RBCC

Full text data of APOB

APOB [Confidence: low (only semi-automatic identification from reviews)]
Apolipoprotein B-100; Apo B-100; Apolipoprotein B-48; Apo B-48; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P04114
ID APOB_HUMAN Reviewed; 4563 AA.
AC P04114; O00502; P78479; P78480; P78481; Q13779; Q13785; Q13786;
read moreAC Q13787; Q13788; Q4ZG63; Q53QC8; Q7Z600; Q9UMN0;
DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot.
DT 13-JUL-2010, sequence version 2.
DT 22-JAN-2014, entry version 171.
DE RecName: Full=Apolipoprotein B-100;
DE Short=Apo B-100;
DE Contains:
DE RecName: Full=Apolipoprotein B-48;
DE Short=Apo B-48;
DE Flags: Precursor;
GN Name=APOB;
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 VARIANTS ASN-273; GLU-1218; CYS-1422;
RP RP VAL-2092; VAL-2313; THR-2365; GLN-2680; HIS-3319; LYS-3427;
RP GLU-3432; THR-3732; LEU-3949; PHE-3964; LYS-4181 AND ASN-4338.
RX PubMed=3763409; DOI=10.1093/nar/14.18.7501;
RA Knott T.C., Wallis S.C., Powell L.M., Pease R.J., Lusis A.J.,
RA Blackhart B., McCarthy B.J., Mahley R.W., Levy-Wilson B., Scott J.;
RT "Complete cDNA and derived protein sequence of human apolipoprotein B-
RT 100.";
RL Nucleic Acids Res. 14:7501-7503(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CYS-1422; VAL-2313;
RP HIS-3319; LYS-3427; GLU-3432 AND ASN-4338.
RX PubMed=3652907;
RA Ludwig E.H., Blackhart B.D., Pierotti V.R., Caiati L., Fortier C.,
RA Knott T., Scott J., Mahley R.W., Levy-Wilson B., McCarthy B.J.;
RT "DNA sequence of the human apolipoprotein B gene.";
RL DNA 6:363-372(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ILE-98; VAL-618; CYS-1422;
RP VAL-2313; HIS-3319; LYS-3427; GLU-3432 AND ASN-4338.
RX PubMed=3759943;
RA Chen S.-H., Yang C.-Y., Chen P.-F., Setzer D., Tanimura M., Li W.-H.,
RA Gotto A.M. Jr., Chan L.;
RT "The complete cDNA and amino acid sequence of human apolipoprotein B-
RT 100.";
RL J. Biol. Chem. 261:12918-12921(1986).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS CYS-1422; ASN-2037; VAL-2313;
RP HIS-3319; LYS-3427; GLU-3432; LEU-3949; LYS-4181 AND ASN-4338.
RX PubMed=3464946; DOI=10.1073/pnas.83.21.8142;
RA Law S.W., Grant S.M., Higuchi K., Hospattankar A.V., Lackner K.J.,
RA Lee N., Brewer H.B. Jr.;
RT "Human liver apolipoprotein B-100 cDNA: complete nucleic acid and
RT derived amino acid sequence.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:8142-8146(1986).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA], NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-40,
RP AND VARIANTS VAL-618; CYS-1422; VAL-2313; HIS-3319; LYS-3427;
RP GLU-3432; THR-3732; LEU-3949; PHE-3964; LYS-4181 AND ASN-4338.
RX PubMed=3030729;
RA Cladaras C., Hadzopoulou-Cladaras M., Nolte R.T., Atkinson D.,
RA Zannis V.I.;
RT "The complete sequence and structural analysis of human apolipoprotein
RT B-100: relationship between apoB-100 and apoB-48 forms.";
RL EMBO J. 5:3495-3507(1986).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CYS-1422; VAL-2313 AND
RP ASN-4338.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-1670, AND VARIANTS ILE-98; CYS-1422
RP AND ASP-1670.
RX PubMed=3461454; DOI=10.1073/pnas.83.15.5678;
RA Protter A.A., Hardman D.A., Sato K.Y., Schilling J.W., Yamanaka M.,
RA Hort Y.J., Hjerrild K.A., Chen G.C., Kane J.P.;
RT "Analysis of cDNA clones encoding the entire B-26 region of human
RT apolipoprotein B.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:5678-5682(1986).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-291.
RX PubMed=3513177; DOI=10.1073/pnas.83.5.1467;
RA Protter A.A., Hardman D.A., Schilling J.W., Miller J., Appleby V.,
RA Chen G.C., Kirsher S.W., McEnroe G., Kane J.P.;
RT "Isolation of a cDNA clone encoding the amino-terminal region of human
RT apolipoprotein B.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:1467-1471(1986).
RN [10]
RP PARTIAL PROTEIN SEQUENCE, DISULFIDE BONDS, AND VARIANT ILE-98.
RX PubMed=2115173; DOI=10.1073/pnas.87.14.5523;
RA Yang C.Y., Kim T.W., Weng S.A., Lee B.R., Yang M.L., Gotto A.M. Jr.;
RT "Isolation and characterization of sulfhydryl and disulfide peptides
RT of human apolipoprotein B-100.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:5523-5527(1990).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 485-1044.
RC TISSUE=Liver;
RX PubMed=3001697; DOI=10.1073/pnas.82.24.8340;
RA Law S.W., Lackner K.J., Hospattankar A.V., Anchors J.M.,
RA Sakaguchi A.Y., Naylor S.L., Brewer H.B. Jr.;
RT "Human apolipoprotein B-100: cloning, analysis of liver mRNA, and
RT assignment of the gene to chromosome 2.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:8340-8344(1985).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 709-906.
RX PubMed=3860836; DOI=10.1073/pnas.82.15.4983;
RA Deeb S.S., Motulsky A.G., Albers J.J.;
RT "A partial cDNA clone for human apolipoprotein B.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:4983-4986(1985).
RN [13]
RP PROTEIN SEQUENCE OF 873-896 AND 3113-3137.
RX PubMed=6373369; DOI=10.1016/0014-5793(84)81378-2;
RA LeBoeuf R.C., Miller C., Shively J.E., Schumaker V.N., Balla M.A.,
RA Lusis A.J.;
RT "Human apolipoprotein B: partial amino acid sequence.";
RL FEBS Lett. 170:105-108(1984).
RN [14]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1042-1232.
RX PubMed=2567736;
RA Huang L.S., Ripps M.E., Korman S.H., Deckelbaum R.J., Breslow J.L.;
RT "Hypobetalipoproteinemia due to an apolipoprotein B gene exon 21
RT deletion derived by Alu-Alu recombination.";
RL J. Biol. Chem. 264:11394-11400(1989).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1282-4503, AND VARIANTS CYS-1422;
RP VAL-2313; HIS-3319; LYS-3427; GLU-3432; THR-3732 AND ASN-4338.
RX PubMed=2883086; DOI=10.1016/0378-1119(86)90383-5;
RA Carlsson P., Darnfors C., Olofsson S.O., Bjursell G.;
RT "Analysis of the human apolipoprotein B gene; complete structure of
RT the B-74 region.";
RL Gene 49:29-51(1986).
RN [16]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1671-2398, AND VARIANT VAL-2313.
RX PubMed=3676265; DOI=10.1021/bi00391a040;
RA Hardman D.A., Protter A.A., Chen G.C., Schilling J.W., Sato K.Y.,
RA Lau K., Yamanaka M., Mikita T., Miller J., Crisp T., McEnroe G.,
RA Scarborough R.M., Kane J.P.;
RT "Structural comparison of human apolipoproteins B-48 and B-100.";
RL Biochemistry 26:5478-5486(1987).
RN [17]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1937-2018 AND 3811-4334.
RX PubMed=3841204; DOI=10.1093/nar/13.24.8813;
RA Carlsson P., Olofsson S.O., Bondjers G., Darnfors C., Wiklund O.,
RA Bjursell G.;
RT "Molecular cloning of human apolipoprotein B cDNA.";
RL Nucleic Acids Res. 13:8813-8826(1985).
RN [18]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2115-2179.
RC TISSUE=Small intestine;
RX PubMed=3621347; DOI=10.1016/0092-8674(87)90510-1;
RA Powell L.M., Wallis S.C., Pease R.J., Edwards Y.H., Knott T.J.,
RA Scott J.;
RT "A novel form of tissue-specific RNA processing produces
RT apolipoprotein-B48 in intestine.";
RL Cell 50:831-840(1987).
RN [19]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2127-2179.
RX PubMed=2450346; DOI=10.1073/pnas.85.6.1772;
RA Higuchi K., Hospattankar A.V., Law S.W., Meglin N., Cortright J.,
RA Brewer H.B. Jr.;
RT "Human apolipoprotein B (apoB) mRNA: identification of two distinct
RT apoB mRNAs, an mRNA with the apoB-100 sequence and an apoB mRNA
RT containing a premature in-frame translational stop codon, in both
RT liver and intestine.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:1772-1776(1988).
RN [20]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2129-2235.
RX PubMed=3426612; DOI=10.1016/0006-291X(87)90537-7;
RA Hardman D.A., Protter A.A., Schilling J.W., Kane J.P.;
RT "Carboxyl terminal analysis of human B-48 protein confirms the novel
RT mechanism proposed for chain termination.";
RL Biochem. Biophys. Res. Commun. 149:1214-1219(1987).
RN [21]
RP PROTEIN SEQUENCE OF 2169-2179.
RX PubMed=2445342; DOI=10.1016/0006-291X(87)91107-7;
RA Hospattankar A.V., Higuchi K., Law S.W., Meglin N., Brewer H.B. Jr.;
RT "Identification of a novel in-frame translational stop codon in human
RT intestine apoB mRNA.";
RL Biochem. Biophys. Res. Commun. 148:279-285(1987).
RN [22]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3056-3159.
RX PubMed=3903660; DOI=10.1093/nar/13.19.6937;
RA Mehrabian M., Schumaker V.N., Fareed G.C., West R., Johnson D.F.,
RA Kirchgessner T.G., Lin H.-C., Wang X., Ma Y., Mendiaz E., Lusis A.J.;
RT "Human apolipoprotein B: identification of cDNA clones and
RT characterization of mRNA.";
RL Nucleic Acids Res. 13:6937-6953(1985).
RN [23]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3109-4563, AND VARIANTS HIS-3319;
RP LYS-3427; GLU-3432; THR-3732; LEU-3949; PHE-3964; LYS-4181 AND
RP ASN-4338.
RX PubMed=2994225; DOI=10.1126/science.2994225;
RA Knott T.J., Rall S.C. Jr., Innerarity T.L., Jacobson S.F., Urdea M.S.,
RA Levy-Wilson B., Powell L.M., Pease R.J., Eddy R., Nakai H., Byers M.,
RA Priestley L.M., Robertson E., Rall L.B., Betsholtz C., Shows T.B.,
RA Mahley R.W., Scott J.;
RT "Human apolipoprotein B: structure of carboxyl-terminal domains, sites
RT of gene expression, and chromosomal localization.";
RL Science 230:37-43(1985).
RN [24]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3728-4563, AND VARIANT ASN-4338.
RX PubMed=2932736; DOI=10.1073/pnas.82.21.7265;
RA Wei C.F., Chen S.H., Yang C.Y., Marcel Y.L., Milne R.W., Li W.H.,
RA Sparrow J.T., Gotto A.M. Jr., Chan L.;
RT "Molecular cloning and expression of partial cDNAs and deduced amino
RT acid sequence of a carboxyl-terminal fragment of human apolipoprotein
RT B-100.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:7265-7269(1985).
RN [25]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3846-4298, AND VARIANTS LEU-3949;
RP PHE-3964 AND LYS-4181.
RC TISSUE=Liver;
RX PubMed=3841481; DOI=10.1016/0021-9150(85)90073-5;
RA Shoulders C.C., Myant N.B., Sidoli A., Rodriguez J.C., Cortese C.,
RA Baralle F.E., Cortese R.;
RT "Molecular cloning of human LDL apolipoprotein B cDNA. Evidence for
RT more than one gene per haploid genome.";
RL Atherosclerosis 58:277-289(1985).
RN [26]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4217-4563.
RX PubMed=3024665;
RA Pfitzner R., Wagener R., Stoffel W.;
RT "Isolation, expression and characterization of a human apolipoprotein
RT B 100-specific cDNA clone.";
RL Biol. Chem. Hoppe-Seyler 367:1077-1083(1986).
RN [27]
RP PARTIAL PROTEIN SEQUENCE, AND IDENTIFICATION OF APO-B48.
RX PubMed=3659919; DOI=10.1126/science.3659919;
RA Chen S.-H., Habib G., Yang C.-H., Gu Z.-W., Lee B.R., Weng S.-H.,
RA Silberman S.R., Cai S.-J., Deslypere J.P., Rosseneu M.,
RA Gotto A.M. Jr., Li W.-H., Chan L.;
RT "Apolipoprotein B-48 is the product of a messenger RNA with an organ-
RT specific in-frame stop codon.";
RL Science 238:363-366(1987).
RN [28]
RP DOMAINS.
RX PubMed=3773997; DOI=10.1038/323734a0;
RA Knott T.C., Pease R.J., Powell L.M., Wallis S.C., Rall S.C. Jr.,
RA Innerarity T.L., Blackhart B., Taylor W.R., Marcel Y., Milne R.,
RA Johnson D., Fuller M., Lusis A.J., McCarthy B.J., Mahley R.W.,
RA Levy-Wilson B., Scott J.;
RT "Complete protein sequence and identification of structural domains of
RT human apolipoprotein B.";
RL Nature 323:734-738(1986).
RN [29]
RP DOMAINS.
RX PubMed=3095664; DOI=10.1038/323738a0;
RA Yang C.-Y., Chen S.-H., Gianturco S.H., Bradley W.A., Sparrow J.T.,
RA Tanimura M., Li W.-H., Sparrow D.A., Deloof H., Rosseneu M.,
RA Lee F.-S., Gu Z.-W., Gotto A.M. Jr., Chan L.;
RT "Sequence, structure, receptor-binding domains and internal repeats of
RT human apolipoprotein B-100.";
RL Nature 323:738-742(1986).
RN [30]
RP CALCIUM-BINDING.
RX PubMed=3087360; DOI=10.1016/0006-291X(86)91237-4;
RA Dashti N., Lee D.M., Mok T.;
RT "Apolipoprotein B is a calcium binding protein.";
RL Biochem. Biophys. Res. Commun. 137:493-499(1986).
RN [31]
RP PALMITOYLATION AT CYS-1112.
RX PubMed=10679026; DOI=10.1091/mbc.11.2.721;
RA Zhao Y., McCabe J.B., Vance J., Berthiaume L.G.;
RT "Palmitoylation of apolipoprotein B is required for proper
RT intracellular sorting and transport of cholesteroyl esters and
RT triglycerides.";
RL Mol. Biol. Cell 11:721-734(2000).
RN [32]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-3358, 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 [33]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1523; ASN-2982; ASN-3465
RP AND ASN-3895, 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 [34]
RP INDUCTION, AND MASS SPECTROMETRY.
RX PubMed=16548883; DOI=10.1111/j.1462-5822.2005.00644.x;
RA Leong W.F., Chow V.T.;
RT "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells
RT reveal differential cellular gene expression in response to
RT enterovirus 71 infection.";
RL Cell. Microbiol. 8:565-580(2006).
RN [35]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-185; ASN-1523; ASN-2239;
RP ASN-2779; ASN-2982; ASN-3101; ASN-3224; ASN-3411; ASN-3465 AND
RP ASN-3895, 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 [36]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-2004, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [37]
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 [38]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH PCSK9.
RX PubMed=22580899; DOI=10.1161/ATVBAHA.112.250043;
RA Sun H., Samarghandi A., Zhang N., Yao Z., Xiong M., Teng B.B.;
RT "Proprotein convertase subtilisin/kexin type 9 interacts with
RT apolipoprotein B and prevents its intracellular degradation,
RT irrespective of the low-density lipoprotein receptor.";
RL Arterioscler. Thromb. Vasc. Biol. 32:1585-1595(2012).
RN [39]
RP VARIANT ASN-4338.
RX PubMed=1979313; DOI=10.1007/BF00205183;
RA Navajas M., Laurent A.-M., Moreel J.-F., Ragab A., Cambou J.-P.,
RA Cunny G., Cambien F., Roizes G.;
RT "Detection by denaturing gradient gel electrophoresis of a new
RT polymorphism in the apolipoprotein B gene.";
RL Hum. Genet. 86:91-93(1990).
RN [40]
RP VARIANT FDB GLN-3527.
RX PubMed=2563166; DOI=10.1073/pnas.86.2.587;
RA Soria L.F., Ludwig E.H., Clarke H.R.G., Vega G.L., Grundy S.M.,
RA McCarthy B.J.;
RT "Association between a specific apolipoprotein B mutation and familial
RT defective apolipoprotein B-100.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:587-591(1989).
RN [41]
RP VARIANT LEU-2739.
RX PubMed=2216805; DOI=10.1093/nar/18.19.5922-a;
RA Huang L.-S., Gavish D., Breslow J.L.;
RT "Sequence polymorphism in the human apoB gene at position 8344.";
RL Nucleic Acids Res. 18:5922-5922(1990).
RN [42]
RP VARIANT FDB CYS-3558.
RX PubMed=7883971; DOI=10.1172/JCI117772;
RA Pullinger C.R., Hennessy L.K., Chatterton J.E., Liu W., Love J.A.,
RA Mendel C.M., Frost P.H., Malloy M.J., Schumaker V.N., Kane J.P.;
RT "Familial ligand-defective apolipoprotein B. Identification of a new
RT mutation that decreases LDL receptor binding affinity.";
RL J. Clin. Invest. 95:1225-1234(1995).
RN [43]
RP VARIANTS LEU-1437; SER-1914; LYS-2566; THR-3121; ALA-3945; MET-4128
RP AND THR-4481.
RX PubMed=8889592;
RX DOI=10.1002/(SICI)1098-1004(1996)8:3<282::AID-HUMU16>3.3.CO;2-Y;
RA Poirier O., Ricard S., Behague I., Souriau C., Evans A.E.,
RA Arveiler D., Marques-Vidal P., Luc G., Roizes G., Cambien F.;
RT "Detection of new variants in the apolipoprotein B (Apo B) gene by
RT PCR-SSCP.";
RL Hum. Mutat. 8:282-285(1996).
RN [44]
RP VARIANTS FDB GLN-3527 AND CYS-3558.
RX PubMed=9259199;
RX DOI=10.1002/(SICI)1098-1004(1997)10:2<160::AID-HUMU8>3.3.CO;2-F;
RA Rabes J.P., Varret M., Saint-Jore B., Erlich D., Jondeau G.,
RA Krempf M., Giraudet P., Junien C., Boileau C.;
RT "Familial ligand-defective apolipoprotein B-100: simultaneous
RT detection of the Arg3500-->Gln and Arg3531-->Cys mutations in a French
RT population.";
RL Hum. Mutat. 10:160-163(1997).
RN [45]
RP VARIANTS SER-1914; ARG-1923; LEU-2739; HIS-3319; LYS-3427; GLU-3432
RP AND ILE-3921.
RX PubMed=9490296; DOI=10.1007/s004390050651;
RA Leren T.P., Bakken K.S., Hoel V., Hjermann I., Berg K.;
RT "Screening for mutations of the apolipoprotein B gene causing
RT hypocholesterolemia.";
RL Hum. Genet. 102:44-49(1998).
RN [46]
RP VARIANT FHBL1 TRP-490, VARIANT ILE-98, CHARACTERIZATION OF VARIANT
RP TRP-490, AND MUTAGENESIS OF ASP-483 AND ARG-490.
RX PubMed=12551903; DOI=10.1074/jbc.M300235200;
RA Burnett J.R., Shan J., Miskie B.A., Whitfield A.J., Yuan J., Tran K.,
RA McKnight C.J., Hegele R.A., Yao Z.;
RT "A novel nontruncating APOB gene mutation, R463W, causes familial
RT hypobetalipoproteinemia.";
RL J. Biol. Chem. 278:13442-13452(2003).
RN [47]
RP VARIANT HIS-1128.
RX PubMed=14732481;
RA Lancellotti S., Di Leo E., Penacchioni J.Y., Balli F., Viola L.,
RA Bertolini S., Calandra S., Tarugi P.;
RT "Hypobetalipoproteinemia with an apparently recessive inheritance due
RT to a 'de novo' mutation of apolipoprotein B.";
RL Biochim. Biophys. Acta 1688:61-67(2004).
RN [48]
RP VARIANT [LARGE SCALE ANALYSIS] CYS-2564.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [49]
RP VARIANT FDB GLN-3527.
RX PubMed=21382890; DOI=10.1161/CIRCULATIONAHA.110.979450;
RA van der Graaf A., Avis H.J., Kusters D.M., Vissers M.N., Hutten B.A.,
RA Defesche J.C., Huijgen R., Fouchier S.W., Wijburg F.A.,
RA Kastelein J.J., Wiegman A.;
RT "Molecular basis of autosomal dominant hypercholesterolemia:
RT assessment in a large cohort of hypercholesterolemic children.";
RL Circulation 123:1167-1173(2011).
RN [50]
RP VARIANTS GLU-1218; ASP-1670; ASN-2037; CYS-2564 AND LYS-2566, AND MASS
RP 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).
RN [51]
RP VARIANTS 12-LEU--LEU-14 DEL; ILE-98; VAL-618; ILE-730; THR-1613;
RP ARG-1923; LYS-2566; LEU-2739; GLN-3638; LEU-3835; LYS-4181; THR-4270;
RP VAL-4314; ASN-4338; THR-4481 AND VAL-4482.
RX PubMed=22095935; DOI=10.1002/humu.21660;
RA Huijgen R., Sjouke B., Vis K., de Randamie J.S., Defesche J.C.,
RA Kastelein J.J., Hovingh G.K., Fouchier S.W.;
RT "Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of
RT pathogenic autosomal dominant hypercholesterolemic mutations with
RT unexpected low LDL-Cl Levels.";
RL Hum. Mutat. 33:448-455(2012).
CC -!- FUNCTION: Apolipoprotein B is a major protein constituent of
CC chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100). Apo
CC B-100 functions as a recognition signal for the cellular binding
CC and internalization of LDL particles by the apoB/E receptor.
CC -!- SUBUNIT: Interacts with PCSK9.
CC -!- INTERACTION:
CC P29991:- (xeno); NbExp=3; IntAct=EBI-3926040, EBI-8869494;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Secreted.
CC -!- INDUCTION: Up-regulated in response to enterovirus 71 (EV71)
CC infection (at protein level).
CC -!- PTM: Palmitoylated; structural requirement for proper assembly of
CC the hydrophobic core of the lipoprotein particle.
CC -!- RNA EDITING: Modified_positions=2180; Note=The stop codon (UAA) at
CC position 2180 is created by RNA editing. Apo B-48, derived from
CC the fully edited RNA, is produced only in the intestine and is
CC found in chylomicrons. Apo B-48 is a shortened form of apo B-100
CC which lacks the LDL-receptor region. The unedited version (apo B-
CC 100) is produced by the liver and is found in the VLDL and LDL.
CC -!- DISEASE: Familial hypobetalipoproteinemia 1 (FHBL1) [MIM:107730]:
CC A disorder of lipid metabolism characterized by less than 5th
CC percentile age- and sex-specific levels of low density
CC lipoproteins, and dietary fat malabsorption. Clinical presentation
CC may vary from no symptoms to severe gastrointestinal and
CC neurological dysfunction similar to abetalipoproteinemia. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Familial ligand-defective apolipoprotein B-100 (FDB)
CC [MIM:144010]: Dominantly inherited disorder of lipoprotein
CC metabolism leading to hypercholesterolemia and increased proneness
CC to coronary artery disease (CAD). The plasma cholesterol levels
CC are dramatically elevated due to impaired clearance of LDL
CC particles by defective APOB/E receptors. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Note=Defects in APOB associated with defects in other
CC genes (polygenic) can contribute to hypocholesterolemia.
CC -!- SIMILARITY: Contains 1 vitellogenin domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA51752.1; Type=Frameshift; Positions=942, 951, 1139, 1165, 1164, 1371, 1385;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/APOB";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=APOB";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Apolipoprotein B entry;
CC URL="http://en.wikipedia.org/wiki/Apolipoprotein_B";
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; X04506; CAA28191.1; -; mRNA.
DR EMBL; M19828; AAB00481.1; -; Genomic_DNA.
