIELD* TX
DESCRIPTION
read more
Apolipoprotein C-III, secreted from the liver and to a lesser extent by
the intestines, is a component of both high density lipoprotein (HDL)
and apolipoprotein B (APOB; 107730)-containing lipoprotein particles,
impairs catabolism and hepatic uptake of apoB-containing lipoproteins,
appears to enhance the catabolism of HDL particles, enhances monocyte
adhesion to vascular endothelial cells, and activates inflammatory
signaling pathways (summary by Pollin et al., 2008).
For background information on apolipoproteins, see APOA1 (107680).
GENE FUNCTION
Hypertriglyceridemia is a metabolic complication of retinoid therapy.
Vu-Dac et al. (1998) analyzed whether retinoids increase the expression
of apoC-III, an antagonist of plasma triglyceride catabolism. In men,
isotretinoin treatment resulted in elevated plasma apoC-III, but not
apoE concentrations. In human hepatoma HepG2 cells, retinoids increased
apoC-III mRNA and protein production. Transient transfection experiments
indicated that retinoids increase apoC-III expression at the
transcriptional level. Vu-Dac et al. (1998) showed that apoC-III is a
target gene for retinoids acting via RXR (see 180245). Increased
apoC-III expression may contribute to the hypertriglyceridemia and
atherogenic lipoprotein profile observed after retinoid therapy.
The APOC3 gene contains a proximal promoter and a distal regulatory
region that acts as a common enhancer for the 3 genes of the
apolipoprotein cluster on 11q23 (APOC3, APOA1, and APOA4 (107690))
(Zannis et al., 2001). Coste and Rodriguez (2002) determined that the
nuclear receptor REV-ERB-alpha (NR1D1; 602408), when transfected and
expressed in human hepatic cells, specifically repressed APOC3 promoter
activity. By deletion and site-directed mutagenesis experiments, they
showed that REV-ERB-alpha bound to an element in the proximal promoter
of the APOC3 gene that is also a ROR-alpha-1 (600825) element. They
provided evidence for cross-talk between REV-ERB-alpha and ROR-alpha-1
in modulating the APOC3 promoter.
Using adenovirus-mediated gene transfer to deliver forkhead box O1A
(FOXO1; 136533) cDNA to cultured hepatocytes and enterocytes, Altomonte
et al. (2004) demonstrated that FOXO1 stimulated APOC3 expression and
that this correlated with FOXO1 binding to the APOC3 promoter. Deletion
or mutation of the FOXO1 binding site abolished the FOXO1-mediated
stimulation and the APOC3 response to insulin (INS; 176730). Transgenic
mice expressing a constitutively active Foxo1 allele exhibited
hypertriglyceridemia; in livers of diabetic NOD or db/db mice, Foxo1
expression was deregulated, culminating in significantly elevated
production and skewed nuclear distribution of Foxo1. Altomonte et al.
(2004) suggested that FOXO1 provides a molecular link between insulin
deficiency or resistance and aberrant apoC-III production in the
pathogenesis of diabetic hypertriglyceridemia.
MAPPING
Karathanasis (1985) determined that the APOC3 gene resides in an
apolipoprotein gene cluster on chromosome 11q23 between the APOA1 and
APOA4 genes.
The APOA1 and APOC3 genes are oriented 'foot-to-foot,' i.e., the 3-prime
end of APOA1 is followed after an interval of about 2.5 kb by the
3-prime end of APOC3 (Karathanasis et al., 1983).
CYTOGENETICS
In certain patients with premature atherosclerosis, Karathanasis et al.
(1987) demonstrated a DNA inversion containing portions of the 3-prime
ends of the APOA1 and APOC3 genes, including the DNA region between
these genes. The breakpoints of this DNA inversion were found to be
located between the fourth exon of the APOA1 gene and the first intron
of the APOC3 gene; thus, the inversion results in reciprocal fusion of
the 2 gene transcriptional units. The absence of transcripts with
correct mRNA sequences causes deficiency of both apolipoproteins in the
plasma of these patients, leading to atherosclerosis. See also
107680.0011.
MOLECULAR GENETICS
- Hyperalphalipoproteinemia
To identify genetic factors contributing to fasting triglycerides and
the postprandial triglyceride dietary response, Pollin et al. (2008)
performed a single high fat feeding intervention and genomewide
association study in 809 Old Order Amish individuals. They found a
loss-of-function mutation in exon 2 of the APOC3 gene, R19X
(107720.0003), that was tagged by a strongly associated
single-nucleotide polymorphism (SNP), dbSNP rs10892151, in an intron of
the DSCAML1 gene (611782). See HALP2, 614028.