DR EMBL; M19808; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19809; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19810; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19811; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19812; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19813; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19815; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19816; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19818; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19820; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19821; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19823; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19824; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19825; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; M19827; AAB00481.1; JOINED; Genomic_DNA.
DR EMBL; J02610; AAA35549.1; -; mRNA.
DR EMBL; M14162; AAB04636.1; -; mRNA.
DR EMBL; M15053; AAB60718.1; -; Genomic_DNA.
DR EMBL; X04714; CAA28420.1; -; mRNA.
DR EMBL; AY324608; AAP72970.1; -; Genomic_DNA.
DR EMBL; AC010872; AAX88848.1; -; Genomic_DNA.
DR EMBL; AC115619; AAX93246.1; -; Genomic_DNA.
DR EMBL; M14081; AAA51752.1; ALT_FRAME; mRNA.
DR EMBL; M12681; AAA51753.1; -; mRNA.
DR EMBL; M12480; AAA51751.1; -; mRNA.
DR EMBL; K03175; AAA51759.1; -; mRNA.
DR EMBL; M15421; AAA51758.1; -; mRNA.
DR EMBL; M17367; AAA51741.1; -; mRNA.
DR EMBL; M31030; AAA51756.1; -; mRNA.
DR EMBL; X03325; CAA27044.1; -; mRNA.
DR EMBL; X03326; CAA27045.1; -; mRNA.
DR EMBL; M17779; AAA51755.1; -; mRNA.
DR EMBL; M19734; AAA35544.1; -; mRNA.
DR EMBL; M18471; AAA35541.1; -; mRNA.
DR EMBL; X03045; CAA26850.1; -; mRNA.
DR EMBL; M10374; AAA51750.1; -; mRNA.
DR EMBL; M12413; AAA51742.1; -; mRNA.
DR EMBL; M36676; AAA35548.1; -; mRNA.
DR PIR; A27850; LPHUB.
DR RefSeq; NP_000375.2; NM_000384.2.
DR UniGene; Hs.120759; -.
DR ProteinModelPortal; P04114; -.
DR DIP; DIP-44767N; -.
DR IntAct; P04114; 7.
DR MINT; MINT-1506918; -.
DR BindingDB; P04114; -.
DR ChEMBL; CHEMBL4549; -.
DR DrugBank; DB01076; Atorvastatin.
DR PhosphoSite; P04114; -.
DR UniCarbKB; P04114; -.
DR DMDM; 300669605; -.
DR PaxDb; P04114; -.
DR PeptideAtlas; P04114; -.
DR PRIDE; P04114; -.
DR Ensembl; ENST00000233242; ENSP00000233242; ENSG00000084674.
DR GeneID; 338; -.
DR KEGG; hsa:338; -.
DR CTD; 338; -.
DR GeneCards; GC02M021135; -.
DR H-InvDB; HIX0024005; -.
DR HGNC; HGNC:603; APOB.
DR HPA; CAB016070; -.
DR MIM; 107730; gene+phenotype.
DR MIM; 144010; phenotype.
DR neXtProt; NX_P04114; -.
DR Orphanet; 14; Abetalipoproteinemia.
DR Orphanet; 406; Familial hypercholesterolemia.
DR Orphanet; 426; Familial hypobetalipoproteinemia.
DR PharmGKB; PA50; -.
DR eggNOG; NOG290405; -.
DR HOVERGEN; HBG050546; -.
DR InParanoid; P04114; -.
DR KO; K14462; -.
DR OMA; HIPEFQL; -.
DR OrthoDB; EOG7VB2DG; -.
DR PhylomeDB; P04114; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; APOB; human.
DR GeneWiki; Apolipoprotein_B; -.
DR GenomeRNAi; 338; -.
DR NextBio; 1399; -.
DR PRO; PR:P04114; -.
DR ArrayExpress; P04114; -.
DR Bgee; P04114; -.
DR Genevestigator; P04114; -.
DR GO; GO:0034360; C:chylomicron remnant; TAS:BHF-UCL.
DR GO; GO:0030669; C:clathrin-coated endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005769; C:early endosome; TAS:Reactome.
DR GO; GO:0071682; C:endocytic vesicle lumen; TAS:Reactome.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0031904; C:endosome lumen; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0034363; C:intermediate-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034362; C:low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034359; C:mature chylomicron; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0017127; F:cholesterol transporter activity; IMP:BHF-UCL.
DR GO; GO:0008201; F:heparin binding; IDA:BHF-UCL.
DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; IMP:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL.
DR GO; GO:0048844; P:artery morphogenesis; IEA:Ensembl.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0071379; P:cellular response to prostaglandin stimulus; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0033344; P:cholesterol efflux; IEA:Ensembl.
DR GO; GO:0042632; P:cholesterol homeostasis; IMP:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IMP:BHF-UCL.
DR GO; GO:0009566; P:fertilization; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0042158; P:lipoprotein biosynthetic process; IEA:Ensembl.
DR GO; GO:0042159; P:lipoprotein catabolic process; IEA:Ensembl.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0042953; P:lipoprotein transport; IEA:Ensembl.
DR GO; GO:0034383; P:low-density lipoprotein particle clearance; IMP:BHF-UCL.
DR GO; GO:0034374; P:low-density lipoprotein particle remodeling; IMP:BHF-UCL.
DR GO; GO:0007399; P:nervous system development; IEA:Ensembl.
DR GO; GO:0007603; P:phototransduction, visible light; TAS:Reactome.
DR GO; GO:0010886; P:positive regulation of cholesterol storage; IDA:BHF-UCL.
DR GO; GO:0010744; P:positive regulation of macrophage derived foam cell differentiation; IDA:BHF-UCL.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0006898; P:receptor-mediated endocytosis; TAS:Reactome.
DR GO; GO:0045540; P:regulation of cholesterol biosynthetic process; IEA:Ensembl.
DR GO; GO:0009743; P:response to carbohydrate stimulus; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0010269; P:response to selenium ion; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR GO; GO:0001523; P:retinoid metabolic process; TAS:Reactome.
DR GO; GO:0030317; P:sperm motility; IEA:Ensembl.
DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
DR GO; GO:0019433; P:triglyceride catabolic process; IEA:Ensembl.
DR GO; GO:0006642; P:triglyceride mobilization; IEA:Ensembl.
DR GO; GO:0034379; P:very-low-density lipoprotein particle assembly; IC:BHF-UCL.
DR Gene3D; 1.25.10.20; -; 1.
DR Gene3D; 2.20.50.20; -; 2.
DR Gene3D; 2.20.80.10; -; 1.
DR Gene3D; 2.30.230.10; -; 1.
DR InterPro; IPR022176; ApoB100_C.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR015819; Lipid_transp_b-sht_shell.
DR InterPro; IPR001747; Lipid_transpt_N.
DR InterPro; IPR009454; Lipid_transpt_open_b-sht.
DR InterPro; IPR015816; Vitellinogen_b-sht_N.
DR InterPro; IPR015255; Vitellinogen_open_b-sht.
DR InterPro; IPR015817; Vitellinogen_open_b-sht_sub1.
DR InterPro; IPR015818; Vitellinogen_open_b-sht_sub2.
DR InterPro; IPR011030; Vitellinogen_superhlx.
DR Pfam; PF12491; ApoB100_C; 1.
DR Pfam; PF06448; DUF1081; 1.
DR Pfam; PF09172; DUF1943; 1.
DR Pfam; PF01347; Vitellogenin_N; 1.
DR SMART; SM00638; LPD_N; 1.
DR SUPFAM; SSF48371; SSF48371; 2.
DR SUPFAM; SSF48431; SSF48431; 1.
DR SUPFAM; SSF56968; SSF56968; 2.
DR PROSITE; PS51211; VITELLOGENIN; 1.
PE 1: Evidence at protein level;
KW Acetylation; Atherosclerosis; Cholesterol metabolism; Chylomicron;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Glycoprotein; Heparin-binding; LDL;
KW Lipid metabolism; Lipid transport; Lipoprotein; Palmitate;
KW Polymorphism; Reference proteome; RNA editing; Secreted; Signal;
KW Steroid metabolism; Sterol metabolism; Transport; VLDL.
FT SIGNAL 1 27
FT CHAIN 28 4563 Apolipoprotein B-100.
FT /FTId=PRO_0000020750.
FT CHAIN 28 2179 Apolipoprotein B-48.
FT /FTId=PRO_0000020751.
FT DOMAIN 46 672 Vitellogenin.
FT REGION 32 126 Heparin-binding.
FT REGION 232 306 Heparin-binding.
FT REGION 902 959 Heparin-binding.
FT REGION 2043 2178 Heparin-binding.
FT REGION 3161 3236 Heparin-binding.
FT REGION 3174 3184 Basic (possible receptor binding region).
FT REGION 3373 3393 LDL receptor binding.
FT REGION 3383 3516 Heparin-binding.
FT REGION 3386 3394 Basic (possible receptor binding region).
FT MOD_RES 2004 2004 N6-acetyllysine.
FT LIPID 1112 1112 S-palmitoyl cysteine.
FT CARBOHYD 34 34 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 185 185 N-linked (GlcNAc...).
FT CARBOHYD 983 983 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1368 1368 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1377 1377 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1523 1523 N-linked (GlcNAc...).
FT CARBOHYD 2239 2239 N-linked (GlcNAc...).
FT CARBOHYD 2560 2560 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2779 2779 N-linked (GlcNAc...).
FT CARBOHYD 2982 2982 N-linked (GlcNAc...).
FT CARBOHYD 3101 3101 N-linked (GlcNAc...).
FT CARBOHYD 3224 3224 N-linked (GlcNAc...).
FT CARBOHYD 3336 3336 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3358 3358 N-linked (GlcNAc...).
FT CARBOHYD 3411 3411 N-linked (GlcNAc...).
FT CARBOHYD 3465 3465 N-linked (GlcNAc...).
FT CARBOHYD 3895 3895 N-linked (GlcNAc...).
FT CARBOHYD 4237 4237 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 4431 4431 N-linked (GlcNAc...) (Potential).
FT DISULFID 39 88
FT DISULFID 78 97
FT DISULFID 186 212
FT DISULFID 245 261
FT DISULFID 385 390
FT DISULFID 478 513
FT DISULFID 966 976
FT DISULFID 3194 3324
FT VARIANT 12 14 Missing.
FT /FTId=VAR_067277.
FT VARIANT 98 98 T -> I (in dbSNP:rs1367117).
FT /FTId=VAR_016184.
FT VARIANT 103 103 Y -> H (in dbSNP:rs9282603).
FT /FTId=VAR_022036.
FT VARIANT 145 145 P -> S (in dbSNP:rs6752026).
FT /FTId=VAR_022037.
FT VARIANT 194 194 T -> M (in dbSNP:rs13306198).
FT /FTId=VAR_056737.
FT VARIANT 273 273 K -> N (in dbSNP:rs1126419).
FT /FTId=VAR_019827.
FT VARIANT 408 408 I -> T (in dbSNP:rs12714225).
FT /FTId=VAR_029341.
FT VARIANT 490 490 R -> W (in FHBL1; reduced protein
FT secretion).
FT /FTId=VAR_022610.
FT VARIANT 554 554 P -> L (in dbSNP:rs12714214).
FT /FTId=VAR_020135.
FT VARIANT 618 618 A -> V (in dbSNP:rs679899).
FT /FTId=VAR_019828.
FT VARIANT 730 730 V -> I (in dbSNP:rs12691202).
FT /FTId=VAR_020136.
FT VARIANT 733 733 V -> I (in dbSNP:rs1800476).
FT /FTId=VAR_016185.
FT VARIANT 741 741 T -> N (in dbSNP:rs12714192).
FT /FTId=VAR_020137.
FT VARIANT 877 877 P -> L (in dbSNP:rs12714097).
FT /FTId=VAR_029342.
FT VARIANT 955 955 P -> S (in dbSNP:rs13306206).
FT /FTId=VAR_056738.
FT VARIANT 1086 1086 G -> S (in dbSNP:rs12720801).
FT /FTId=VAR_029343.
FT VARIANT 1113 1113 D -> H (in dbSNP:rs12713844).
FT /FTId=VAR_029344.
FT VARIANT 1128 1128 R -> H (in dbSNP:rs12713843).
FT /FTId=VAR_022611.
FT VARIANT 1218 1218 Q -> E (polymorphism confirmed at protein
FT level; dbSNP:rs1041956).
FT /FTId=VAR_019829.
FT VARIANT 1388 1388 R -> H (in dbSNP:rs13306187).
FT /FTId=VAR_029345.
FT VARIANT 1422 1422 Y -> C (in dbSNP:rs568413).
FT /FTId=VAR_061558.
FT VARIANT 1437 1437 F -> L (in dbSNP:rs1801697).
FT /FTId=VAR_005016.
FT VARIANT 1613 1613 S -> T.
FT /FTId=VAR_067278.
FT VARIANT 1670 1670 E -> D (polymorphism confirmed at protein
FT level).
FT /FTId=VAR_068911.
FT VARIANT 1914 1914 N -> S (in dbSNP:rs1801699).
FT /FTId=VAR_005017.
FT VARIANT 1923 1923 H -> R (in dbSNP:rs533617).
FT /FTId=VAR_005018.
FT VARIANT 2037 2037 I -> N (polymorphism confirmed at protein
FT level).
FT /FTId=VAR_068912.
FT VARIANT 2092 2092 L -> V (in dbSNP:rs1041960).
FT /FTId=VAR_019830.
FT VARIANT 2299 2299 D -> H (in dbSNP:rs12713681).
FT /FTId=VAR_029346.
FT VARIANT 2313 2313 I -> V (in dbSNP:rs584542).
FT /FTId=VAR_059582.
FT VARIANT 2365 2365 A -> T (in dbSNP:rs1041971).
FT /FTId=VAR_019831.
FT VARIANT 2456 2456 A -> D (in dbSNP:rs12713675).
FT /FTId=VAR_020138.
FT VARIANT 2564 2564 F -> C (in a colorectal cancer sample;
FT somatic mutation; polymorphism confirmed
FT at protein level).
FT /FTId=VAR_035795.
FT VARIANT 2566 2566 E -> K (polymorphism confirmed at protein
FT level; dbSNP:rs1801696).
FT /FTId=VAR_005019.
FT VARIANT 2680 2680 L -> Q (in dbSNP:rs1042013).
FT /FTId=VAR_019832.
FT VARIANT 2739 2739 P -> L (in dbSNP:rs676210).
FT /FTId=VAR_005020.
FT VARIANT 2785 2785 N -> H (in dbSNP:rs2163204).
FT /FTId=VAR_022038.
FT VARIANT 3121 3121 A -> T (in dbSNP:rs1801694).
FT /FTId=VAR_005021.
FT VARIANT 3182 3182 H -> N (in dbSNP:rs12720848).
FT /FTId=VAR_029347.
FT VARIANT 3279 3279 S -> G (in dbSNP:rs12720854).
FT /FTId=VAR_029348.
FT VARIANT 3294 3294 S -> P (in dbSNP:rs12720855).
FT /FTId=VAR_020139.
FT VARIANT 3319 3319 D -> H.
FT /FTId=VAR_005022.
FT VARIANT 3427 3427 T -> K.
FT /FTId=VAR_005023.
FT VARIANT 3432 3432 Q -> E (in dbSNP:rs1042023).
FT /FTId=VAR_005024.
FT VARIANT 3527 3527 R -> Q (in FDB; dbSNP:rs5742904).
FT /FTId=VAR_005025.
FT VARIANT 3558 3558 R -> C (in FDB; dbSNP:rs12713559).
FT /FTId=VAR_005026.
FT VARIANT 3638 3638 R -> Q (in dbSNP:rs1801701).
FT /FTId=VAR_016186.
FT VARIANT 3732 3732 I -> T (in dbSNP:rs1042025).
FT /FTId=VAR_019833.
FT VARIANT 3801 3801 S -> T (in dbSNP:rs12713540).
FT /FTId=VAR_029349.
FT VARIANT 3835 3835 I -> L.
FT /FTId=VAR_067279.
FT VARIANT 3921 3921 V -> I (in dbSNP:rs72654409).
FT /FTId=VAR_005027.
FT VARIANT 3945 3945 T -> A (in dbSNP:rs1801698).
FT /FTId=VAR_005028.
FT VARIANT 3949 3949 F -> L (in dbSNP:rs1042027).
FT /FTId=VAR_019834.
FT VARIANT 3964 3964 Y -> F (in dbSNP:rs1126468).
FT /FTId=VAR_019835.
FT VARIANT 4128 4128 V -> M (in dbSNP:rs1801703).
FT /FTId=VAR_005029.
FT VARIANT 4181 4181 E -> K (in dbSNP:rs1042031).
FT /FTId=VAR_016187.
FT VARIANT 4270 4270 R -> T (in dbSNP:rs1801702).
FT /FTId=VAR_016188.
FT VARIANT 4314 4314 I -> V (in dbSNP:rs72654423).
FT /FTId=VAR_067280.
FT VARIANT 4338 4338 S -> N (in dbSNP:rs1042034).
FT /FTId=VAR_005030.
FT VARIANT 4394 4394 V -> A (in dbSNP:rs12720843).
FT /FTId=VAR_029350.
FT VARIANT 4481 4481 A -> T (in dbSNP:rs1801695).
FT /FTId=VAR_005031.
FT VARIANT 4482 4482 I -> V.
FT /FTId=VAR_067281.
FT VARIANT 4484 4484 T -> M (in dbSNP:rs12713450).
FT /FTId=VAR_020140.
FT MUTAGEN 483 483 D->N: Impairs protein secretion.
FT MUTAGEN 483 483 D->Q: Does not affect protein secretion.
FT MUTAGEN 490 490 R->A: Impairs protein secretion.
FT MUTAGEN 490 490 R->K: Does not affect protein secretion.
FT CONFLICT 11 13 Missing (in Ref. 5; AAB60718/CAA28420).
FT CONFLICT 329 329 L -> V (in Ref. 3; AAA35549).
FT CONFLICT 645 645 L -> I (in Ref. 3; AAA35549).
FT CONFLICT 704 704 L -> P (in Ref. 4; AAB04636).
FT CONFLICT 792 809 LQLLGKLLLMGARTLQGI -> SSSWKAASHGCPHSAGD
FT (in Ref. 12; AAA51759).
FT CONFLICT 793 793 Q -> R (in Ref. 4; AAB04636).
FT CONFLICT 893 893 D -> K (in Ref. 13; AA sequence).
FT CONFLICT 919 919 A -> P (in Ref. 3; AAA35549).
FT CONFLICT 1109 1109 H -> D (in Ref. 5; CAA28420).
FT CONFLICT 1180 1180 T -> R (in Ref. 8; AAA51752).
FT CONFLICT 1271 1271 F -> S (in Ref. 4; AAB04636).
FT CONFLICT 1418 1418 F -> S (in Ref. 5; CAA28420).
FT CONFLICT 1445 1445 N -> I (in Ref. 8; AAA51752).
FT CONFLICT 1535 1535 G -> E (in Ref. 8; AAA51752).
FT CONFLICT 1867 1867 R -> G (in Ref. 4; AAB04636).
FT CONFLICT 2098 2098 N -> K (in Ref. 5; CAA28420).
FT CONFLICT 2218 2218 I -> T (in Ref. 4; AAB04636).
FT CONFLICT 2221 2221 N -> I (in Ref. 5; CAA28420).
FT CONFLICT 2324 2326 LIG -> PYW (in Ref. 16; AAA51741).
FT CONFLICT 2353 2353 Q -> H (in Ref. 16; AAA51741).
FT CONFLICT 2540 2540 G -> S (in Ref. 5; CAA28420).
FT CONFLICT 2718 2737 Missing (in Ref. 15; AAA51758).
FT CONFLICT 2933 2933 C -> S (in Ref. 4; AAB04636).
FT CONFLICT 3114 3114 H -> L (in Ref. 13; AA sequence).
FT CONFLICT 3131 3131 T -> R (in Ref. 13; AA sequence).
FT CONFLICT 3134 3134 E -> P (in Ref. 13; AA sequence).
FT CONFLICT 3137 3137 L -> R (in Ref. 13; AA sequence).
FT CONFLICT 3239 3239 H -> Q (in Ref. 5; CAA28420).
FT CONFLICT 3286 3286 L -> I (in Ref. 4; AAB04636).
FT CONFLICT 3291 3291 R -> L (in Ref. 15; AAA51758).
FT CONFLICT 3337 3337 I -> N (in Ref. 15; AAA51758).
FT CONFLICT 3431 3431 A -> P (in Ref. 4; AAB04636).
FT CONFLICT 3728 3728 D -> N (in Ref. 24; AAA51742).
FT CONFLICT 3782 3782 N -> T (in Ref. 4; AAB04636).
FT CONFLICT 3824 3824 Q -> R (in Ref. 5; CAA28420 and 23;
FT AAA51750).
FT CONFLICT 3876 3876 V -> A (in Ref. 3; AAA35549 and 24;
FT AAA51742).
FT CONFLICT 3911 3911 T -> Y (in Ref. 10; AA sequence).
FT CONFLICT 3983 3983 F -> S (in Ref. 24; AAA51742).
FT CONFLICT 4002 4002 A -> P (in Ref. 24; AAA51742).
FT CONFLICT 4110 4111 NN -> DH (in Ref. 3; AAA35549 and 24;
FT AAA51742).
FT CONFLICT 4122 4122 Q -> E (in Ref. 3; AAA35549 and 24;
FT AAA51742).
FT CONFLICT 4128 4128 V -> E (in Ref. 3; AAA35549 and 24;
FT AAA51742).
FT CONFLICT 4133 4133 A -> G (in Ref. 3; AAA35549 and 24;
FT AAA51742).
FT CONFLICT 4188 4188 H -> K (in Ref. 4; AAB04636).
FT CONFLICT 4217 4218 CT -> FP (in Ref. 26; AAA35548).
FT CONFLICT 4221 4221 I -> M (in Ref. 4; AAB04636).
SQ SEQUENCE 4563 AA; 515605 MW; 6800F94BF6ADF698 CRC64;
MDPPRPALLA LLALPALLLL LLAGARAEEE MLENVSLVCP KDATRFKHLR KYTYNYEAES
SSGVPGTADS RSATRINCKV ELEVPQLCSF ILKTSQCTLK EVYGFNPEGK ALLKKTKNSE
EFAAAMSRYE LKLAIPEGKQ VFLYPEKDEP TYILNIKRGI ISALLVPPET EEAKQVLFLD
TVYGNCSTHF TVKTRKGNVA TEISTERDLG QCDRFKPIRT GISPLALIKG MTRPLSTLIS
SSQSCQYTLD AKRKHVAEAI CKEQHLFLPF SYKNKYGMVA QVTQTLKLED TPKINSRFFG
EGTKKMGLAF ESTKSTSPPK QAEAVLKTLQ ELKKLTISEQ NIQRANLFNK LVTELRGLSD
EAVTSLLPQL IEVSSPITLQ ALVQCGQPQC STHILQWLKR VHANPLLIDV VTYLVALIPE
PSAQQLREIF NMARDQRSRA TLYALSHAVN NYHKTNPTGT QELLDIANYL MEQIQDDCTG
DEDYTYLILR VIGNMGQTME QLTPELKSSI LKCVQSTKPS LMIQKAAIQA LRKMEPKDKD
QEVLLQTFLD DASPGDKRLA AYLMLMRSPS QADINKIVQI LPWEQNEQVK NFVASHIANI
LNSEELDIQD LKKLVKEALK ESQLPTVMDF RKFSRNYQLY KSVSLPSLDP ASAKIEGNLI
FDPNNYLPKE SMLKTTLTAF GFASADLIEI GLEGKGFEPT LEALFGKQGF FPDSVNKALY
WVNGQVPDGV SKVLVDHFGY TKDDKHEQDM VNGIMLSVEK LIKDLKSKEV PEARAYLRIL
GEELGFASLH DLQLLGKLLL MGARTLQGIP QMIGEVIRKG SKNDFFLHYI FMENAFELPT
GAGLQLQISS SGVIAPGAKA GVKLEVANMQ AELVAKPSVS VEFVTNMGII IPDFARSGVQ
MNTNFFHESG LEAHVALKAG KLKFIIPSPK RPVKLLSGGN TLHLVSTTKT EVIPPLIENR
QSWSVCKQVF PGLNYCTSGA YSNASSTDSA SYYPLTGDTR LELELRPTGE IEQYSVSATY
ELQREDRALV DTLKFVTQAE GAKQTEATMT FKYNRQSMTL SSEVQIPDFD VDLGTILRVN
DESTEGKTSY RLTLDIQNKK ITEVALMGHL SCDTKEERKI KGVISIPRLQ AEARSEILAH
WSPAKLLLQM DSSATAYGST VSKRVAWHYD EEKIEFEWNT GTNVDTKKMT SNFPVDLSDY
PKSLHMYANR LLDHRVPQTD MTFRHVGSKL IVAMSSWLQK ASGSLPYTQT LQDHLNSLKE
FNLQNMGLPD FHIPENLFLK SDGRVKYTLN KNSLKIEIPL PFGGKSSRDL KMLETVRTPA
LHFKSVGFHL PSREFQVPTF TIPKLYQLQV PLLGVLDLST NVYSNLYNWS ASYSGGNTST
DHFSLRARYH MKADSVVDLL SYNVQGSGET TYDHKNTFTL SYDGSLRHKF LDSNIKFSHV
EKLGNNPVSK GLLIFDASSS WGPQMSASVH LDSKKKQHLF VKEVKIDGQF RVSSFYAKGT
YGLSCQRDPN TGRLNGESNL RFNSSYLQGT NQITGRYEDG TLSLTSTSDL QSGIIKNTAS
LKYENYELTL KSDTNGKYKN FATSNKMDMT FSKQNALLRS EYQADYESLR FFSLLSGSLN
SHGLELNADI LGTDKINSGA HKATLRIGQD GISTSATTNL KCSLLVLENE LNAELGLSGA
SMKLTTNGRF REHNAKFSLD GKAALTELSL GSAYQAMILG VDSKNIFNFK VSQEGLKLSN
DMMGSYAEMK FDHTNSLNIA GLSLDFSSKL DNIYSSDKFY KQTVNLQLQP YSLVTTLNSD
LKYNALDLTN NGKLRLEPLK LHVAGNLKGA YQNNEIKHIY AISSAALSAS YKADTVAKVQ
GVEFSHRLNT DIAGLASAID MSTNYNSDSL HFSNVFRSVM APFTMTIDAH TNGNGKLALW
GEHTGQLYSK FLLKAEPLAF TFSHDYKGST SHHLVSRKSI SAALEHKVSA LLTPAEQTGT
WKLKTQFNNN EYSQDLDAYN TKDKIGVELT GRTLADLTLL DSPIKVPLLL SEPINIIDAL
EMRDAVEKPQ EFTIVAFVKY DKNQDVHSIN LPFFETLQEY FERNRQTIIV VLENVQRNLK
HINIDQFVRK YRAALGKLPQ QANDYLNSFN WERQVSHAKE KLTALTKKYR ITENDIQIAL
DDAKINFNEK LSQLQTYMIQ FDQYIKDSYD LHDLKIAIAN IIDEIIEKLK SLDEHYHIRV
NLVKTIHDLH LFIENIDFNK SGSSTASWIQ NVDTKYQIRI QIQEKLQQLK RHIQNIDIQH
LAGKLKQHIE AIDVRVLLDQ LGTTISFERI NDILEHVKHF VINLIGDFEV AEKINAFRAK
VHELIERYEV DQQIQVLMDK LVELAHQYKL KETIQKLSNV LQQVKIKDYF EKLVGFIDDA
VKKLNELSFK TFIEDVNKFL DMLIKKLKSF DYHQFVDETN DKIREVTQRL NGEIQALELP
QKAEALKLFL EETKATVAVY LESLQDTKIT LIINWLQEAL SSASLAHMKA KFRETLEDTR
DRMYQMDIQQ ELQRYLSLVG QVYSTLVTYI SDWWTLAAKN LTDFAEQYSI QDWAKRMKAL
VEQGFTVPEI KTILGTMPAF EVSLQALQKA TFQTPDFIVP LTDLRIPSVQ INFKDLKNIK
IPSRFSTPEF TILNTFHIPS FTIDFVEMKV KIIRTIDQML NSELQWPVPD IYLRDLKVED
IPLARITLPD FRLPEIAIPE FIIPTLNLND FQVPDLHIPE FQLPHISHTI EVPTFGKLYS
ILKIQSPLFT LDANADIGNG TTSANEAGIA ASITAKGESK LEVLNFDFQA NAQLSNPKIN
PLALKESVKF SSKYLRTEHG SEMLFFGNAI EGKSNTVASL HTEKNTLELS NGVIVKINNQ
LTLDSNTKYF HKLNIPKLDF SSQADLRNEI KTLLKAGHIA WTSSGKGSWK WACPRFSDEG
THESQISFTI EGPLTSFGLS NKINSKHLRV NQNLVYESGS LNFSKLEIQS QVDSQHVGHS
VLTAKGMALF GEGKAEFTGR HDAHLNGKVI GTLKNSLFFS AQPFEITAST NNEGNLKVRF
PLRLTGKIDF LNNYALFLSP SAQQASWQVS ARFNQYKYNQ NFSAGNNENI MEAHVGINGE
ANLDFLNIPL TIPEMRLPYT IITTPPLKDF SLWEKTGLKE FLKTTKQSFD LSVKAQYKKN
KHRHSITNPL AVLCEFISQS IKSFDRHFEK NRNNALDFVT KSYNETKIKF DKYKAEKSHD
ELPRTFQIPG YTVPVVNVEV SPFTIEMSAF GYVFPKAVSM PSFSILGSDV RVPSYTLILP
SLELPVLHVP RNLKLSLPDF KELCTISHIF IPAMGNITYD FSFKSSVITL NTNAELFNQS
DIVAHLLSSS SSVIDALQYK LEGTTRLTRK RGLKLATALS LSNKFVEGSH NSTVSLTTKN
MEVSVATTTK AQIPILRMNF KQELNGNTKS KPTVSSSMEF KYDFNSSMLY STAKGAVDHK
LSLESLTSYF SIESSTKGDV KGSVLSREYS GTIASEANTY LNSKSTRSSV KLQGTSKIDD
IWNLEVKENF AGEATLQRIY SLWEHSTKNH LQLEGLFFTN GEHTSKATLE LSPWQMSALV
QVHASQPSSF HDFPDLGQEV ALNANTKNQK IRWKNEVRIH SGSFQSQVEL SNDQEKAHLD
IAGSLEGHLR FLKNIILPVY DKSLWDFLKL DVTTSIGRRQ HLRVSTAFVY TKNPNGYSFS
IPVKVLADKF IIPGLKLNDL NSVLVMPTFH VPFTDLQVPS CKLDFREIQI YKKLRTSSFA
LNLPTLPEVK FPEVDVLTKY SQPEDSLIPF FEITVPESQL TVSQFTLPKS VSDGIAALDL
NAVANKIADF ELPTIIVPEQ TIEIPSIKFS VPAGIVIPSF QALTARFEVD SPVYNATWSA
SLKNKADYVE TVLDSTCSST VQFLEYELNV LGTHKIEDGT LASKTKGTFA HRDFSAEYEE
DGKYEGLQEW EGKAHLNIKS PAFTDLHLRY QKDKKGISTS AASPAVGTVG MDMDEDDDFS
KWNFYYSPQS SPDKKLTIFK TELRVRESDE ETQIKVNWEE EAASGLLTSL KDNVPKATGV
LYDYVNKYHW EHTGLTLREV SSKLRRNLQN NAEWVYQGAI RQIDDIDVRF QKAASGTTGT
YQEWKDKAQN LYQELLTQEG QASFQGLKDN VFDGLVRVTQ EFHMKVKHLI DSLIDFLNFP
RFQFPGKPGI YTREELCTMF IREVGTVLSQ VYSKVHNGSE ILFSYFQDLV ITLPFELRKH
KLIDVISMYR ELLKDLSKEA QEVFKAIQSL KTTEVLRNLQ DLLQFIFQLI EDNIKQLKEM
KFTYLINYIQ DEINTIFSDY IPYVFKLLKE NLCLNLHKFN EFIQNELQEA SQELQQIHQY
IMALREEYFD PSIVGWTVKY YELEEKIVSL IKNLLVALKD FHSEYIVSAS NFTSQLSSQV
EQFLHRNIQE YLSILTDPDG KGKEKIAELS ATAQEIIKSQ AIATKKIISD YHQQFRYKLQ
DFSDQLSDYY EKFIAESKRL IDLSIQNYHT FLIYITELLK KLQSTTVMNP YMKLAPGELT
IIL
//

MIM 107730
*RECORD*
*FIELD* NO
107730
*FIELD* TI
+107730 APOLIPOPROTEIN B; APOB
APOB100, INCLUDED;;
APOB48, INCLUDED;;
APOLIPOPROTEIN B ALLOTYPES, INCLUDED;;
read moreAg LIPOPROTEIN TYPES, INCLUDED; LOW DENSITY LIPOPROTEIN CHOLESTEROL
LEVEL QUANTITATIVE TRAIT LOCUS 4, INCLUDED; LDLCQ4, INCLUDED
*FIELD* TX

DESCRIPTION

Apolipoprotein B is the main apolipoprotein on chylomicrons and low
density lipoproteins (LDLs). It occurs in the plasma in 2 main forms,
apoB48 and apoB100. The first is synthesized exclusively by the
intestine, the second by the liver (summary by Law et al., 1985).

CLONING

Lusis et al. (1985) identified cDNA clones for rat liver apoB. Law et
al. (1985) cloned human APOB.

Deeb et al. (1986) found that APOB RNA isolated from monkey small
intestine contained sequences homologous to the cDNA of apolipoprotein
B100. These results were interpreted as indicating that intestinal (B48)
and hepatic (B100) forms of apoB are coded by a single gene. Glickman et
al. (1986) found a single mRNA transcript for apoB regardless of the
form of apoB (apoB100 or apoB48) synthesized in the liver or intestine.

Hospattankar et al. (1986) presented some immunologic data suggesting
that the 2 proteins share a common carboxyl region sequence. Chen et al.
(1986) determined the complete cDNA and amino acid sequence of apoB100.
Knott et al. (1986) reported the primary structure of apolipoprotein B.
The precursor has 4,563 amino acids; the mature apoB100 has 4,536 amino
acid residues. This represents a very large mRNA of more than 16 kb. Law
et al. (1986) also provided the complete nucleotide and derived amino
acid sequence of apoB100 from a study of cDNA. Strong evidence that
apoB100 and apoB48 are products of the same gene was provided by Young
et al. (1986).

Cladaras et al. (1986) concluded from the sequence of apolipoprotein
B100 that apoB48 may result from differential splicing of the same
primary apoB mRNA transcript.

Hardman et al. (1987) found that mature, circulating B48 is homologous
over its entire length (estimated to be between 2,130 and 2,144 amino
acid residues) with the amino-terminal portion of B100 and contains no
sequence from the carboxyl end of B100. From structural studies,
Innerarity et al. (1987) concluded that apoB48 represents the
amino-terminal 47% of apoB100 and that the carboxyl terminus of apoB48
is in the vicinity of residue 2151 of apoB100. Chen et al. (1987)
deduced that human apolipoprotein B48 is the product of an intestinal
mRNA with an in-frame UAA stop codon resulting from a C-to-U change in
the codon CAA encoding Gln(2153) in apoB100 mRNA. The carboxyl-terminal
ile-2152 of apoB48 purified from chylous ascites fluid has apparently
been cleaved from the initial translation product, leaving met-2151 as
the new carboxyl-terminus. The organ-specific introduction of a stop
codon to an mRNA is an unprecedented finding. Only the sequence that
codes B100 is present in genomic DNA. The change from CAA to UAA as
codon 2153 of the message is a unique RNA editing process. Higuchi et
al. (1988) reported similar findings. ApoB48 contains 2,152 residues
compared to 4,535 residues in apoB100. Using a cloned rat cDNA as a
probe, Lau et al. (1994) cloned cDNA and genomic sequences of the gene
for the human APOB mRNA editing protein (BEDP; 600130). Expression of
the cDNA in HepG2 cells resulted in editing of the intracellular apoB
mRNA. By Northern blot analysis, they showed that the human BEDP mRNA is
expressed exclusively in the small intestine.