- Association of SstI Polymorphism with Hypertriglyceridemia
Ferns et al. (1985) found an uncommon allelic variant (called S2) of the
apoA-I/C-III gene cluster in 10 of 48 postmyocardial infarction patients
(21%). In 47 control subjects it was present in only 2 and in none of
those who were normotriglyceridemic. (The S2 allele, a DNA polymorphism,
is characterized by SstI restriction fragments of 5.7 and 3.2 kb,
whereas the common S1 allele produces fragments of 5.7 and 4.2 kb.) In
the same group of patients, Ferns et al. (1985) found no difference in
the distribution of alleles in the highly polymorphic region of 11p near
the insulin gene.
Henderson et al. (1987) found an increased prevalence of an SstI RFLP,
localized to the APOC3 gene, in lipid clinic patients with a variety of
hyperlipidemic phenotypes.
- Association of Promoter Polymorphisms with Hypertriglyceridemia
Dammerman et al. (1993) detected 5 DNA polymorphisms in the promoter of
the APOC3 gene in a subject with type III hyperlipidemia and severe
hypertriglyceridemia. The sites were in strong linkage disequilibrium
with each other and with the polymorphic SstI site in the APOC3 3-prime
untranslated region whose presence (S2 allele) had been shown to be
associated with hypertriglyceridemia. Carriers of the haplotype
designated 211 were at decreased risk and carriers of the so-called 222
haplotype were at increased risk for hypertriglyceridemia.
The promoter of the APOC3 gene contains 5 sites of single basepair
sequence variation between -641 and -455. Li et al. (1995) stated that
one possible explanation for the association of the variant promoter
with elevated triglycerides is that one or more these changes increases
the transcriptional activity of the APOC3 gene, thereby causing an
increase in apoC-III levels and inducing the development of
hypertriglyceridemia. Overexpression of plasma apoC-III causes
hypertriglyceridemia in transgenic mice. In animals and in cultured
cells, the APOC3 gene is transcriptionally downregulated by insulin. Li
et al. (1995) found that, unlike the wildtype promoter, the variant
promoter is defective in its response to insulin treatment, remaining
constitutively active in all concentrations of insulin. The loss of
insulin regulation was mapped to the polymorphic sites -482C-T and
-455T-C, which fall within a previously identified insulin response
element. The authors stated that loss of insulin regulation could result
in overexpression of the APOC3 gene and contribute to the development of
hypertriglyceridemia. The variant promoter is common in the general
population and may represent a major contributing factor to the
development of hypertriglyceridemia.
Variation in the insulin-responsive element of the APOC3 promoter is
associated with insulin and glucose concentrations after an oral glucose
tolerance test in young healthy men. Waterworth et al. (2003) presented
evidence that men who carry the rare alleles of the insulin-responsive
element variants have disturbed glucose homeostasis and an unfavorable
lipid phenotype. They found elevated 30-minute nonesterified fatty acid
values on the oral glucose tolerance test and suggested that this may be
an important mechanistic link between triglyceride-rich lipoprotein
metabolism and glucose homeostasis.
In 2,808 healthy middle-aged men, Talmud et al. (2002) used association
studies to examine the relative influence of APOA5 (606368) variants on
plasma lipids compared to the impact of variation in APOC3 and APOA4,
which lie in the same cluster. The major triglyceride-raising alleles
were defined by trp19 in APOA5 (see 606368.0002) and -482T in APOC3. The
authors concluded that variation in APOA5 is associated with differences
in triglycerides in healthy men, independent of those for APOC3, whereas
association between APOA4 and triglycerides reflects linkage
disequilibrium with these sites.
- Association of Promoter Polymorphisms with Nonalcoholic
Fatty Liver Disease
For a discussion of an association between variation in the APOC3 gene
and nonalcoholic fatty liver disease, see NAFLD2 (613387).
ANIMAL MODEL
To determine whether baboons, like humans, have particular haplotypes
associated with lipid phenotypes, Wang et al. (2004) genotyped 634 well
characterized baboons using 16 haplotype tagging SNPs within the
apolipoprotein gene cluster on chromosome 11q23, for which the human
orthologs have well established roles in influencing plasma HDL
cholesterol and triglyceride concentrations. Genetic analysis of single
SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3
variants with HDL cholesterol and triglyceride concentrations,
respectively. The authors concluded that independent variation in
orthologous genomic intervals associates with similar quantitative lipid
traits in both species, supporting the possibility of identifying human
quantitative trait loci genes in a highly controlled nonhuman primate
model.
*FIELD* AV
.0001
APOLIPOPROTEIN C-III, NONGLYCOSYLATED
APOC3, THR74ALA
In a subject whose serum contained unusually high amounts of apoC-III
lacking the carbohydrate moiety, Maeda et al. (1987) found that the
cloned APOC3 gene contained a single nucleotide substitution (A-to-G)
that encodes an alanine at position 74 instead of the normal threonine.
As a result of this amino acid replacement, the mutant apoC-III
polypeptide was not glycosylated. The mutation also created a novel AluI
site which permitted diagnosis of the change by Southern blotting of
genomic DNA. The family, first described by Maeda et al. (1981), showed
the unusual apolipoprotein (called apolipoprotein C-III-0) in an
autosomal dominant pedigree pattern. Three polymorphic forms of
apo-C-III, designated apolipoprotein C-III-0, apolipoprotein C-III-1,
and apolipoprotein C-III-2, depend on sialic acid content. The proband
of Maeda et al. (1981) was a mildly hypertensive 63-year-old woman whose
very low density lipoprotein and high density lipoprotein contained
unusually high amounts of apolipoprotein C-III-0. This lipoprotein was
inherited by 2 of her 4 children without clinical symptoms. Blood lipid
levels were normal.
.0002
HYPERALPHALIPOPROTEINEMIA 2
APOC3, LYS58GLU
In a family with hyperalphalipoproteinemia (HALP2; 614028), von
Eckardstein et al. (1991) identified a heterozygous carrier of an
apolipoprotein C-III variant by the presence of additional bands after
isoelectric focusing (IEF) of very low density lipoprotein (VLDL).
Structural analysis of the variant protein revealed a lysine-to-glutamic
acid change in position 58 (K58E). The underlying A-to-G exchange was
verified by direct sequencing subsequent to amplification by polymerase
chain reaction (PCR) of exon 4 of the APOC3 gene. Two variant carriers
exhibited plasma concentrations of HDL cholesterol and APOA1 above the
95th percentile for sex-matched controls. Their plasma concentrations of
apoC-III were 30 to 40% lower than those of 2 unaffected family members
and random controls.
.0003
HYPERALPHALIPOPROTEINEMIA 2
APOC3, ARG19TER
Pollin et al. (2008) found that 5% of the Lancaster Amish are
heterozygous carriers of a null mutation in exon 2 of the APOC3 gene
consisting of a C-to-T transition at nucleotide 55, resulting in an
arg19-to-ter (R19X) substitution. As the mutation occurs in the signal
peptide of the protein, a complete lack of production of apoC-III from
alleles carrying the mutation was predicted. Carriers had half the
amount of apoC-III present in noncarriers. Mutation carriers compared
with noncarriers had lower fasting and postprandial serum triglycerides,
higher levels of HDL cholesterol, and lower levels of LDL cholesterol.
Subclinical atherosclerosis, as measured by coronary artery
calcification, was less common in carriers than noncarriers, which
suggested that lifelong deficiency of apoC-III (614028) has a
cardioprotective effect.
*FIELD* SA
Oettgen et al. (1986)
*FIELD* RF
1. Altomonte, J.; Cong, L.; Harbaran, S.; Richter, A.; Xu, J.; Meseck,
M.; Dong, H. H.: Foxo1 mediates insulin action on apoC-III and triglyceride
metabolism. J. Clin. Invest. 114: 1493-1503, 2004.
2. Coste, H.; Rodriguez, J. C.: Orphan nuclear hormone receptor Rev-erb-alpha
regulates the human apolipoprotein C-III promoter. J. Biol. Chem. 277:
27120-27129, 2002.
3. Dammerman, M.; Sandkuijl, L. A.; Halaas, J. L.; Chung, W.; Breslow,
J. L.: An apolipoprotein CIII haplotype protective against hypertriglyceridemia
is specified by promoter and 3-prime untranslated region polymorphisms. Proc.
Nat. Acad. Sci. 90: 4562-4566, 1993.