MAPPING

Law et al. (1985) assigned the APOB gene to chromosome 2 by filter
hybridization with DNA from human/mouse somatic cell hybrids.

By somatic cell hybrid studies and by in situ hybridization, Knott et
al. (1985) assigned the APOB gene to the tip of 2p in band p24.

Deeb et al. (1986) used a hybridization probe to detect homologous
sequences in both flow-sorted and in situ metaphase chromosomes. The
gene was assigned to 2p24-p23.

From study of chromosomal aberrations in somatic cell hybrids, Huang et
al. (1986) concluded that the APOB locus is located in either the
2p21-p23 or the 2pter-p24 segment. Mehrabian et al. (1986) localized
APOB to 2p24-p23 by somatic cell hybridization and in situ
hybridization. Filter hybridization studies with genomic DNA and with
hepatic and intestinal mRNA suggested that hepatic and intestinal apoB
are derived from the same gene.

MOLECULAR GENETICS

Law et al. (1986) used a specific mouse monoclonal antibody, MB19, to
characterize a common form of genetic polymorphism of APOB. They found
that the polymorphism was expressed in a parallel manner in apoB100 and
apoB48.

Law et al. (1986) found that 60 of 83 middle-aged white men had an XbaI
restriction site polymorphism within the coding sequence of the apoB
gene. Persons homozygous or heterozygous for the XbaI restriction site
had mean serum triglyceride levels 36% higher than homozygotes without
the site. Mean serum cholesterol was less strikingly elevated in those
with the restriction site. The Ag system of lipoprotein antigens (see
later) is known to represent polymorphism of the APOB locus. It is in
strong linkage disequilibrium with the XbaI RFLP; the 2 probably reveal
the same association with plasma lipids. Mehrabian et al. (1986) also
identified 2 common RFLPs which should be useful in family studies.

Ludwig et al. (1989) described a hypervariable region 3-prime to the
human APOB gene. By PCR amplification of the region followed by
electrophoresis in a denaturing acrylamide gel, they found 14 different
alleles containing 25 to 52 repeats of a 15-basepair unit in 318
unrelated individuals. Boerwinkle et al. (1989) also made observations
on this variable-number-of-tandem-repeats (VNTR) polymorphism. Boehnke
(1991) used the VNTR polymorphism near the APOB locus as a test case for
his method of estimating allele frequency from data on relatives. He
stated that there are 15 known APOB VNTR alleles and that 12 were
observed in the families he studied.

By use of both pedigree linkage analysis and sib-pair linkage analysis
in 23 informative families, Coresh et al. (1992) found no evidence of
common APOB alleles that had a major influence on plasma levels of
apoB100.

Singh et al. (2004) examined the association between the XbaI
polymorphism of APOB100 and gallbladder diseases, including gallbladder
cancer, in a non-Indian population in which both gallstones and
gallbladder cancer are common. They found that the frequency of X-
allele was significantly increased in gallbladder cancer patients with
or without gallstones (odds ratio = 2.3 and 1.7, respectively). They
suggested that the apoB-XbaI gene polymorphism confers susceptibility to
carcinoma of the gallbladder under specific environmental conditions.

The base change in APOB that creates the XbaI site, 7673C-T, does not
change the amino acid threonine at codon 2488 (T2488T). In a study
comprising 9,185 individuals from the general population, 2,157 patients
with ischemic heart disease (IHD), and 378 patients with ischemic
cerebrovascular disease (ICVD), Benn et al. (2005) found that the APOB
7673C-T polymorphism is associated with moderate increases in total
cholesterol, LDL cholesterol, and apoB in both genders in the general
population, but not with risk of IHD or ICVD or with total mortality.

Benn et al. (2007) found that APOB K4154K homozygotes for the E4154K
polymorphism had an age-adjusted hazard ratio of 0.4 (95% CI, 0.2-0.9)
for ischemic cerebrovascular disease and 0.2 (CI, 0.1-0.7) for ischemic
stroke relative to E4154E homozygotes. Furthermore, E4154K heterozygotes
and K4154K homozygotes had lower levels of apolipoprotein B and LDL
cholesterol, compared with E4154E homozygotes. APOB K4154K homozygosity
predicted a 3- to 5-fold reduction in risk of ischemic cerebrovascular
disease and ischemic stroke.

Demant et al. (1988) found a significant association between a
particular RFLP of the APOB gene and the total fractional clearance rate
of LDL. Presumably, this effect acts through variable binding to the
LDLR and is a significant factor in the rate of catabolism of LDL.

Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from
the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9
SNPs, including dbSNP rs693 of APOB, had previously been associated with
elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the
associations with each SNP and created a genotype score on the basis of
the number of unfavorable alleles. With increasing genotype scores, the
level of LDL cholesterol increased, whereas the level of HDL cholesterol
decreased. At 10-year follow-up, the genotype score was found to be an
independent risk factor for incident cardiovascular disease (myocardial
infarction, ischemic stroke, or death from coronary heart disease); the
score did not improve risk discrimination but modestly improved clinical
risk reclassification for individual subjects beyond standard clinical
factors.

Teslovich et al. (2010) performed a genomewide association study for
plasma lipids in more than 100,000 individuals of European ancestry and
reported 95 significantly associated loci (P = less than 5 x 10(-8)),
with 59 showing genomewide significant association with lipid traits for
the first time. The newly reported associations included SNPs near known
lipid regulators as well as in scores of loci not previously implicated
in lipoprotein metabolism. The 95 loci contributed not only to normal
variation in lipid traits but also to extreme lipid phenotypes and had
an impact on lipid traits in 3 non-European populations (East Asians,
South Asians, and African Americans). Teslovich et al. (2010) identified
several novel loci associated with plasma lipids that are also
associated with coronary artery disease. Teslovich et al. (2010)
identified dbSNP rs1367117 in the APOB gene as having an effect on LDL
cholesterol with an effect size of +4.05 mg per deciliter and a P value
of 4 x 10(-114).

- Familial Hypercholesterolemia Type B

Familial hypercholesterolemia can be caused not only by defects in the
LDL receptor (LDLR; 606945) but also by mutations in apolipoprotein B
causing decreased LDLR binding affinity, so-called familial
ligand-defective apolipoprotein B (144010). The first mutation of this
sort was described by Soria et al. (1989); see 107730.0009. A second was
described by Pullinger et al. (1995); see 107730.0017.

Corsini et al. (1989) described familial hypercholesterolemia (FH) due,
not to a defect in the LDLR as in conventional FH (143890), but to
binding-defective LDL, presumably familial defective apoB100.
Rajput-Williams et al. (1988) demonstrated association of specific
alleles for the apoB gene with obesity, high blood cholesterol levels,
and increased risk of coronary artery disease. Several of the RFLPs used
as markers do not change the amino acid sequence. The authors concluded
that these RFLPs are in linkage disequilibrium with nearby functional
variation predisposing to obesity or increased risk of coronary artery
disease. Variations in serum cholesterol level were associated with 3
functional alleles corresponding to amino acid variants at positions
3611 and 4154, both of which lie near the LDLR binding region of apoB.
Products of the APOB gene with high or low affinity for the MB-19
monoclonal antibody can be distinguished. Gavish et al. (1989) used this
antibody to identify heterozygotes and detect allele-specific
differences in the amount of APOB in the plasma. A family study
confirmed that the unequal expression phenotype was inherited in an
autosomal dominant manner and was linked to the APOB locus.

Noting that large-scale genetic cascade screening for familial
hypercholesterolemia showed that 15% of LDLR or APOB mutation carriers
had LDLC levels below the 75th percentile, Huijgen et al. (2010)
proposed 3 criteria for determining pathogenicity of such mutations:
mean LDLC greater than the 75th percentile, higher mean LDLC level in
untreated than in treated carriers, and higher percentage of medication
users in carriers than in noncarriers at screening. Applying these
criteria to 46 mutations found in more than 50 untreated adults, 3 of
the mutations were determined to be nonpathogenic: 1 in LDLR and 2 in
APOB. Nonpathogenicity of the 3 variants was confirmed by segregation
analysis. Huijgen et al. (2010) emphasized that novel sequence changes
in LDLR and APOB should be interpreted with caution before being
incorporated into a cascade screening program.

- Familial Hypobetalipoproteinemia

Antonarakis (1987) and his colleagues identified a missense point
mutation in the APOB gene associated with hypobetalipoproteinemia
(615558).

The mutation occurred at a potential site of binding of APOB to LDLR and
apparently resulted in interference with the metabolism of
apolipoprotein B. The finding of no recombination between the
hypobetalipoproteinemia phenotype and a particular DNA haplotype of the
APOB gene (Leppert et al., 1988) indicated that, at least in the family
studied, hypobetalipoproteinemia was the result of a molecular defect in
apolipoprotein B.

As indicated in the listing of allelic variants, a number of mutations
resulting in a truncated apolipoprotein B have been found as the basis
of hypobetalipoproteinemia. Other patients with this disorder have been
found to have reduced concentrations of a full-length apoB100 (Young et
al., 1987; Berger et al., 1983; Gavish et al., 1989).

Linton et al. (1993) tabulated 25 apoB gene mutations associated with
familial hypobetalipoproteinemia.

Pulai et al. (1998) commented that various truncated forms of apoB have
been found to segregate with the FHBL phenotype in more than 30
kindreds.

Schonfeld (1995, 1998) stated that in all reported kindreds in which the
'hypobeta' trait cosegregated with an apoB truncation, heterozygotes
(documented by either protein or genomic DNA analysis) showed the trait.
In fasting heterozygotes, there are 2 populations of apoB-containing
lipoproteins: those that contain the truncation and those that contain
the normal full-length apoB100. The low cholesterol levels are due to
the low levels of apoB-containing lipoproteins (VLDL and particularly
LDL) that transport most of the cholesterol in plasma. In turn, low
levels of apoB are due to low production rates of both mutant and
wildtype forms of apoB in heterozygotes. In some cases, there is also
enhanced clearance from plasma. Low production of a truncated form is
probably due to low levels of the truncation-specifying mRNA. It is not
clear why wildtype apoB100 is produced at lower than expected rates in
heterozygotes. The truncated forms of apoB are named according to a
centile nomenclature.

Kairamkonda and Dalzell (2003) described 3 sibs with vitamin E
deficiency and symptoms of malabsorption with documented excessive fecal
fat excretion and low cholesterol, apoB, and vitamin E levels. Although
the pathogenesis was not established, the authors postulated that the
sibs had heterozygous FHBL due to a novel mutation of apoB because of
persistent posttherapeutic low cholesterol and apoB levels.

Di Leo et al. (2007) identified 3 novel splice site mutations of the
APOB gene in 4 FHBL patients and analyzed apoB mRNA in the liver of 1
proband and in transfected COS-1 cells in the other probands. The
authors determined that all 3 mutations resulted in truncated apoB
proteins that were not secreted as constituents of plasma lipoproteins,
confirming the pathogenic effect of rare splice site mutations of the
APOB gene found in FHBL.

In a 27-year-old woman from a consanguineous French Canadian family, who
was diagnosed with FHBL in the first months of life, Gangloff et al.
(2011) identified a homozygous truncating mutation in the APOB gene
(107730.0022). The authors stated that this was the first case of
homozygous FHBL in a French Canadian family.

- Apolipoprotein B Allotypes

Allison and Blumberg (1961) and Blumberg et al. (1963) described a
polymorphic system including serum beta lipoprotein distinct from that
discovered by Berg and Mohr and designated Lp(a) (see 152200). They
detected this by the study of patients who had received multiple
transfusions. The first type was called Ag-a; the second was called
Ag-b. Blumberg et al. (1964) proposed the symbol LP for lipoprotein.
Lower case letters are used for designating different loci (i.e., LPa,
LPb, LPc, etc.) and superscript numbers for alleles at the locus (i.e.,
LPa-1, LPa-2, etc.). Retention of the Ag designation may be advisable to
avoid confusion with the Berg type. Jackson et al. (1974) observed a
family in which variation of a chromosome 21 appeared to be linked with
Ag type. The peak lod score was 2.1 at a recombination fraction of 0.0.
Berg et al. (1975), on the other hand, found considerable recombination
with IPO-A (147450), in family studies. IPO-A is known to be on
chromosome 21 from hybrid cell studies. Berg et al. (1976) showed that
serum cholesterol and triglyceride levels were higher in Ag(x-) than in
Ag(x+) persons. Thus, a small but significant effect of a single
autosomal locus in atherogenesis may have been demonstrated. Morganti et
al. (1975) indicated that there are at least 5 closely linked loci. This
serum protein polymorphism was discovered by Blumberg on the basis of
his hypothesis that multitransfused patients should have antibodies
against polymorphic serum proteins. The Australia antigen was found in
the process of the same studies, applying the additional principle that
the wider the anthropologic spread of sera tested (e.g., Australian
aborigines), the greater the likelihood of finding a polymorphism. Of
course, the Australia antigen proved to be not a polymorphism but a
viremia--an even more important discovery, as recognized by the Nobel
Prize. By this approach, Blumberg (1978) found other apparent
polymorphisms that he has not yet fully studied. Allotypic variation in
LDL comparable to Ag has been found in most species studied. Berg et al.
(1986) demonstrated close linkage of the Ag allotypes of LDL and DNA
polymorphisms at the APOB locus. Linkage disequilibrium (allelic
association) was found between the Ag polymorphism and 2 of the 3 DNA
polymorphisms studied. Xu et al. (1989) demonstrated that a particular
Ag epitope (h/i) is determined by an arginine-to-glutamine substitution
at residue 3611 of the mature protein. The amino acid difference results
from a CGG-to-CAG change and causes loss of an MspI restriction site.
Breguet et al. (1990) found that, with the exception of the Amerindians,
the Ag system is highly polymorphic in populations worldwide. They
suggested that the system has evolved as a neutral or nearly-neutral
polymorphism and is therefore highly informative for 'modern human
peopling history' studies. Following the cloning of the human APOB gene,
nucleotide substitutions were reported as candidates for the molecular
basis of all the Ag epitopes (reviewed by Dunning et al., 1992). Dunning
et al. (1992) found complete linkage disequilibrium between the
immunochemical polymorphism of LDL that is designated antigen group
Ag(x/y) and the alleles at 2 sites in the mature apoB100 molecule:
pro2712-to-leu and asn4311-to-ser. It appeared that the Ag(y) epitope
was associated with asparagine-4311 plus proline-2712, whereas the
allele encoding serine-4311 plus leucine-2712 represented the Ag(x)
epitope. In 4 different population groups, they found complete
association between the sites encoding residues 2712 and 4311, although
there were large allele frequency differences between these populations.
In addition, there was strong linkage disequilibrium with allelic
association between the alleles of these sites and those of the XbaI
RFLP in all populations examined. Taken together, these data suggest
that there has been little or no recombination in the 3-prime end of the
human APOB gene since the divergence of the major ethnic groups.

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

ANIMAL MODEL

Rapacz et al. (1986) described a strain of pigs bearing 3
immunogenetically defined lipoprotein-associated markers (allotypes)
associated with marked hypercholesterolemia despite a low-fat,
cholesterol-free diet. LDL receptor activity was normal. By 7 months of
age the animals had extensive atherosclerotic lesions in all 3 coronary
arteries. One of the 3 variant apolipoproteins was apolipoprotein B. The
identity of the other 2 apolipoproteins was not clear, although one was
a component of low density lipoprotein and was genetically linked to the
variant identified with apolipoprotein B.

Homanics et al. (1993) used gene targeting to generate a mouse model of
hypobetalipoproteinemia. Mice carrying the disrupted Apob gene
synthesized apoB48 and a truncated apoB (apoB70) but no apoB100. In
addition to having a lipoprotein phenotype remarkably similar to
familial hypobetalipoproteinemia in humans, these mice also exhibited
exencephalus and hydrocephalus. Huang et al. (1995) likewise generated
APOB gene knockout mice by targeting the gene in embryonic stem cells.
Homozygous deficiency led to embryonic lethality, with resorption of all
embryos by gestational day 9. Heterozygotes showed an increased tendency
to intrauterine death with some fetuses having incomplete neural tube
closure and some liveborn heterozygotes developing hydrocephalus. Most
heterozygous males were sterile, although the GU system and sperm were
grossly normal. Viable heterozygotes had normal triglycerides, but total
LDL and HDL cholesterol levels were decreased by 37, 37, and 39%,
respectively. Hepatic and intestinal APOB mRNA levels were decreased in
heterozygotes.

Callow et al. (1995) noted that the engineering of mice that express a
human APOB transgene results in animals with high levels of human-like
LDL particles. Additionally, through crosses with transgenics for the
human LPA gene, high levels of human-like lipoprotein(a) particles are
seen. Callow et al. (1995) found that such mice demonstrated marked
increases in apoB and LDL, resulting in atherosclerotic lesions
extending down the aorta that resembled human lesions immunochemically.
The findings suggested to the authors that APO(a) associated with apo(B)
and lipid may result in a more pro-atherogenic state than when APO(a) is
free in plasma.

Huang et al. (1996) found that male mice heterozygous for targeted
mutation of the ApoB gene exhibit severely compromised fertility. Sperm
from these mice fail to fertilize eggs both in vitro and in vivo.
However, these sperm were able to fertilize eggs once the zona pellucida
was removed but displayed persistent abnormal binding to the egg after
fertilization. In vitro fertilization-related and other experiments
revealed reduced sperm motility, survival time, and sperm count also
contributed to the infertility phenotype. Recognition of the infertility
phenotype led to the identification of ApoB mRNA in the testes and
epididymides of normal mice, and these transcripts were substantially
reduced in the mutant animal. Moreover, when the genomic sequence
encoding human ApoB was introduced into these animals, normal fertility
was restored. The findings of Huang et al. (1996) suggested that APOB
may have an important impact on male fertility and identified a
previously unrecognized function of ApoB.

To provide models for understanding the physiologic purpose for the 2
forms of apoB (B100 and B48), Farese et al. (1996) used targeted
mutagenesis of the APOB gene to generate mice that synthesized apoB48
exclusively and mice that synthesized apoB100 exclusively. The B48-only
and B100-only mice were produced by introducing into mouse ES cells stop
and nonstop mutations, respectively, in the apoB48 editing codon (codon
2153) of the mouse Apob gene. Both types of mice developed normally,
were healthy, and were fertile. Thus, apoB48 synthesis sufficed for
normal embryonic development, and the synthesis of apoB100 in the
intestine adult mice caused no readily apparent adverse effects on
intestinal function or nutrition. Compared with wildtype mice fed the
same diet, the levels of LDL cholesterol and VLDL and LPL
triacylglycerols were lower in the B48-only mice and higher in the
B100-only mice. Farese et al. (1996) stated that in the setting of apo-E
deficiency, the B100-only mutation lowered cholesterol levels,
consistent with the fact that B100-lipoproteins can be cleared from the
plasma via the LDL receptor, whereas B48-lipoproteins lacking apo-E
cannot.

Boren et al. (1998) expressed mutant forms of human apoB in transgenic
mice, purified the resulting human recombinant LDL, and tested for their
receptor-binding activity. They showed that amino acids 3359 to 3369
bind to the LDL receptor and that arginine-3500 is not directly involved
in receptor binding. However, the C-terminal 20% of apoB100 is necessary
for the R3500Q mutation to disrupt receptor binding, since removal of
the C terminus in familial defective apoB100 (FDB) LDL resulted in
normal receptor-binding activity. Similarly, removal of the C terminus
of apoB100 on receptor-inactive VLDL dramatically increased
apoB-mediated receptor-binding activity. Boren et al. (1998) proposed
that the C terminus normally functions to inhibit the interaction of
apoB100 VLDL with the LDL receptor, but after the conversion of
triglyceride-rich VLDL to smaller cholesterol-rich LDL, arginine-3500
interacts with the C terminus, permitting normal interaction between LDL
and its receptor. Moreover, the loss of arginine at this site
destabilizes this interaction, resulting in receptor-binding defective
LDL.

Skalen et al. (2002) created transgenic mice expressing 5 types of human
recombinant LDL, fed them an atherogenic diet for 20 weeks, and
quantitated the extent of atherosclerosis. They used these models to
test the hypothesis that the subendothelial retention of atherogenic
apoB-containing lipoproteins is the initiating event in atherogenesis.
The extracellular matrix of the subendothelium, particularly
proteoglycans, is thought to play a major role in the retention of
atherogenic lipoproteins. The interaction between atherogenic
lipoproteins and proteoglycans involves an ionic interaction between
basic amino acids in apoB100 and negatively-charged sulfate groups on
the proteoglycans. Skalen et al. (2002) presented direct experimental
evidence that the atherogenicity of apoB-containing low-density
lipoproteins is linked to their affinity for artery wall proteoglycans.
Mice expressing proteoglycan-binding-defective LDL developed
significantly less atherosclerosis than mice expressing wildtype control
LDL. Skalen et al. (2002) concluded that subendothelial retention of
apoB100-containing lipoprotein is an early step in atherogenesis.

In order to demonstrate the therapeutic potential of short interfering
RNAs (siRNAs), Soutschek et al. (2004) demonstrated that chemically
modified siRNAs can silence an endogenous gene encoding apoB after
intravenous injection in mice. Administration of chemically modified
siRNAs resulted in silencing of the apoB mRNA in liver and jejunum,
decreased plasma levels of apoB protein, and reduced total cholesterol.
Soutschek et al. (2004) also showed that these siRNAs could silence
human apoB in a transgenic mouse model. In their in vivo study, the
mechanism of action for the siRNAs was proven to occur through RNA
interference (RNAi)-mediated mRNA degradation, and Soutschek et al.
(2004) determined that cleavage of the apoB mRNA occurred specifically
at the predicted site.

Espinosa-Heidmann et al. (2004) studied the development of basal laminar
deposits in the eyes of transgenic mice that overexpressed apoB100. The
mice were fed a high-fat diet, and their eyes were exposed to blue-green
laser light. The results suggested that age and high-fat diet
predisposed to the formation of basal laminar deposits by altering
hepatic and/or retinal pigment epithelial lipid metabolism in ways more
complicated than plasma hyperlipidemia alone. Vitamin E-treated mice
showed minimal formation of basal laminar deposits.

In the eyes of transgenic mice overexpressing human apoB100 in the RPE,
Fujihara et al. (2009) observed ultrastructural changes consistent with
early human age-related macular degeneration (ARMD) (see 603075),
including loss of basal infoldings and accumulation of cytoplasmic
vacuoles in the RPE and basal laminar deposits containing long-spacing
collagen and heterogeneous debris in Bruch membrane. In apoB100 mice
given a high-fat diet, basal linear-like deposits were identified in
12-month-old mice. Linear regression analysis showed that the genotype
was a stronger influencing factor than high-fat diet in producing
ARMD-like lesions.

*FIELD* AV
.0001
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, 4-BP DEL, NT5391

In a patient with hypobetalipoproteinemia (615558) and small amounts of
a truncated apoB protein (B37) in VLDL, LDL, and HDL fractions of the
plasma, Young et al. (1987, 1988) found deletion of 4 nucleotides
(5391_5394del4) resulting in a frameshift causing change of asn1728 to
thr (N1728T) and ser1729 to stop (S1729X). The truncated apoB protein
contained 1,728 amino acids. This was one of the mutant alleles in the
family with hypobetalipoproteinemia first reported by Steinberg et al.
(1979). Linton et al. (1992) investigated the reason for the curious
finding that low levels of apoB100 were produced by the mutant allele
carrying this mutation. The clue that led to the understanding of what
was going on with this allele was the recognition that the proband in
the family, H.J.B., as well as the other 2 compound heterozygotes,
actually had 4 bona fide apoB species within their plasma lipoproteins:
apoB37, apoB48, apoB100, and apoB86. Linton et al. (1992) demonstrated
that the apoB86 and apoB100 were products of a single mutant apoB
allele, which they designated the apoB86 allele. They showed that this
allele has a 1-bp deletion in exon 26 of the APOB gene (107730.0016) and
that this frameshift is responsible for the synthesis of apoB86.
Nevertheless, as shown by cell culture expression studies, the apoB86
allele, which contains a premature stop codon, results in the synthesis
of a full-length apoB protein. The 1-bp deletion creates a stretch of 8
consecutive adenines. Addition of a single adenine within the 8
consecutive adenines appears to take place during transcription,
restoring the correct reading frame and accounting for the formation of
apoB100 by the apoB86 allele. Eleven percent of the cDNA clones had an
additional adenine within the stretch of 8 adenines.

.0002
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB39
APOB, 1-BP DEL, FS1799TER

Collins et al. (1988) described a truncated apoB protein due to deletion
of a single guanine nucleotide from leucine codon 1794, resulting in a
frameshift and a stop codon after codon 1799, as a cause of familial
hypobetalipoproteinemia (615558). The truncated protein was referred to
as apoB39. The mutation occurred in a CpG dinucleotide.

.0003
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, ARG1306TER

A second truncated variant of apoB found in familial
hypobetalipoproteinemia (615558) by Collins et al. (1988) had a change
of arginine codon 1306, converting it to a stop codon and resulting in a
protein of 1,305 residues which, however, could not be detected in the
circulation. This mutation was a C-to-T transition in a CpG
dinucleotide.

.0004
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB40
APOB, VAL1829CYS

Krul et al. (1989) found 2 distinct truncated apoB proteins, apoB40 and
apoB90, in a kindred with hypobetalipoproteinemia (615558). Talmud et
al. (1989) showed that the molecular basis was deletion of 2 nucleotides
converting val1829 to cys and codon 1830 to stop.

.0005
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB90 OR APOB89
APOB, GLU4034ARG

See Krul et al. (1989). The molecular basis of familial
hypobetalipoproteinemia (615558) was deletion of 1 nucleotide in
glutamic acid codon 4034 converting that codon to arginine and causing a
frameshift with a stop codon at position 4040 (Talmud et al., 1989).
Parhofer et al. (1992) showed that enhanced catabolism of VLDL, IDL, and
LDL particles containing the truncated apolipoprotein is responsible for
the relatively low levels of apoB89 seen in these subjects.

.0006
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB46
APOB, ARG2058TER

Young et al. (1989) characterized an apoB gene mutation in a kindred
with familial hypobetalipoproteinemia (615558). Six members of the
family had low plasma apoB and LDL cholesterol levels, and each was
shown to be heterozygous for a mutant apoB allele that yielded a unique
truncated species of apoB, namely apoB46, with only 2,037 amino acids.
They further showed that apoB46 is caused by the substitution of T for C
at apoB cDNA nucleotide 6381, resulting in a nonsense mutation. The
change occurred in a CG dinucleotide. A C-to-T transition in the APOB
gene was responsible for hypobetalipoproteinemia in one of the families
studied by Collins et al. (1988). Like CETP deficiency (143470), this
appears to be an antiatherogenic mutation.

.0007
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB87
APOB, 1-BP DEL, 12032G

In a family segregating hypobetalipoproteinemia (615558), Gabelli et al.
(1996) identified 2 members who were homozygous for a 1-bp deletion in
the APOB gene (12032delG), causing a frameshift and termination at amino
acid 3978. The truncated apoB form was designated apoB-87-Padova.
Although the 2 homozygous members had only trace amounts of low density
lipoprotein, they were virtually free from symptoms typical of
homozygous FHBL subjects.

.0008
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB31
APOB, 1-BP DEL, 1425G

Young et al. (1990) identified a mutation of the APOB gene that resulted
in formation of a truncated apoB species, apoB31, as a cause of familial
hypobetalipoproteinemia. The mutation consisted of deletion of a single
guanine residue which caused a frameshift and a premature termination
with formation of a protein predicted to contain 1,425 amino acids. This
is the shortest of the mutant apoB species identified in the plasma of
subjects with hypobetalipoproteinemia. In contrast to the longer
truncated proteins, apoB31 was undetectable in VLDL and LDL but was
present in the HDL fraction and in the lipoprotein-deficient fraction of
the plasma. This mutation was found in the course of studying the apoB46
mutant (Young et al., 1989).

.0009
HYPERCHOLESTEROLEMIA DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B100
APOB, ARG3500GLN

By extensive sequence analysis of the 2 alleles of the APOB gene in a
man with moderate hypercholestorolemia (144010), who was originally
reported by Vega and Grundy (1986) and was found to be heterozygous for
familial defective apolipoprotein by Innerarity et al. (1987), Soria et
al. (1989) demonstrated a mutation in the codon for amino acid 3500 that
results in the substitution of glutamine for arginine. This same mutant
allele was found in 6 other, unrelated subjects and in 8 affected
relatives in 2 of these families. A partial haplotype of this mutant
apoB100 allele was constructed by sequence analysis and restriction
enzyme digestion at positions where variations in the apoB100 are known
to occur. This haplotype was found to be the same in 3 probands and 4
affected members of 1 family and lacks a polymorphic XbaI site whose
presence has been correlated with high cholesterol levels. Thus, it
appears that the mutation in the codon for amino acid 3500 (CGG-to-CAG),
a CG mutation hotspot, defines a minor apoB100 allele associated with
defective low density lipoproteins and hypercholesterolemia.

Ludwig and McCarthy (1990) used 10 markers for haplotyping at the APOB
locus in cases of familial defective apolipoprotein B100: 8 diallelic
markers within the structural gene and 2 hypervariable markers flanking
the gene. In 14 unrelated subjects heterozygous for the mutation, 7 of 8
unequivocally deduced haplotypes were identical, and 1 revealed only a
minor difference at one of the hypervariable loci. The genotypes of the
other 6 affected subjects was consistent with the same haplotype.
Familial defective apolipoprotein B100 (FDB) results from a G-to-A
transition at nucleotide 10708 in exon 26 of the APOB gene. Ludwig and
McCarthy (1990) interpreted the data as consistent with the existence of
a common ancestral chromosome.

In a screening for the APOB3500 mutation by PCR amplification and
hybridization with an allele-specific oligonucleotide, Loux et al.
(1993) found only 1 case among 101 French subjects with familial
hypercholesterolemia. The son of this individual, a 45-year-old man, was
found also to have the mutation. Haplotype analysis revealed strict
identity to that previously reported by Ludwig and McCarthy (1990), thus
supporting a unique European ancestry. The family lived in the southwest
of France and had no knowledge of Germanic origin.

Rauh et al. (1992) stated that the frequency of the arg3500-to-gln
mutation has been found to be approximately 1/500 to 1/700 in several
Caucasian populations in North America and Europe. On the other hand,
Friedlander et al. (1993) found no instance of this mutation in a large
screening program in Israel. They pointed out that the mutation has also
not been found in Finland (Hamalainen et al., 1990) and is said to be
absent in Japan. Tybjaerg-Hansen and Humphries (1992) gave a review
suggesting that the risk of premature coronary artery disease in the
carriers of the mutation is increased to levels as high as those seen in
patients with familial hypercholesterolemia; at age 50, about 40% of
males and 20% of females heterozygous for the mutation have developed
coronary artery disease.

Marz et al. (1992) found only moderate hypercholesterolemia in a
54-year-old man who was homozygous for the arg3500-to-gln mutation and
on a normal diet without lipid-lowering medication. There was no
evidence of atherosclerosis and no history of cardiovascular complaints.
The levels of apoE-containing lipoproteins were normal. Marz et al.
(1992) suggested that the intact metabolism of apoE-containing particles
decreases LDL production in this disorder, explaining the difference
from familial hypercholesterolemia due to a receptor defect in which
apoE levels are raised. Marz et al. (1993) investigated possible
compensatory mechanisms that may have alleviated the consequences of the
familial defective apoB100 (FDB). They showed that the receptor
interaction of buoyant LDL is normal due to the presence of apoE in
these particles. In addition, they provided evidence that the
arg3500-to-gln substitution profoundly alters the conformation of the
apoB receptor binding domain when apolipoprotein B resides on particles
at the lower and upper limits of the LDL density range. They concluded
that these mechanisms distinguish FDB from FH and account for the mild
hypercholesterolemia in homozygous FDB. Among 43 patients with
clinically and biochemically defined type III hyperlipoproteinemia
(107741), Feussner and Schuster (1992) found no instance of the
arg3500-to-gln mutation.

In the course of investigating 2 unrelated French patients heterozygous
for mutations in the LDLR gene (606945) who had aggravated
hypercholesterolemia, Benlian et al. (1996) found that each carried the
identical arg3500-to-gln mutation in the APOB gene, i.e., were double
heterozygotes. One of the patients was a 10-year-old boy when he was
referred for hypercholesterolemia discovered at the time of a cardiac
arrest. He had no planar xanthomata, although he exhibited bilateral
xanthomas of the Achilles and metacarpal phalangeal tendons. Peripheral
arterial disease was demonstrated by the presence of arterial murmurs
and by arterial wall irregularity on ultrasound analysis. Stenoses of
coronary arteries necessitated surgical angioplasty. The second patient
was a 39-year-old man with myocardial infarction and acute ischemia of
the legs. Both families came from the Perche region from which many
French Canadians originated. The LDLR mutations trp66-to-gly
(606945.0003) and glu207-to-lys (606945.0007) had been previously
described in French Canadians. Rubinsztein et al. (1993) described an
Afrikaner family with 6 FH/FDB double heterozygotes carrying another
LDLR mutation, asp206-to-glu (606945.0006). (Benlian et al. (1996), in
the title of their article, correctly referred to these patients as
double heterozygotes; in the paper itself they incorrectly referred to
them as FH/FDB compound heterozygotes. The latter term is used for
heterozygosity for alleles at the same locus.)

In a patient homozygous for the R3500Q mutation, Schaefer et al. (1997)
found LDL cholesterol and apoB concentrations approximately twice
normal, whereas apoE plasma level was low. Using a stable-isotope
labeling technique, they obtained data showing that the in vivo
metabolism of apoB100-containing lipoproteins in FDB is different from
that in familial hypercholesterolemia, in which LDL receptors are
defective. Although the residence times of LDL apoB100 appeared to be
increased to approximately the same degree, LDL apoB100 synthetic rate
was increased in FH and decreased in FDB. The decreased production of
LDL apoB100 in FDB may originate from enhanced removal of
apoE-containing LDL precursors by LDL receptors, which may be
upregulated in response to the decreased flux of LDL-derived cholesterol
into hepatocytes.

Almost all individuals with familial defective apoB100 are of European
descent, and in almost all cases the mutation is on a chromosome with a
rare haplotype at the apoB locus, suggesting that all probands are
descended from a common ancestor in whom the original mutation occurred.
Distribution of the mutation is consistent with an origin in Europe
6,000 to 7,000 years ago. Myant et al. (1997) estimated the amount of
recombination between the APOB gene and markers on chromosome 2 in 34
FDB (R3500Q) probands in whom the mutation is on the usual 194
haplotype. Significant linkage disequilibrium was found between the APOB
gene and marker D2S220. They identified 3 YACs that contained the APOB
gene and D2S220. The shortest restriction fragment common to the 3 YACs
that contain both loci was 240 kb long. No shorter fragments with both
loci were identified. On the assumption that 1000 kb corresponds to 1
cM, Myant et al. (1997) deduced that the recombination distance between
D2S220 and the APOB gene is about 0.24 cM. Combining this value with the
linkage disequilibrium observed between the 2 loci in the probands, they
estimated that the ancestral mutation occurred about 270 generations
ago. They postulated that the original mutation occurred in the common
ancestor of living FDB (R3500Q) probands, who lived in Europe about
6,750 years ago.

Tybjaerg-Hansen et al. (1998) found that the R3500Q mutation in the APOB
gene is present in approximately 1 in 1,000 persons in Denmark and
causes severe hypercholesterolemia and increases the risk of ischemic
heart disease. Heterozygous carriers of the arg3531-to-cys (107730.0017)
mutation, which is present in the population in approximately the same
frequency and also is associated with familial defective apolipoprotein
B100, was not associated with higher-than-normal plasma cholesterol
levels or an increased risk of ischemic heart disease.

Saint-Jore et al. (2000) estimated the respective contributions of the
LDLR gene defect, APOB gene defect, and other gene defects in autosomal
dominant type IIa hypercholesterolemia by studying 33 well-characterized
French families in which this disorder had been diagnosed over at least
3 generations. Using the candidate gene approach, they found that
defects in the LDLR gene accounted for the disorder in about 50% of the
families. The estimated contribution of an APOB gene defect was only
15%. This low estimation of involvement of the APOB gene defect was
strengthened by the existence of only 2 probands carrying the R3500Q
mutation. Surprisingly, 35% of the families were estimated to be linked
to neither LDLR nor APOB. The results suggested that genetic
heterogeneity in type IIa hypercholesterolemia had been underestimated
and that at least 3 major groups of defects were involved. The authors
were unable to estimate the contribution of the FH3 gene (603776).

Boren et al. (2001) concluded that normal receptor binding of LDL
involves an interaction between arginine-3500 and tryptophan-4369 in the
carboxyl tail of apoB100. Trp4369 to tyr (W4369Y) LDL and arg3500 to gln
(R3500Q) LDL isolated from transgenic mice had identically defective LDL
binding and a higher affinity for a monoclonal antibody that has an
epitope flanking residue 3500. Boren et al. (2001) concluded that
arginine-3500 interacts with tryptophan-4369 and facilitates the
conformation of apoB100 required for normal receptor binding of LDL.
They developed a model that explained how the carboxyl terminus of
apoB100 interacts with the backbone of apoB100 that enwraps the LDL
particle. The model explained how all known ligand-defective mutations
in apoB100, including a newly discovered R3480W mutation, cause
defective receptor binding.

Horvath et al. (2001) studied 130 unrelated individuals with
hypercholesterolemia in Bulgaria. Four of these individuals were found
to be carriers of this mutation. Horvath et al. (2001) concluded that
this mutation accounts for 0.99 to 8.17% (95% CI) of cases of
hypercholesterolemia in Bulgaria and therefore represents the most
common single mutation associated with this condition in Bulgaria.

Bednarska-Makaruk et al. (2001) found the arg3500-to-gln mutation in
2.5% (13/525) of unrelated patients with hypercholesterolemia in Poland.
All the patients belonged to the type IIA hyperlipoproteinemia group. In
65 patients with the clinical characteristics of familial
hypercholesterolemia, the frequency of the arg3500-to-gln mutation was
10.8% (7/65). The same haplotype at the APOB locus in the carriers of
this mutation in Poland as in other populations from western Europe
suggested its common origin.

.0010
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, EX21DEL

In an Arab patient with hypobetalipoproteinemia and absent plasma
apolipoprotein B (615558), Huang et al. (1989) demonstrated deletion of
the entire exon 21 (211 basepairs coding for amino acids 1014 to 1084).

.0011
APOB POLYMORPHISM IN SIGNAL PEPTIDE
APOB, INS AND DEL

Visvikis et al. (1990) described an insertion/deletion polymorphism in
the signal peptide. One allele, coding a peptide 27 amino acids long,
had a frequency of 0.655; the second allele, coding a peptide 24 amino
acids long, had a frequency of 0.345.

.0012
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, LEU3041TER

In a man and 6 of his children with hypobetalipoproteinemia (615558),
Welty et al. (1991) found that the plasma lipoproteins contained a
unique species of apolipoprotein B, apoB67, in addition to the normal
species, apoB100 and apoB48. Further study indicated that the apoB67 was
a truncated species that contained approximately the amino-terminal
3,000 to 3,100 amino acids of apoB100. Heterozygosity was identified for
a mutant APOB allele containing a single nucleotide deletion in exon 26
(cDNA nucleotide 9327). The change in codon 3041 from ATA (leu) to TAG
(stop) led to truncation after amino acid 3040. Mean total and LDL
cholesterol levels were 120 and 42 mg/dl, respectively. All affected
members of the kindred had high HDL cholesterol levels.