4. Ferns, G. A. A.; Stocks, J.; Ritchie, C.; Galton, D. J.: Genetic
polymorphisms of apolipoprotein C-III and insulin in survivors of
myocardial infarction. Lancet 326: 300-303, 1985. Note: Originally
Volume II.
5. Henderson, H. E.; Landon, S. V.; Michie, J.; Berger, G. M. B.:
Association of a DNA polymorphism in the apolipoprotein C-III gene
with diverse hyperlipidaemic phenotypes. Hum. Genet. 75: 62-65,
1987.
6. Karathanasis, S. K.: Apolipoprotein multigene family: tandem organization
of human apolipoprotein AI, CIII, and AIV genes. Proc. Nat. Acad.
Sci. 82: 6374-6378, 1985.
7. Karathanasis, S. K.; Ferris, E.; Haddad, I. A.: DNA inversion
within the apolipoproteins AI/CIII/AIV-encoding gene cluster of certain
patients with premature atherosclerosis. Proc. Nat. Acad. Sci. 84:
7198-7202, 1987.
8. Karathanasis, S. K.; McPherson, J.; Zannis, V. I.; Breslow, J.
L.: Linkage of human apolipoproteins A-I and C-III genes. Nature 304:
371-373, 1983.
9. Li, W. W.; Dammerman, M. M.; Smith, J. D.; Metzger, S.; Breslow,
J. L.; Leff, T.: Common genetic variation in the promoter of the
human apo CIII gene abolishes regulation by insulin and may contribute
to hypertriglyceridemia. J. Clin. Invest. 96: 2601-2605, 1995.
10. Maeda, H.; Hashimoto, R. K.; Oguro, T.; Hiraga, S.; Uzawa, H.
: Molecular cloning of a human apoC-III variant: thr 74-to-ala 74
mutation prevents O-glycosylation. J. Lipid Res. 28: 1405-1409,
1987.
11. Maeda, H.; Uzawa, H.; Kamei, R.: Unusual familial lipoprotein
C-III associated with apolipoprotein C-III-0 preponderance. Biochim.
Biophys. Acta 665: 578-585, 1981.
12. Oettgen, P.; Antonarakis, S. E.; Karathanasis, S. K.: PvuII polymorphic
site upstream to the human apoCIII gene. Nucleic Acids Res. 14:
5571, 1986.
13. Pollin, T. I.; Damcott, C. M.; Shen, H.; Ott, S. H.; Shelton,
J.; Horenstein, R. B.; Post, W.; McLenithan, J. C.; Bielak, L. F.;
Peyser, P. A.; Mitchell, B. D.; Miller, M.; O'Connell, J. R.; Shuldiner,
A. R.: A null mutation in human APOC3 confers a favorable plasmid
lipid profile and apparent cardioprotection. Science 322: 1702-1705,
2008. Note: Erratum: Science 323: 583 only, 2009.
14. Talmud, P. J.; Hawe, E.; Martin, S.; Olivier, M.; Miller, G. J.;
Rubin, E. M.; Pennacchio, L. A.; Humphries, S. E.: Relative contribution
of variation within the APOC3/A4/A5 gene cluster in determining plasma
triglycerides. Hum. Molec. Genet. 11: 3039-3046, 2002.
15. von Eckardstein, A.; Holz, H.; Sandkamp, M.; Weng, W.; Funke,
H.; Assmann, G.: Apolipoprotein C-III(lys58-to-glu): identification
of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia. J.
Clin. Invest. 87: 1724-1731, 1991.
16. Vu-Dac, N.; Gervois, P.; Torra, I. P.; Fruchart, J.-C.; Kosykh,
V.; Kooistra, T.; Princen, H. M. G.; Dallongeville, J.; Staels, B.
: Retinoids increase human Apo C-III expression at the transcriptional
level via the retinoid X receptor: contribution to the hypertriglyceridemic
action of retinoids. J. Clin. Invest. 102: 625-632, 1998.
17. Wang, Q.; Liu, X.; O'Connell, J.; Peng, Z.; Krauss, R. M.; Rainwater,
D. L.; VandeBerg, J. L.; Rubin, E. M.; Cheng, J.-F.; Pennachio, L.
A.: Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids
in both humans and baboons. Hum. Molec. Genet. 13: 1049-1056, 2004.