.0013
HYPOBETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC
APOB, GLN2252TER

Malloy et al. (1981) described a patient (A.F.) with a metabolic
disorder that they termed normotriglyceridemic abetalipoproteinemia
(615558). Similar cases were reported by Takashima et al. (1985),
Herbert et al. (1985), and Harano et al. (1989). The disorder was
characterized by the absence of LDLs and apoB100 in plasma with
apparently normal secretion of triglyceride-rich lipoproteins containing
apoB48. Subsequent studies in A.F. suggested that the patient's plasma
might be a truncated form of apoB100, slightly longer than the normal
apoB48 chain. Hardman et al. (1991) demonstrated that the patient was
homozygous for a single C-to-T substitution at nucleotide 6963 of apoB
cDNA. This substitution resulted in a change from CAG (glutamine) to TAG
(stop) at position 2252. Thus, this was a rare example of homozygous
hypobetalipoproteinemia. Because LDL particles that contained apoB50
lacked the putative ligand domain of the LDL receptor, the very low
level of LDL was presumably due to the rapid removal of the abnormal
VLDL particles before their conversion to LDL could take place. As
reviewed by Hardman et al. (1991), a considerable number of mutations
resulting in truncated versions of apoB have been described, the
smallest variant being apoB31, and the longest, apoB90. Using 3 genetic
markers of the APOB gene in a study of the family reported by Takashima
et al. (1985), Naganawa et al. (1992) found that the proband and her
affected brother showed completely different APOB alleles, indicating
that in this family the defect was not in the APOB gene.

Homer et al. (2005) suggested that the term 'normotriglyceridemic
hypobetalipoproteinemia' is preferred to 'normotriglyceridemic
abetalipoproteinemia' because abetalipoproteinemia (ABL; 200100) refers
to the disorder caused by mutation in the MTP gene (157147).

.0014
HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB32
APOB, GLN1450TER

In a person with heterozygous hypobetalipoproteinemia (615558),
McCormick et al. (1992) identified a nonsense mutation, gln1450-to-ter
(Q1450X), that prevented full-length translation. The new apolipoprotein
B, apoB32, is predicted to contain the 1,449 N-terminal amino acids of
apoB100. It was associated with a markedly decreased level of low
density lipoprotein (LDL cholesterol). Unique among the truncated apoB
species, apoB32 was found in the high density lipoprotein and
lipoprotein-depleted fractions, suggesting that it was mainly assembled
into abnormally dense lipoprotein particles.

.0015
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, ARG2495TER

In a patient with familial hypobetalipoproteinemia (615558), Talmud et
al. (1992) identified a C-to-T transition at nucleotide 7692 of the APOB
gene which changed the CGA arginine codon to a stop codon resulting in a
premature termination of apoB100. The truncated protein was predicted to
be 2,494 amino acids long with the predicted size of apoB55. The patient
had low total cholesterol and LDL-cholesterol as did also other
relatives in an autosomal dominant pattern. In addition, the propositus,
his mother, and both of his sibs had atypical retinitis pigmentosa.
Since the RP-affected brother did not have the APOB mutation, Talmud et
al. (1992) concluded that the eye disease was independent of the
hypobetalipoproteinemia. They speculated, however, that a reduction in
apoB-containing lipoproteins might alter the balance of the fatty acid
supply to the retina and thus affect the evolution of retinitis
pigmentosa in this family. The retinitis pigmentosa was late in onset.

.0016
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, 1-BP DEL, NT11840

In H.J.B. and 2 sibs with asymptomatic familial hypobetalipoproteinemia
(615558) reported by Steinberg et al. (1979), Linton et al. (1992)
demonstrated that one of the alleles, which yielded very low levels of
apoB100, had a deletion of a single cytosine in exon 26 (nucleotide
11840 of the apoB cDNA). This frameshift mutation was predicted to yield
a 20-amino acid sequence (KKQIMLKQSWIPHAAQPYSS) not found in the
wildtype, followed by a premature stop codon. Indeed, they found an
antiserum to a synthetic peptide containing this 20-amino acid sequence
(frameshift peptide 3877-3896) bound specifically to apoB86 but not to
apoB100. Thus the compound heterozygotes had 2 mutant apoB alleles, one
primarily responsible for apoB37 (107730.0001) and the other responsible
for apoB86, both of which contained frameshift mutations in exon 26.
Linton et al. (1992) further demonstrated that the 1-bp deletion in the
apoB86 allele created a stretch of 8 consecutive adenines. Addition of a
single adenine within the 8 consecutive adenines would be predicted to
correct the altered reading frame, thereby resulting in the production
of a full-length protein. They presented evidence that a significant
percentage (about 11%) of the apoB cDNA clones from rat hepatoma cells
transformed with an apoB construct containing the 1-bp deletion indeed
had 9 consecutive adenines. It appeared that the addition of an extra
adenine during transcription restored the correct reading frame and
accounted for the formation of some apoB100 from the apoB86 allele.
Other experiments were thought to exclude an alternative explanation,
the activation of a cryptic splice site within exon 26 upstream from the
deletion.

.0017
HYPERCHOLESTEROLEMIA DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B100
APOB, ARG3531CYS

Suspecting that mutations in the APOB gene other than the arg3500-to-gln
mutation (107730.0009) may cause familial hypercholesterolemia (144010),
Pullinger et al. (1995) used single-strand conformation polymorphism
analysis to screen genomic DNA from patients attending a lipid clinic
and looked for mutations in the putative LDL receptor-binding domain of
apoB100. They found a novel arg3531-to-cys mutation, caused by a C-to-T
transition at nucleotide 10800, in a 46-year-old woman of Celtic and
Native American ancestry with primary hypercholesterolemia and
pronounced peripheral vascular disease. After screening 1,560
individuals, one unrelated 59-year-old man of Italian ancestry was found
to have the same mutation. He had coronary heart disease, a triglyceride
cholesterol of 310 mg/dl, and an LDL cholesterol of 212 mg/dl. A total
of 8 individuals were found with the same defect in the families of
these 2 patients. The age- and sex-adjusted TC and LDL-C were 240 and
169, respectively, for the 8 affected individuals, as compared with 185
and 124, respectively, for 8 unaffected family members. In a
dual-labeled fibroblast binding assay, LDL from the 8 subjects with the
mutation had an affinity for the LDL receptor that was 63% of that of
control LDL. LDL from 8 unaffected family members had an affinity of
91%. By way of comparison, LDL from 6 patients heterozygous for the
arg3500-to-gln mutation had an affinity of 36%. Deduced haplotypes using
10 APOB gene markers showed the arg3531-to-cys alleles to be different
in the 2 kindreds and indicated that the mutations arose independently.
This was the second reported cause of familial ligand-defective apoB.

.0018
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, IVS7AS, A-G, -2

Hegele and Miskie (2002) described acanthocytosis in a 31-year-old woman
with homozygous familial hypobetalipoproteinemia (615558) due to a
splicing mutation in the APOB gene, IVS7-2A-G. Treatment with
fat-soluble vitamins was associated with arrest of the usually
progressive neurologic complications of this condition. However,
acanthocytosis persisted. The diagnosis of hypobetalipoproteinemia was
made at the age of 11 years on the basis of acanthocytosis and the
absence of apoB-containing lipoproteins. The consanguineous parents were
heterozygotes.

.0019
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, 1-BP DEL, 4432T

In a family segregating familial hypobetalipoproteinemia (615558), Yue
et al. (2002) described a 1-bp deletion, 4432delT, in exon 26 of the
APOB gene, producing a frameshift and a premature stop codon and
resulting in a truncated apoB-30.9. Although this truncation was only 10
amino acids shorter than the well-documented apoB31 (107730.0008), which
is readily detectable in plasma, apoB-30.9 was undetectable. Most
truncations shorter than apoB-30 are not detectable in plasma.

.0020
HYPOBETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC
APOB, 4-BP DEL, NT36491

In a patient with normotriglyceridemic hypobetalipoproteinemia (615558),
obesity, and mental retardation, Homer et al. (2005) identified compound
heterozygosity for 2 mutations in the APOB gene. One was a 4-bp deletion
beginning at nucleotide 36491 in exon 26, predicted to result in a
frameshift and incorporation of 5 new amino acids before encountering a
premature termination codon at position 3053. This translated protein
would be 66% of full-length apoB, which would allow for expression in
the liver and for production of minute amounts of VLDL and LDL.
Accordingly, the patient did not have failure to thrive or steatorrhea.
The second mutation was a 29142T-A transversion in exon 23, resulting in
a tyr1173-to-ter (Y1173X; 107730.0021) substitution. The translated
Y1173X protein is predicted to be 25.8% of apoB100 and is not expressed
in apoB-containing lipoproteins. Homer et al. (2005) suggested that the
clinical features of ataxia, visual impairment, and probable neuropathy
seen in the patient resulted from the inability to transport the active
stereoisomer of vitamin E from the liver. These clinical features were
similar to those seen in isolated vitamin E deficiency (VED; 277460).
Homer et al. (2005) noted that the clinical features of this patient
were similar to those of the patient reported by Malloy et al. (1981)
(see 107730.0013).

Homer et al. (2005) suggested that the term 'normotriglyceridemic
hypobetalipoproteinemia' is preferred to 'normotriglyceridemic
abetalipoproteinemia' because abetalipoproteinemia (ABL; 200100) refers
to the disorder caused by mutation in the MTP gene (157147).

.0021
HYPOBETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC
APOB, TYR1173TER

See 107730.0020 and Homer et al. (2005).

.0022
HYPOBETALIPOPROTEINEMIA, FAMILIAL
APOB, 2-BP INS, 825GG

In a 27-year-old woman from a consanguineous French Canadian family, who
was diagnosed with FHBL (615558) in the first months of life, Gangloff
et al. (2011) identified a 2-bp insertion (825insGG) in exon 9 of the
APOB gene, causing a frameshift predicted to result in a truncated
protein that is approximately 7% of the normal APOB length. The proband
and 2 younger brothers, aged 12 and 4 years, had undetectable apoB
levels, extremely low levels of cholesterol in all lipoprotein
fractions, low levels of lipophilic vitamins, and acanthocytosis.
Vitamin E deficiency was present in all 3. The obligate-heterozygote
parents had plasma levels of apoB-containing lipoproteins that were
approximately 50% of normal, suggesting a codominant pattern of
inheritance. The parents declined genetic testing for themselves and
their younger children.

*FIELD* SA
Aggerbeck et al. (1974); Allison and Blumberg (1965); Barni et al.
(1986); Butler and Brunner (1969); Butler et al. (1970); Carlsson
et al. (1985); Chan et al. (1985); Cottrill et al. (1974); Frossard
et al. (1986); Hegele et al. (1986); Illingworth et al. (1992); Innerarity
et al. (1987); Knott et al. (1986); Law et al. (1986); Morganti et
al. (1970); Protter et al. (1986); Protter et al. (1986); Shoulders
et al. (1985); Talmud et al. (1988); Tamir et al. (1976); Weisgraber
et al. (1988); Yang et al. (1986); Young et al. (1987); Young et al.
(1986)
*FIELD* RF
1. Aggerbeck, L. P.; McMahon, J. P.; Scanu, A. M.: Hypobetalipoproteinemia:
clinical and biochemical description of a new kindred with Friedreich's
ataxia. Neurology 24: 1051-1063, 1974.

2. Allison, A. C.; Blumberg, B. S.: Serum lipoprotein allotypes in
man. Prog. Med. Genet. 4: 176-201, 1965.

3. Allison, A. C.; Blumberg, B. S.: An isoprecipitation reaction
distinguishing human serum-protein types. Lancet 277: 634-637, 1961.
Note: Originally Volume I.

4. Antonarakis, S. E.: Personal Communication. Baltimore, Md.
6/1987.

5. Barni, N.; Talmud, P. J.; Carlsson, P.; Azoulay, M.; Darnfors,
C.; Harding, D.; Weil, D.; Grzeschik, K. H.; Bjursell, G.; Junien,
C.; Williamson, R.; Humphries, S. E.: The isolation of genomic recombinants
for the human apolipoprotein B gene and the mapping of three common
DNA polymorphisms of the gene--a useful marker for human chromosome
2. Hum. Genet. 73: 313-319, 1986.

6. Bednarska-Makaruk, M.; Bisko, M.; Pulawska, M. F.; Hoffman-Zacharska,
D.; Rodo, M.; Roszczynko, M.; Solik-Tomassi, A.; Broda, G.; Polakowska,
M.; Pytlak, A.; Wehr, H.: Familial defective apolipoprotein B-100
in a group of hypercholesterolaemic patients in Poland: identification
of a new mutation Thr3492Ile in the apolipoprotein B gene. Europ.
J. Hum. Genet. 9: 836-842, 2001.

7. Benlian, P.; de Gennes, J. L.; Dairou, F.; Hermelin, B.; Ginon,
I.; Villain, E.; Lagarde, J. P.; Federspiel, M. C.; Bertrand, V.;
Bernard, C.; Bereziat, G.: Phenotypic expression in double heterozygotes
for familial hypercholesterolemia and familial defective apolipoprotein
B-100. Hum. Mutat. 7: 340-345, 1996.

8. Benn, M.; Nordestgaard, B. G.; Jensen, J. S.; Grande, P.; Sillesen,
H.; Tybjaerg-Hansen, A.: Polymorphism in APOB associated with increases
low-density lipoprotein levels in both genders in the general population. J.
Clin. Endocr. Metab. 90: 5797-5803, 2005.

9. Benn, M.; Nordestgaard, B. G.; Jensen, J. S.; Tybjaerg-Hansen,
A.: Polymorphisms in apolipoprotein B and risk of ischemic stroke. J.
Clin. Endocr. Metab. 92: 3611-3617, 2007.

10. Berg, K.; Beckman, G.; Beckman, L.: A search for linkage between
the Ag and (dimeric) superoxide dismutase (SOD-1) loci. Birth Defects
Orig. Art. Ser. XI(3): 67-70, 1975. Note: Alternate: Cytogenet. Cell
Genet. 14: 237-240, 1975.

11. Berg, K.; Hames, C.; Dahlen, G.; Frick, M. H.; Krishan, I.: Genetic
variation in serum low density lipoproteins and lipid levels in man. Proc.
Nat. Acad. Sci. 73: 937-940, 1976.

12. Berg, K.; Powell, L. M.; Wallis, S. C.; Pease, R.; Knott, T. J.;
Scott, J.: Genetic linkage between the antigenic group (Ag) variation
and the apolipoprotein B gene: assignment of the Ag locus. Proc.
Nat. Acad. Sci. 83: 7367-7370, 1986.

13. Berger, G. M. B.; Brown, G.; Henderson, H. E.; Bonnici, F.: Apolipoprotein
B detected in the plasma of a patient with homozygous hypobetalipoproteinaemia:
implications for aetiology. J. Med. Genet. 20: 189-195, 1983.

14. Blumberg, B. S.: Personal Communication. Philadelphia, Penn.
5/16/1978.

15. Blumberg, B. S.; Alter, H. J.; Riddell, N. M.: Inherited antigenic
differences in human serum beta lipoproteins: a second antiserum. J.
Clin. Invest. 42: 867-875, 1963.

16. Blumberg, B. S.; Alter, H. J.; Riddell, N. M.; Erlandson, M.:
Multiple antigenic specificities of serum lipoproteins detected with
sera of transfused patients. Vox Sang. 9: 128-145, 1964.

17. Boehnke, M.: Allele frequency estimation from data on relatives. Am.
J. Hum. Genet. 48: 22-25, 1991.

18. Boerwinkle, E.; Xiong, W.; Fourest, E.; Chan, L.: Rapid typing
of tandemly repeated hypervariable loci by the polymerase chain reaction:
application to the apolipoprotein B 3-prime hypervariable region. Proc.
Nat. Acad. Sci. 86: 212-216, 1989.

19. Boren, J.; Ekstrom, U.; Agren, B.; Nilsson-Ehle, P.; Innerarity,
T. L.: The molecular mechanism for the genetic disorder familial
defective apolipoprotein B100. J. Biol. Chem. 276: 9214-9218, 2001.

20. Boren, J.; Lee, I.; Zhu, W.; Arnold, K.; Taylor, S.; Innerarity,
T. L.: Identification of the low density lipoprotein receptor-binding
site in apolipoprotein B100 and the modulation of its binding activity
by the carboxyl terminus in familial defective apo-B100. J. Clin.
Invest. 101: 1084-1093, 1998.

21. Breguet, G.; Butler, R.; Butler-Brunner, E.; Sanchez-Mazas, A.
: A worldwide population study of the Ag-system haplotypes: a genetic
polymorphism of human low-density lipoprotein. Am. J. Hum. Genet. 46:
502-517, 1990.

22. Butler, R.; Brunner, E.: On the genetics of the low density lipoprotein
factors Ag(c) and Ag(e). Hum. Hered. 19: 174-179, 1969.

23. Butler, R.; Brunner, E.; Morganti, G.; Vierucci, A.; Scaloumbacas,
N.; Politis, E.: A new factor in the Ag-system: Ag(g). Vox Sang. 18:
85-89, 1970.

24. Callow, M. J.; Verstuyft, J.; Tangirala, R.; Palinski, W.; Rubin,
E. M.: Atherogenesis in transgenic mice with human apolipoprotein
B and lipoprotein(a). J. Clin. Invest. 96: 1639-1646, 1995.

25. Carlsson, P.; Olofsson, S. O.; Bondjers, G.; Darnfors, C.; Wiklund,
O.; Bjursell, G.: Molecular cloning of human apolipoprotein B cDNA. Nucleic
Acids Res. 13: 8813-8826, 1985.

26. Chan, L.; VanTuinen, P.; Ledbetter, D. H.; Daiger, S. P.; Gotto,
A. M., Jr.; Chen, S. H.: The human apolipoprotein B-100 gene: a highly
polymorphic gene that maps to the short arm of chromosome 2. Biochem.
Biophys. Res. Commun. 133: 248-255, 1985.

27. Chen, S.-H.; Habib, G.; Yang, C.-Y.; Gu, Z.-W.; Lee, B. R.; Weng,
S.; Silberman, S. R.; Cai, S.-J.; Deslypere, J. P.; Rosseneu, M.;
Gotto, A. M., Jr.; Li, W.-H.; Chan, L.: Apolipoprotein B-48 is the
product of a messenger RNA with an organ-specific in-frame stop codon. Science 238:
363-366, 1987.

28. Chen, S.-H.; Yang, C.-Y.; Chen, P.-F.; Setzer, D.; Tanimura, M.;
Li, W. H.; Gotto, A. M., Jr.; Chan, L.: The complete cDNA and amino
acid sequence of human apolipoprotein B-100. J. Biol. Chem. 261:
12918-12921, 1986.

29. Cladaras, C.; Hadzopoulou-Cladaras, M.; Nolte, R. T.; Atkinson,
D.; Zannis, V. I.: The complete sequence and structural analysis
of human apolipoprotein B-100: relationship between apoB-100 and apoB-48
forms. EMBO J. 5: 3495-3507, 1986.

30. Collins, D. R.; Knott, T. J.; Pease, R. J.; Powell, L. M.; Wallis,
S. C.; Robertson, S.; Pullinger, C. R.; Milne, R. W.; Marcel, Y. L.;
Humphries, S. E.; Talmud, P. J.; Lloyd, J. K.; Miller, N. E.; Muller,
D.; Scott, J.: Truncated variants of apolipoprotein B cause hypobetalipoproteinaemia. Nucleic
Acids Res. 16: 8361-8375, 1988.

31. Coresh, J.; Beaty, T. H.; Kwiterovich, P. O., Jr.; Antonarakis,
S. E.: Pedigree and sib-pair linkage analysis suggest the apolipoprotein
B gene is not the major gene influencing plasma apolipoprotein B levels. Am.
J. Hum. Genet. 50: 1038-1045, 1992.

32. Corsini, A.; Fantappie, S.; Granata, A.; Bernini, F.; Catapano,
A. L.; Fumagalli, R.; Romano, L.; Romano, C.: Binding-defective low-density
lipoprotein in family with hypercholesterolaemia.(Letter) Lancet 339:
623 only, 1989. Note: Originally Volume I.

33. Cottrill, C.; Glueck, C. J.; Leuba, V.; Millett, F.; Puppione,
D.; Brown, W. V.: Familial homozygous hypobetalipoproteinemia. Metabolism 23:
779-792, 1974.

34. Deeb, S. S.; Disteche, C.; Motulsky, A. G.; Lebo, R. V.; Kan,
Y. W.: Chromosomal localization of the human apolipoprotein B gene
and detection of homologous RNA in monkey intestine. Proc. Nat. Acad.
Sci. 83: 419-422, 1986.

35. Demant, T.; Houlston, R. S.; Caslake, M. J.; Series, J. J.; Shepherd,
J.; Packard, C. J.; Humphries, S. E.: Catabolic rate of low density
lipoprotein is influenced by variation in the apolipoprotein B gene. J.
Clin. Invest. 82: 797-802, 1988.

36. Di Leo, E.; Magnolo, L.; Lancellotti, S.; Croce, L.; Visintin,
L.; Tiribelli, C.; Bertolini, S.; Calandra, S.; Tarugi, P.: Abnormal
apolipoprotein B pre-mRNA splicing in patients with familial hypobetalipoproteinemia.
(Letter) J. Med. Genet. 44: 219-224, 2007.

37. Dunning, A. M.; Renges, H.-H.; Xu, C.-F.; Peacock, R.; Brasseur,
R.; Laxer, G.; Tikkanen, M. J.; Butler, R.; Saha, N.; Hamsten, A.;
Rosseneu, M.; Talmud, P.; Humphries, S. E.: Two amino acid substitutions
in apolipoprotein B are in complete allelic association with the antigen
group (x/y) polymorphism: evidence for little recombination in the
3-prime end of the human gene. Am. J. Hum. Genet. 50: 208-221, 1992.

38. Espinosa-Heidmann, D. G.; Sall, J.; Hernandez, E. P.; Cousins,
S. W.: Basal laminar deposit formation in APO B100 transgenic mice:
complex interactions between dietary fat, blue light, and vitamin
E. Invest. Ophthal. Vis. Sci. 45: 260-266, 2004.

39. Farese, R. V., Jr.; Veniant, M. M.; Cham, C. M.; Flynn, L. M.;
Pierotti, V.; Loring, J. F.; Traber, M.; Ruland, S.; Stokowski, R.
S.; Huszar, D.; Young, S. G.: Phenotypic analysis of mice expressing
exclusively apolipoprotein B48 or apolipoprotein B100. Proc. Nat.
Acad. Sci. 93: 6393-6398, 1996.

40. Feussner, G.; Schuster, H.: Screening for the apolipoprotein
B-100 arginine3500-to-glutamine mutation in patients with type III
hyperlipoproteinemia. Clin. Genet. 42: 302-305, 1992.

41. Friedlander, Y.; Dann, E. J.; Leitersdorf, E.: Absence of familial
defective apolipoprotein B-100 in Israeli patients with dominantly
inherited hypercholesterolemia and in offspring with parental history
of myocardial infarction.(Letter) Hum. Genet. 91: 299-300, 1993.

42. Frossard, P. M.; Gonzalez, P. A.; Protter, A. A.; Coleman, R.
T.; Funke, H.; Assmann, G.: Pvu II RFLP in the 5-prime of the human
apolipoprotein B gene. Nucleic Acids Res. 14: 4373, 1986.

43. Fujihara, M.; Bartels, E.; Nielsen, L. B.; Handa, J. T.: A human
apoB100 transgenic mouse expresses human apoB100 in the RPE and develops
features of early AMD. Exp. Eye Res. 88: 1115-1123, 2009.

44. Gabelli, C.; Bilato, C.; Martini, S.; Tennyson, G. E.; Zech, L.
A.; Corsini, A.; Albanese, M.; Brewer, H. B., Jr.; Crepaldi, G.; Baggio,
G.: Homozygous familial hypobetalipoproteinemia: increased LDL catabolism
in hypobetalipoproteinemia due to a truncated apolipoprotein B species,
apo B-87-Padova. Arterioscler. Thromb. Vasc. Biol. 16: 1189-1196,
1996.

45. Gangloff, A.; Bergeron, J.; Couture, P.; Martins, R.; Hegele,
R. A.; Gagne, C.: A novel mutation of apolipoprotein B in a French
Canadian family with homozygous hypobetalipoproteinemia. J. Clin.
Lipidol. 5: 414-417, 2011.

46. Gavish, D.; Brinton, E. A.; Breslow, J. L.: Heritable allele-specific
differences in amounts of apoB and low-density lipoproteins in plasma. Science 244:
72-76, 1989.

47. Glickman, R. M.; Rogers, M.; Glickman, J. N.: Apolipoprotein
B synthesis by human liver and intestine in vitro. Proc. Nat. Acad.
Sci. 83: 5296-5300, 1986.

48. Hamalainen, T.; Palotie, A.; Aalto-Setala, K.; Kontula, K.; Tikkanen,
M. J.: Absence of familial defective apolipoprotein B-100 in Finnish
patients with elevated serum cholesterol. Atherosclerosis 82: 177-183,
1990.

49. Harano, Y.; Kojima, H.; Nakano, T.; Harada, M.; Kashiwagi, A.;
Nakajima, Y.; Hidaka, T. H.; Ohtsuki, T.; Suzuki, T.; Tamura, A.;
Fujii, T.; Nishimura, T.; Ohtaka, T.; Shigeta, Y.: Homozygous hypobetalipoproteinemia
with spared chylomicron formation. Metabolism 38: 1-7, 1989.

50. Hardman, D. A.; Protter, A. A.; Chen, G. C.; Schilling, J. W.;
Sato, K. Y.; Lau, K.; Yamanaka, M.; Mikita, T.; Miller, J.; Crisp,
T.; McEnroe, G.; Scarborough, R. M.; Kane, J. P.: Structural comparisons
of human apolipoproteins B-48 and B-100. Biochemistry 26: 5478-5486,
1987.

51. Hardman, D. A.; Pullinger, C. R.; Hamilton, R. L.; Kane, J. P.;
Malloy, M. J.: Molecular and metabolic basis for the metabolic disorder
normotriglyceridemic abetalipoproteinemia. J. Clin. Invest. 88:
1722-1729, 1991.

52. Hegele, R. A.; Huang, L.-S.; Herbert, P. N.; Blum, C. B.; Buring,
J. E.; Hennekens, C. H.; Breslow, J. L.: Apolipoprotein B-gene polymorphisms
associated with myocardial infarction. New Eng. J. Med. 315: 1509-1515,
1986.

53. Hegele, R. A.; Miskie, B. A.: Acanthocytosis in a patient with
homozygous familial hypobetalipoproteinemia due to a novel APOB splice
site mutation. Clin. Genet. 61: 101-103, 2002.

54. Herbert, P. N.; Hyams, J. S.; Bernier, D. N.; Berman, M. M.; Saritelli,
A. L.; Lynch, K. M.; Nichols, A. V.; Forte, T. M.: Apolipoprotein
B-100 deficiency: intestinal steatosis despite apolipoprotein B-48
synthesis. J. Clin. Invest. 76: 403-412, 1985.

55. Higuchi, K.; Hospattankar, A. V.; Law, S. W.; Meglin, N.; Cortright,
J.; Brewer, H. B., Jr.: Human apolipoprotein B (apoB) mRNA: identification
of two distinct apoB mRNAs, an mRNA with the apoB-100 sequence and
an apoB mRNA containing a premature in-frame translational stop codon,
in both liver and intestine. Proc. Nat. Acad. Sci. 85: 1772-1776,
1988.

56. Homanics, G. E.; Smith, T. J.; Zhang, S. H.; Lee, D.; Young, S.
G.; Maeda, N.: Targeted modification of the apolipoprotein B gene
results in hypobetalipoproteinemia and developmental abnormalities
in mice. Proc. Nat. Acad. Sci. 90: 2389-2393, 1993.

57. Homer, V. M.; George, P. M.; du Toit, S.; Davidson, J. S.; Wilson,
C. J.: Mental retardation and ataxia due to normotriglyceridemic
hypobetalipoproteinemia. Ann. Neurol. 58: 160-163, 2005.

58. Horvath, A.; Savov, A.; Kirov, S.; Karshelova, E.; Paskaleva,
I.; Goudev, A.; Ganev, V.: High frequency of the ApoB-100 R3500Q
mutation in Bulgarian hypercholesterolaemic subjects. J. Med. Genet. 38:
536-540, 2001. Note: Erratum: J. Med. Genet. 39: 303 only, 2002.

59. Hospattankar, A. V.; Fairwell, T.; Meng, M.; Ronan, R.; Brewer,
H. B., Jr.: Identification of sequence homology between human plasma
apolipoprotein B-100 and apolipoprotein B-48. J. Biol. Chem. 261:
9102-9104, 1986.

60. Huang, L.-S.; Miller, D. A.; Bruns, G. A. P.; Breslow, J. L.:
Mapping of the human APOB gene to chromosome 2p and demonstration
of a two-allele restriction fragment length polymorphism. Proc. Nat.
Acad. Sci. 83: 644-648, 1986.

61. Huang, L.-S.; Ripps, M. E.; Korman, S. H.; Deckelbaum, R. J.;
Breslow, J. L.: Hypobetalipoproteinemia due to an apolipoprotein
B gene exon 21 deletion derived by Alu-Alu recombination. J. Biol.
Chem. 264: 11394-11400, 1989.

62. Huang, L.-S.; Voyiaziakis, E.; Chen, H. L.; Rubin, E. M.; Gordon,
J. W.: A novel functional role for apolipoprotein B in male infertility
in heterozygous apolipoprotein B knockout mice. Proc. Nat. Acad.
Sci. 93: 10903-10907, 1996.

63. Huang, L.-S.; Voyiaziakis, E.; Markenson, D. F.; Sokol, K. A.;
Hayek, T.; Breslow, J. L.: apo B gene knockout in mice results in
embryonic lethality in homozygotes and neural tube defects, male infertility,
and reduced HDL cholesterol ester and apo A-1 transport rates in heterozygotes. J.
Clin. Invest. 96: 2152-2161, 1995.

64. Huijgen, R.; Kindt, I.; Fouchier, S. W.; Defesche, J. C.; Hutten,
B. A.; Kastelein, J. J. P.; Vissers, M. N.: Functionality of sequence
variants in the genes coding for the low-density lipoprotein receptor
and apolipoprotein B in individuals with inherited hypercholesterolemia. Hum.
Mutat. 31: 752-760, 2010.

65. Illingworth, D. R.; Vakar, F.; Mahley, R. W.; Weisgraber, K. H.
: Hypocholesterolaemic effects of lovastatin in familial defective
apolipoprotein B-100. Lancet 339: 598-600, 1992.

66. Innerarity, T. L.; Weisgraber, K. H.; Arnold, K. S.; Mahley, R.
W.; Krauss, R. M.; Vega, G. L.; Grundy, S. M.: Familial defective
apolipoprotein B-100: low density lipoproteins with abnormal receptor
binding. Proc. Nat. Acad. Sci. 84: 6919-6923, 1987.

67. Innerarity, T. L.; Young, S. G.; Poksay, K. S.; Mahley, R. W.;
Smith, R. S.; Milne, R. W.; Marcel, Y. L.; Weisgraber, K. H.: Structural
relationship of human apolipoprotein B48 to apolipoprotein B100. J.
Clin. Invest. 80: 1794-1798, 1987.

68. Jackson, L.; Falk, C. T.; Allen, F. H., Jr.; Barr, M.: A possible
gene assignment to chromosome 21. Cytogenet. Cell Genet. 13: 100-102,
1974.

69. Kairamkonda, V.; Dalzell, M.: Unusual presentation of three siblings
with familial heterozygous hypobetalipoproteinaemia. Europ. J. Pediat. 162:
129-131, 2003.

70. Kathiresan, S.; Melander, O.; Anevski, D.; Guiducci, C.; Burtt,
N. P.; Roos, C.; Hirschhorn, J. N.; Berglund, G.; Hedblad, B.; Groop,
L.; Altshuler, D. M.; Newton-Cheh, C.; Orho-Melander, M.: Polymorphisms
associated with cholesterol and risk of cardiovascular events. New
Eng. J. Med. 358: 1240-1249, 2008.

71. Knott, T. J.; Pease, R. J.; Powell, L. M.; Wallis, S. C.; Rall,
S. C., Jr.; Innerarity, T. L.; Blackhart, B.; Taylor, W. H.; Marcel,
Y.; Milne, R.; Johnson, D.; Fuller, M.; Lusis, A. J.; McCarthy, B.
J.; Mahley, R. W.; Levy-Wilson, B.; Scott, J.: Complete protein sequence
and identification of structural domains of human apolipoprotein B. Nature 323:
734-738, 1986.

72. Knott, T. J.; Rall, S. C., Jr.; Innerarity, T. L.; Jacobson, S.
F.; Urdea, M. S.; Levy-Wilson, B.; Powell, L. M.; Pease, R. J.; Eddy,
R.; Nakai, H.; Byers, M.; Priestley, L. M.; Robertson, E.; Rall, L.
B.; Betsholtz, C.; Shows, T. B.; Mahley, R. W.; Scott, J.: Human
apolipoprotein B: structure of carboxyl-terminal domains, sites of
gene expression, and chromosomal localization. Science 230: 37-43,
1985.

73. Knott, T. J.; Wallis, S. C.; Powell, L. M.; Pease, R. J.; Lusis,
A. J.; Blackhart, B.; McCarthy, B. J.; Mahley, R. W.; Levy-Wilson,
B.; Scott, J.: Complete cDNA and derived protein sequence of human
apolipoprotein B-100. Nucleic Acids Res. 14: 7501-7503, 1986.

74. Krul, E. S.; Kinoshita, M.; Talmud, P.; Humphries, S. E.; Turner,
S.; Goldberg, A. C.; Cook, K.; Boerwinkle, E.; Schonfeld, G.: Two
distinct truncated apolipoprotein B species in a kindred with hypobetalipoproteinemia. Arteriosclerosis 9:
856-868, 1989.

75. Lau, P. P.; Zhu, H.-J.; Baldini, A.; Charnsangavej, C.; Chan,
L.: Dimeric structure of a human apolipoprotein B mRNA editing protein
and cloning and chromosomal localization of its gene. Proc. Nat.
Acad. Sci. 91: 8522-8526, 1994.

76. Law, A.; Wallis, S. C.; Powell, L. M.; Pease, R. J.; Brunt, H.;
Priestley, L. M.; Knott, T. J.; Scott, J.; Altman, D. G.; Miller,
G. J.; Rajput, J.; Miller, N. E.: Common DNA polymorphism within
coding sequence of apolipoprotein B gene associated with altered lipid
levels. Lancet 327: 1301-1303, 1986. Note: Originally Volume I.

77. Law, S. W.; Grant, S. M.; Higuchi, K.; Hospattankar, A.; Lackner,
K.; Lee, N.; Brewer, H. B., Jr.: Human liver apolipoprotein B-100
cDNA: complete nucleic acid and derived amino acid sequence. Proc.
Nat. Acad. Sci. 83: 8142-8146, 1986.

78. Law, S. W.; Lackner, K. J.; Hospattankar, A. V.; Anchors, J. M.;
Sakaguchi, A. Y.; Naylor, S. L.; Brewer, H. B., Jr.: Human apolipoprotein
B-100: cloning, analysis of liver mRNA, and assignment of the gene
to chromosome 2. Proc. Nat. Acad. Sci. 82: 8340-8344, 1985.

79. Leppert, M.; Breslow, J. L.; Wu, L.; Hasstedt, S.; O'Connell,
P.; Lathrop, M.; Williams, R. R.; White, R.; Lalouel, J.-M.: Inference
of a molecular defect of apolipoprotein B in hypobetalipoproteinemia
by linkage analysis in a large kindred. J. Clin. Invest. 82: 847-851,
1988.

80. Linton, M. F.; Farese, R. V., Jr.; Young, S. G.: Familial hypobetalipoproteinemia. J.
Lipid Res. 34: 521-541, 1993.

81. Linton, M. F.; Pierotti, V.; Young, S. G.: Reading-frame restoration
with an apolipoprotein B gene frameshift mutation. Proc. Nat. Acad.
Sci. 89: 11431-11435, 1992.

82. Loux, N.; Saint-Jore, B.; Collod, G.; Benlian, P.; Cambou, J.
P.; Denat, M.; Junien, C.; Boileau, C.: Identification of the haplotype
associated with the APOB-3500 mutation in a French hypercholesterolemic
subject: further support for a unique European ancestral mutation. Hum.
Mutat. 2: 145-147, 1993.

83. Ludwig, E. H.; Friedl, W.; McCarthy, B. J.: High-resolution analysis
of a hypervariable region in the human apolipoprotein B gene. Am.
J. Hum. Genet. 45: 458-464, 1989.

84. Ludwig, E. H.; McCarthy, B. J.: Haplotype analysis of the human
apolipoprotein B mutation associated with familial defective apolipoprotein
B100. Am. J. Hum. Genet. 47: 712-720, 1990.

85. Lusis, A. J.; West, R.; Mehrabian, M.; Reuben, M. A.; LeBoeuf,
R. C.; Kaptein, J. S.; Johnson, D. F.; Schumaker, V. N.; Yuhasz, M.
P.; Schotz, M. C.; Elovson, J.: Cloning and expression of apolipoprotein
B, the major protein of low and very low density lipoproteins. Proc.
Nat. Acad. Sci. 82: 4597-4601, 1985.

86. Malloy, M. J.; Kane, J. P.; Hardman, D. A.; Hamilton, R. L.; Dalal,
K. B.: Normotriglyceridemic abetalipoproteinemia: absence of the
B-100 apolipoprotein. J. Clin. Invest. 67: 1441-1450, 1981.

87. Marz, W.; Baumstark, M. W.; Scharnagl, H.; Ruzicka, V.; Buxbaum,
S.; Herwig, J.; Pohl, T.; Russ, A.; Schaaf, L.; Berg, A.; Bohles,
H.-J.; Usadel, K. H.; Gro, W.: Accumulation of 'small dense' low
density lipoproteins (LDL) in a homozygous patient with familial defective
apolipoprotein B-100 results from heterogenous interaction of LDL
subfractions with the LDL receptor. J. Clin. Invest. 92: 2922-2933,
1993.

88. Marz, W.; Ruzicka, C.; Pohl, T.; Usadel, K. H.; Gross, W.: Familial
defective apolipoprotein B-100: mild hypercholesterolaemia without
atherosclerosis in a homozygous patient.(Letter) Lancet 340: 1362,
1992.

89. McCormick, S. P. A.; Fellowes, A. P.; Walmsley, T. A.; George,
P. M.: Apolipoprotein B-32: a new truncated mutant of human apolipoprotein
B capable of forming particles in the low density lipoprotein range. Biochim.
Biophys. Acta 1138: 290-296, 1992.

90. Mehrabian, M.; Sparkes, R. S.; Mohandas, T.; Klisak, I. J.; Schumaker,
V. N.; Heinzmann, C.; Zollman, S.; Ma, Y.; Lusis, A. J.: Human apolipoprotein
B: chromosomal mapping and DNA polymorphisms of hepatic and intestinal
species. Somat. Cell Molec. Genet. 12: 245-254, 1986.

91. Morganti, G.; Beolchini, P. B.; Butler, R.; Butler-Brunner, E.;
Vierucci, A.: Contribution to the genetics of serum beta-lipoproteins
in man. VIII. Linkage of the Ag(h-i)locus with the Ag(x-y), Ag(a1-d),
Ag(c-g), and Ag(t-z) loci. Humangenetik 30: 341-342, 1975.

92. Morganti, G.; Beolchini, P. E.; Butler, R.; Brunner, E.; Vierucci,
A.: Contribution to the genetics of serum beta-lipoproteins in man.
IV. Evidence for the existence of the Ag(A1-D) and Ag(C-G) loci, closely
linked to the Ag(X-Y) locus. Humangenetik 10: 244-253, 1970.

93. Myant, N. B.; Forbes, S. A.; Day, I. N. M.; Gallaghers, J.: Estimation
of the age of the ancestral arginine3500-to-glutamine mutation in
human apoB-100. Genomics 45: 78-87, 1997.

94. Naganawa, S.; Kodama, T.; Aburatani, H.; Matsumoto, A.; Itakura,
H.; Takashima, Y.; Kawamura, M.; Muto, Y.: Genetic analysis of a
Japanese family with normotriglyceridemic abetalipoproteinemia indicates
a lack of linkage to the apolipoprotein B gene. Biochem. Biophys.
Res. Commun. 182: 99-104, 1992.