18. Waterworth, D. M.; Talmud, P. J.; Luan, J.; Flavell, D. M.; Byrne,
C. D.; Humphries, S. E.; Wareham, N. J.: Variants in the APOC3 promoter
insulin responsive element modulate insulin secretion and lipids in
middle-aged men. Biochim. Biophys. Acta 1637: 200-206, 2003.
19. Zannis, V. I.; Kan, H.-Y.; Kritis, A.; Zanni, E. E.; Kardassis,
D.: Transcriptional regulatory mechanisms of the human apolipoprotein
genes in vitro and in vivo. Curr. Opin. Lipid. 12: 181-207, 2001.
*FIELD* CN
Marla J. F. O'Neill - updated: 4/27/2010
Marla J. F. O'Neill - updated: 2/12/2009
Ada Hamosh - updated: 12/29/2008
Marla J. F. O'Neill - updated: 9/8/2006
George E. Tiller - updated: 9/5/2006
Marla J. F. O'Neill - updated: 1/19/2005
George E. Tiller - updated: 8/25/2004
Victor A. McKusick - updated: 7/2/2003
Patricia A. Hartz - updated: 10/29/2002
Victor A. McKusick - updated: 10/1/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
alopez: 06/08/2011
alopez: 6/8/2011
carol: 4/28/2010
carol: 4/27/2010
ckniffin: 4/7/2010
alopez: 2/17/2009
carol: 2/13/2009
carol: 2/12/2009
carol: 1/9/2009
terry: 1/7/2009
alopez: 12/30/2008
terry: 12/29/2008
wwang: 9/12/2006
terry: 9/8/2006
alopez: 9/5/2006
carol: 2/2/2005
carol: 1/31/2005
terry: 1/19/2005
tkritzer: 8/25/2004
cwells: 7/21/2003
terry: 7/2/2003
tkritzer: 11/19/2002
mgross: 10/29/2002
carol: 10/6/1998
terry: 10/1/1998
mark: 1/27/1996
carol: 6/17/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 1/27/1992
carol: 5/21/1991
carol: 12/6/1990
MIM
614028
*RECORD*
*FIELD* NO
614028
*FIELD* TI
#614028 HYPERALPHALIPOPROTEINEMIA 2; HALP2
;;APOLIPOPROTEIN C-III DEFICIENCY
*FIELD* TX
read moreA number sign (#) is used with this entry because this form of
hyperalphalipoproteinemia is caused by loss-of-function mutation in the
APOC3 gene (107720) on chromosome 11q23.
For a discussion of phenotypic features and genetic heterogeneity of
hyperalphalipoproteinemia, see HALP1 (143470).
MOLECULAR GENETICS
In a family with hyperalphalipoproteinemia, von Eckardstein et al.
(1991) identified a heterozygous carrier of an apolipoprotein C-III
variant (107720.0002) by the presence of additional bands after
isoelectric focusing (IEF) of very low density lipoprotein (VLDL). Two
variant carriers exhibited plasma concentrations of HDL cholesterol and
APOA1 (107680) above the 95th percentile for sex-matched controls. Their
plasma concentrations of apoC-III were 30 to 40% lower than those of 2
unaffected family members and random controls.
To identify genetic factors contributing to fasting triglycerides and
the postprandial triglyceride dietary response, Pollin et al. (2008)
performed a single high fat feeding intervention and genomewide
association study in 809 Old Order Amish individuals. They found a
loss-of-function mutation in exon 2 of the APOC3 gene, R19X
(107720.0003), that was tagged by a strongly associated
single-nucleotide polymorphism (SNP), dbSNP rs10892151, in an intron of
the DSCAML1 gene (611782). Pollin et al. (2008) found that approximately
5% of Lancaster Amish individuals are heterozygous carriers of the
mutation and as a result express half the amount of apoC-III present in
noncarriers. Mutation carriers compared with noncarriers had lower
fasting and postprandial serum triglycerides, higher levels of HDL
cholesterol, and lower levels of LDL cholesterol. Subclinical
atherosclerosis, as measured by coronary artery calcification, was less
common in carriers than noncarriers, which suggested that lifelong
deficiency of apoC-III has a cardioprotective effect. The effect of the
R19X mutation on decreased fasting triglycerides and increased HDL
cholesterol levels was replicated in 698 nonoverlapping Amish
individuals. Pedigree and haplotype analysis were consistent with a
single copy of the mutated allele having entered the population before
the year 1800.
*FIELD* RF
1. Pollin, T. I.; Damcott, C. M.; Shen, H.; Ott, S. H.; Shelton, J.;
Horenstein, R. B.; Post, W.; McLenithan, J. C.; Bielak, L. F.; Peyser,
P. A.; Mitchell, B. D.; Miller, M.; O'Connell, J. R.; Shuldiner, A.
R.: A null mutation in human APOC3 confers a favorable plasmid lipid
profile and apparent cardioprotection. Science 322: 1702-1705, 2008.
Note: Erratum: Science 323: 583 only, 2009.
2. von Eckardstein, A.; Holz, H.; Sandkamp, M.; Weng, W.; Funke, H.;
Assmann, G.: Apolipoprotein C-III(lys58-to-glu): identification of
an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia. J.
Clin. Invest. 87: 1724-1731, 1991.
*FIELD* CD
Anne M. Stumpf: 6/7/2011
*FIELD* ED
terry: 06/17/2011
alopez: 6/8/2011
*RECORD*
*FIELD* NO
614028
*FIELD* TI
#614028 HYPERALPHALIPOPROTEINEMIA 2; HALP2
;;APOLIPOPROTEIN C-III DEFICIENCY
*FIELD* TX
read moreA number sign (#) is used with this entry because this form of
hyperalphalipoproteinemia is caused by loss-of-function mutation in the
APOC3 gene (107720) on chromosome 11q23.
For a discussion of phenotypic features and genetic heterogeneity of
hyperalphalipoproteinemia, see HALP1 (143470).
MOLECULAR GENETICS
In a family with hyperalphalipoproteinemia, von Eckardstein et al.
(1991) identified a heterozygous carrier of an apolipoprotein C-III
variant (107720.0002) by the presence of additional bands after
isoelectric focusing (IEF) of very low density lipoprotein (VLDL). Two
variant carriers exhibited plasma concentrations of HDL cholesterol and
APOA1 (107680) above the 95th percentile for sex-matched controls. Their
plasma concentrations of apoC-III were 30 to 40% lower than those of 2
unaffected family members and random controls.
To identify genetic factors contributing to fasting triglycerides and
the postprandial triglyceride dietary response, Pollin et al. (2008)
performed a single high fat feeding intervention and genomewide
association study in 809 Old Order Amish individuals. They found a
loss-of-function mutation in exon 2 of the APOC3 gene, R19X
(107720.0003), that was tagged by a strongly associated
single-nucleotide polymorphism (SNP), dbSNP rs10892151, in an intron of
the DSCAML1 gene (611782). Pollin et al. (2008) found that approximately
5% of Lancaster Amish individuals are heterozygous carriers of the
mutation and as a result express half the amount of apoC-III present in
noncarriers. Mutation carriers compared with noncarriers had lower
fasting and postprandial serum triglycerides, higher levels of HDL
cholesterol, and lower levels of LDL cholesterol. Subclinical
atherosclerosis, as measured by coronary artery calcification, was less
common in carriers than noncarriers, which suggested that lifelong
deficiency of apoC-III has a cardioprotective effect. The effect of the
R19X mutation on decreased fasting triglycerides and increased HDL
cholesterol levels was replicated in 698 nonoverlapping Amish
individuals. Pedigree and haplotype analysis were consistent with a
single copy of the mutated allele having entered the population before
the year 1800.
*FIELD* RF
1. Pollin, T. I.; Damcott, C. M.; Shen, H.; Ott, S. H.; Shelton, J.;
Horenstein, R. B.; Post, W.; McLenithan, J. C.; Bielak, L. F.; Peyser,
P. A.; Mitchell, B. D.; Miller, M.; O'Connell, J. R.; Shuldiner, A.
R.: A null mutation in human APOC3 confers a favorable plasmid lipid
profile and apparent cardioprotection. Science 322: 1702-1705, 2008.
Note: Erratum: Science 323: 583 only, 2009.
2. von Eckardstein, A.; Holz, H.; Sandkamp, M.; Weng, W.; Funke, H.;
Assmann, G.: Apolipoprotein C-III(lys58-to-glu): identification of
an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia. J.
Clin. Invest. 87: 1724-1731, 1991.
*FIELD* CD
Anne M. Stumpf: 6/7/2011
*FIELD* ED
terry: 06/17/2011
alopez: 6/8/2011