95. Parhofer, K. G.; Barrett, P. H. R.; Bier, D. M.; Schonfeld, G.
: Lipoproteins containing the truncated apolipoprotein, apoB-89, are
cleared from human plasma more rapidly than apoB-100-containing lipoproteins
in vivo. J. Clin. Invest. 89: 1931-1937, 1992.

96. Protter, A. A.; Hardman, D. A.; Sato, K. Y.; Schilling, J. W.;
Yamanaka, M.; Hort, Y. J.; Hjerrild, K. A.; Chen, G. C.; Kane, J.
P.: Analysis of cDNA clones encoding the entire B-26 region of human
apolipoprotein B. Proc. Nat. Acad. Sci. 83: 5678-5682, 1986.

97. Protter, A. A.; Hardman, D. A.; Schilling, J. W.; Miller, J.;
Appleby, V.; Chen, G. C.; Kirsher, S. W.; McEnroe, G.; Kane, J. P.
: Isolation of a cDNA clone encoding the amino-terminal region of
human apolipoprotein B. Proc. Nat. Acad. Sci. 83: 1467-1471, 1986.

98. Pulai, J. I.; Neuman, R. J.; Groenewegen, A. W.; Wu, J.; Schonfeld,
G.: Genetic heterogeneity in familial hypobetalipoproteinemia: linkage
and non-linkage to the apoB gene in Caucasian families. Am. J. Med.
Genet. 76: 79-86, 1998.

99. Pullinger, C. R.; Hennessy, L. K.; Chatterton, J. E.; Liu, W.;
Love, J. A.; Mendel, C. M.; Frost, P. H.; Malloy, M. J.; Schumaker,
V. N.; Kane, J. P.: Familial ligand-defective apolipoprotein B: identification
of a new mutation that decreases LDL receptor binding affinity. J.
Clin. Invest. 95: 1225-1234, 1995.

100. Rajput-Williams, J.; Knott, T. J.; Wallis, S. C.; Sweetnam, P.;
Yarnell, J.; Cox, N.; Bell, G. I.; Miller, N. E.; Scott, J.: Variation
of apolipoprotein-B gene is associated with obesity, high blood cholesterol
levels, and increased risk of coronary heart disease. Lancet 332:
1442-1446, 1988. Note: Originally Volume II.

101. Rapacz, J.; Hasler-Rapacz, J.; Taylor, K. M.; Checovich, W. J.;
Attie, A. D.: Lipoprotein mutations in pigs are associated with elevated
plasma cholesterol and atherosclerosis. Science 234: 1573-1577,
1986.

102. Rauh, G.; Keller, C.; Schuster, H.; Wolfram, G.; Zollner, N.
: Familial defective apolipoprotein B-100: a common cause of primary
hypercholesterolemia. Clin. Invest. 70: 77-84, 1992.

103. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution. New York: Oxford Univ. Press (pub.) 1988.

104. Rubinsztein, D. C.; Raal, F. J.; Seftel, H. C.; Pilcher, G.;
Coetzee, G. A.; van der Westhuyzen, D. R.: Characterization of six
patients who are double heterozygotes for familial hypercholesterolemia
and familial defective apo B-100. Arterioscler. Thromb. 13: 1076-1081,
1993.

105. Saint-Jore, B.; Varret, M.; Dachet, C.; Rabes, J.-P.; Devillers,
M.; Erlich, D.; Blanchard, P.; Krempf, M.; Mathe, D.; Chanu, B.; Jacotot,
B.; Farnier, M.; Bonaiti-Pellie, C.; Junien, C.; Boileau, C.: Autosomal
dominant type IIa hypercholesterolemia: evaluation of the respective
contributions of LDLR and APOB gene defects as well as a third major
group of defects. Europ. J. Hum. Genet. 8: 621-630, 2000.

106. Schaefer, J. R.; Scharnagl, H.; Baumstark, M. W.; Schweer, H.;
Zech, L. A.; Seyberth, H.; Winkler, K.; Steinmetz, A.; Marz, W.:
Homozygous familial defective apolipoprotein B-100: enhanced removal
of apolipoprotein E-containing VLDLs and decreased production of LDLs. Arteriosclerosis
Thromb. Vasc. Biol. 17: 348-353, 1997.

107. Schonfeld, G.: The hypobetalipoproteinemias. Annu. Rev. Nutr. 15:
23-34, 1995.

108. Schonfeld, G.: Personal Communication. St. Louis, Mo. 3/24/1998.

109. Shoulders, C. C.; Myant, N. B.; Sidoli, A.; Rodriguez, J. C.;
Cortese, C.; Baralle, F. E.; Cortese, R.: Molecular cloning of human
LDL apolipoprotein B cDNA: evidence for more than one gene per haploid
genome. Atherosclerosis 58: 277-289, 1985.

110. Singh, M. K.; Pandey, U. B.; Ghoshal, U. C.; Srivenu, I.; Kapoor,
V. K.; Choudhuri, G.; Mittal, B.: Apolipoprotein B-100 XbaI gene
polymorphism in gallbladder cancer. Hum. Genet. 114: 280-283, 2004.

111. Skalen, K.; Gustafsson, M.; Rydberg, E. K.; Hulten, L. M.; Wiklund,
O.; Innerarity, T. L.; Boren, J.: Subendothelial retention of atherogenic
lipoproteins in early atherosclerosis. Nature 417: 750-754, 2002.

112. Soria, L. F.; Ludwig, E. H.; Clarke, H. R. G.; Vega, G. L.; Grundy,
S. M.; McCarthy, B. J.: Association between a specific apolipoprotein
B mutation and familial defective apolipoprotein B-100. Proc. Nat.
Acad. Sci. 86: 587-591, 1989.

113. Soutschek, J.; Akinc, A.; Bramlage, B.; Charisse, K.; Constien,
R.; Donoghue, M.; Elbashir, S.; Geick, A.; Hadwiger, P.; Harborth,
J.; John, M.; Kesavan, V.; and 13 others: Therapeutic silencing
of an endogenous gene by systemic administration of modified siRNAs. Nature 432:
173-178, 2004.

114. Steinberg, D.; Grundy, S. M.; Mok, H. Y. I.; Turner, J. D.; Weinstein,
D. B.; Brown, W. V.; Albers, J. J.: Metabolic studies in an unusual
case of asymptomatic familial hypobetalipoproteinemia with hypoalphalipoproteinemia
and fasting chylomicronemia. J. Clin. Invest. 64: 292-301, 1979.

115. Takashima, Y.; Kodama, T.; Iida, H.; Kawamura, M.; Aburatani,
H.; Itakura, H.; Akanuma, Y.; Takaku, F.; Kawade, M.: Normotriglyceridemic
abetalipoproteinemia in infancy: an isolated apolipoprotein B-100
deficiency. Pediatrics 75: 541-546, 1985.

116. Talmud, P.; King-Underwood, L.; Krul, E.; Schonfeld, G.; Humphries,
S.: The molecular basis of truncated forms of apolipoprotein B in
a kindred with compound heterozygous hypobetalipoproteinemia. J.
Lipid Res. 30: 1773-1779, 1989.

117. Talmud, P. J.; Converse, C.; Krul, E.; Huq, L.; McIlwaine, G.
G.; Series, J. J.; Boyd, P.; Schonfeld, G.; Dunning, A.; Humphries,
S.: A novel truncated apolipoprotein B (apo B55) in a patient with
familial hypobetalipoproteinemia and atypical retinitis pigmentosa. Clin.
Genet. 42: 62-70, 1992.

118. Talmud, P. J.; Lloyd, J. K.; Muller, D. P. R.; Collins, D. R.;
Scott, J.; Humphries, S.: Genetic evidence from two families that
the apolipoprotein B gene is not involved in abetalipoproteinemia. J.
Clin. Invest. 82: 1803-1806, 1988.

119. Tamir, I.; Levtow, O.; Lotan, D.; Legum, C.; Heldenberg, D.;
Werbin, B.: Further observations on familial hypobetalipoproteinemia. Clin.
Genet. 9: 149-155, 1976.

120. Teslovich, T. M.; Musunuru, K.; Smith, A. V.; Edmondson, A. C.;
Stylianou, I. M.; Koseki, M.; Pirruccello, J. P.; Ripatti, S.; Chasman,
D. I.; Willer, C. J.; Johansen, C. T.; Fouchier, S. W.; and 197 others
: Biological, clinical and population relevance of 95 loci for blood
lipids. Nature 466: 707-713, 2010.

121. Tybjaerg-Hansen, A.; Humphries, S. E.: Familial defective apolipoprotein
B-100: a single mutation that causes hypercholesterolemia and premature
coronary artery disease. Atherosclerosis 96: 91-107, 1992.

122. Tybjaerg-Hansen, A.; Steffensen, R.; Meinertz, H.; Schnohr, P.;
Nordestgaard, B. G.: Association of mutations in the apolipoprotein
B gene with hypercholesterolemia and the risk of ischemic heart disease. New
Eng. J. Med. 338: 1577-1584, 1998.

123. Vega, G. L.; Grundy, S. M.: In vivo evidence for reduced binding
of low density lipoproteins to receptors as a cause of primary moderate
hypercholesterolemia. J. Clin. Invest. 78: 1410-1414, 1986.

124. Visvikis, S.; Chan, L.; Siest, G.; Drouin, P.; Boerwinkle, E.
: An insertion deletion polymorphism in the signal peptide of the
human apolipoprotein B gene. Hum. Genet. 84: 373-375, 1990.

125. Weisgraber, K. H.; Innerarity, T. L.; Newhouse, Y. M.; Young,
S. G.; Arnold, K. S.; Krauss, R. M.; Vega, G. L.; Grundy, S. M.; Mahley,
R. W.: Familial defective apolipoprotein B-100: enhanced binding
of monoclonal antibody MB47 to abnormal low density lipoproteins. Proc.
Nat. Acad. Sci. 85: 9758-9762, 1988.

126. Welty, F. K.; Hubl, S. T.; Pierotti, V. R.; Young, S. G.: A
truncated species of apolipoprotein B (B67) in a kindred with familial
hypobetalipoproteinemia. J. Clin. Invest. 87: 1748-1754, 1991.

127. Xu, C.; Nanjee, N.; Tikkanen, M. J.; Huttunen, J. K.; Pietinen,
P.; Butler, R.; Angelico, F.; Del Ben, M.; Mazzarella, B.; Antonio,
R.; Miller, N. G.; Humphries, S.; Talmud, P. J.: Apolipoprotein B
amino acid 3611 substitution from arginine to glutamine creates the
Ag (h/i) epitope: the polymorphism is not associated with differences
in serum cholesterol and apolipoprotein B levels. Hum. Genet. 82:
322-326, 1989.

128. Yang, C.-Y.; Chen, S.-H.; Gianturco, S. H.; Bradley, W. A.; Sparrow,
J. T.; Tanimura, M.; Li, W.-H.; Sparrow, D. A.; DeLoof, H.; Rosseneu,
M.; Lee, F.-S.; Gu, Z.-W.; Gotto, A. M., Jr.; Chan, L.: Sequence,
structure, receptor-binding domains and internal repeats of human
apolipoprotein B-100. Nature 323: 738-742, 1986.

129. Young, S. G.; Bertics, S. J.; Curtiss, L. K.; Casal, D. C.; Witztum,
J. L.: Monoclonal antibody MB19 detects genetic polymorphism in human
apolipoprotein B. Proc. Nat. Acad. Sci. 83: 1101-1105, 1986.

130. Young, S. G.; Bertics, S. J.; Curtiss, L. K.; Dubois, B. W.;
Witztum, J. L.: Genetic analysis of a kindred with familial hypobetalipoproteinemia:
evidence for two separate gene defects: one associated with an abnormal
apolipoprotein B species, apolipoprotein B-37; and a second associated
with low plasma concentrations of apolipoprotein B-100. J. Clin.
Invest. 79: 1842-1851, 1987.

131. Young, S. G.; Bertics, S. J.; Curtiss, L. K.; Witztum, J. L.
: Characterization of an abnormal species of apolipoprotein B, apolipoprotein
B-37, associated with familial hypobetalipoproteinemia. J. Clin.
Invest. 79: 1831-1841, 1987.

132. Young, S. G.; Bertics, S. J.; Scott, T. M.; Dubois, B. W.; Curtiss,
L. K.; Witztum, J. L.: Parallel expression of the MB19 genetic polymorphism
in apoprotein B-100 and apoprotein B-48: evidence that both apoproteins
are products of the same gene. J. Biol. Chem. 261: 2995-2998, 1986.

133. Young, S. G.; Hubl, S. T.; Chappell, D. A.; Smith, R. S.; Claiborne,
F.; Snyder, S. M.; Terdiman, J. F.: Familial hypobetalipoproteinemia
associated with a mutant species of apolipoprotein B (B-46). New
Eng. J. Med. 320: 1604-1610, 1989.

134. Young, S. G.; Hubl, S. T.; Smith, R. S.; Snyder, S. M.; Terdiman,
J. F.: Familial hypobetalipoproteinemia caused by a mutation in the
apolipoprotein B gene that results in a truncated species of apolipoprotein
B (B-31): a unique mutation that helps to define the portion of the
apolipoprotein B molecule required for the formation of buoyant, triglyceride-rich
lipoproteins. J. Clin. Invest. 85: 933-942, 1990.

135. Young, S. G.; Northey, S. T.; McCarthy, B. J.: Low plasma cholesterol
levels caused by a short deletion in the apolipoprotein B gene. Science 241:
591-593, 1988.

136. Yue, P.; Yuan, B.; Gerhard, D. S.; Neuman, R. J.; Isley, W. L.;
Harris, W. S.; Schonfeld, G.: Novel mutations of APOB cause ApoB
truncations undetectable in plasma and familial hypobetalipoproteinemia. Hum.
Mutat. 20: 110-116, 2002. Note: Erratum: Hum. Mutat. 20: 402 only,
2002.

*FIELD* CN
Marla J. F. O'Neill - updated: 10/15/2013
Marla J. F. O'Neill - updated: 10/24/2011
Marla J. F. O'Neill - updated: 4/21/2011
Ada Hamosh - updated: 9/27/2010
Marla J. F. O'Neill - updated: 5/7/2009
Ada Hamosh - updated: 4/1/2008
John A. Phillips, III - updated: 3/21/2008
Ada Hamosh - updated: 6/27/2007
Marla J. F. O'Neill - updated: 6/7/2007
John A. Phillips, III - updated: 5/11/2007
Cassandra L. Kniffin - updated: 1/5/2006
Jane Kelly - updated: 6/14/2004
Natalie E. Krasikov - updated: 3/2/2004
Victor A. McKusick - updated: 2/9/2004
Victor A. McKusick - updated: 8/20/2002
Michael B. Petersen - updated: 8/5/2002
Michael J. Wright - updated: 7/29/2002
Ada Hamosh - updated: 7/10/2002
Victor A. McKusick - updated: 5/10/2002
Victor A. McKusick - updated: 4/12/2001
Victor A. McKusick - updated: 3/15/2001
Victor A. McKusick - updated: 7/30/1998
Victor A. McKusick - updated: 5/18/1998
Victor A. McKusick - updated: 4/13/1998
Victor A. McKusick - updated: 10/13/1997
Victor A. McKusick - updated: 5/16/1997

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
carol: 12/20/2013
mcolton: 12/20/2013
carol: 12/9/2013
carol: 11/27/2013
carol: 10/15/2013
carol: 4/12/2013
terry: 7/6/2012
carol: 5/1/2012
carol: 10/24/2011
terry: 10/24/2011
terry: 10/13/2011
joanna: 10/5/2011
terry: 6/17/2011
wwang: 4/21/2011
alopez: 9/27/2010
terry: 6/3/2009
wwang: 5/11/2009
terry: 5/7/2009
terry: 2/3/2009
terry: 1/7/2009
wwang: 5/21/2008
terry: 5/19/2008
carol: 4/14/2008
carol: 4/2/2008
carol: 4/1/2008
carol: 3/21/2008
alopez: 7/5/2007
terry: 6/27/2007
wwang: 6/13/2007
terry: 6/7/2007
alopez: 5/11/2007
wwang: 9/21/2006
wwang: 1/12/2006
ckniffin: 1/5/2006
terry: 5/17/2005
terry: 4/18/2005
alopez: 6/14/2004
carol: 3/17/2004
carol: 3/2/2004
cwells: 2/18/2004
terry: 2/9/2004
alopez: 5/16/2003
mgross: 10/25/2002
tkritzer: 8/26/2002
tkritzer: 8/23/2002
terry: 8/20/2002
tkritzer: 8/7/2002
tkritzer: 8/5/2002
alopez: 7/31/2002
terry: 7/29/2002
alopez: 7/11/2002
terry: 7/10/2002
ckniffin: 6/5/2002
alopez: 5/28/2002
terry: 5/10/2002
mcapotos: 4/24/2001
mcapotos: 4/18/2001
terry: 4/12/2001
carol: 3/29/2001
mcapotos: 3/26/2001
mcapotos: 3/22/2001
terry: 3/15/2001
carol: 2/13/2001
mgross: 5/26/2000
alopez: 7/31/1998
terry: 7/30/1998
terry: 5/29/1998
carol: 5/18/1998
terry: 5/18/1998
alopez: 5/14/1998
alopez: 5/4/1998
carol: 4/13/1998
terry: 3/30/1998
alopez: 3/23/1998
terry: 3/19/1998
terry: 10/13/1997
alopez: 9/5/1997
alopez: 7/10/1997
alopez: 5/19/1997
terry: 5/16/1997
terry: 2/6/1997
jamie: 12/6/1996
terry: 12/4/1996
mark: 11/22/1996
terry: 11/7/1996
mark: 7/22/1996
terry: 6/11/1996
terry: 6/7/1996
terry: 5/30/1996
mark: 2/2/1996
terry: 1/26/1996
mark: 10/12/1995
terry: 7/18/1994
jason: 7/5/1994
davew: 6/8/1994
warfield: 4/7/1994
pfoster: 3/25/1994

MIM 144010
*RECORD*
*FIELD* NO
144010
*FIELD* TI
#144010 HYPERCHOLESTEROLEMIA, AUTOSOMAL DOMINANT, TYPE B
;;APOLIPOPROTEIN B-100, FAMILIAL LIGAND-DEFECTIVE;;
read moreHYPERCHOLESTEROLEMIA, FAMILIAL, DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN
B;;
APOLIPOPROTEIN B-100, FAMILIAL DEFECTIVE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
autosomal dominant type B hypercholesterolemia is caused by heterozygous
mutation in the APOB gene (107730) on chromosome 2p24.

CLINICAL FEATURES

Higgins et al. (1975) described father and daughter with
hypercholesterolemia which appeared to be due to an abnormality in LDL
such that it did not interact properly with the receptor. The proband's
leukocytes showed normal suppression of HMG CoA reductase activity when
exposed to lipoprotein from sources other than the 2 patients. (Perhaps
a letter designation can be used for the several forms of familial
hypercholesterolemia. Roman numbers run the risk of confusion with the
Fredrickson types of hyperlipoproteinemia.) The Ag system of lipoprotein
types (see 107730) represents variation in the apoprotein of LDL and
each LDL molecule may contain 2 identical protein subunits. Thus, the
locus of this mutation might be the Ag locus (if the abnormal binding is
due to a change in the protein of LDL).

Vega and Grundy (1986) showed that some patients with
hypercholesterolemia have reduced clearance of LDL not because of
decreased activity of LDL receptors but because of a defect in the
structure (or composition) of LDL that reduces its affinity for
receptors. In 5 of 15 patients, turnover rates indicated that clearance
of autologous LDL was significantly lower than for homologous normal
LDL. In these 5 patients, autologous LDL appeared to be a poor ligand
for LDL receptors. The authors did not carry the investigations far
enough to determine whether abnormality in the primary structure of
apoB100 accounted for the poor binding to receptors.

Innerarity et al. (1987) found that moderate hypercholesterolemia could
be attributed to defective receptor binding of a genetically altered
apoB100 to the LDL receptor; they designated the disorder 'familial
defective apolipoprotein B100.' The proband of the family studied by
Innerarity et al. (1987) was described earlier by Vega and Grundy
(1986). A finding of the same abnormality in several of the proband's
first-degree relatives indicated the inherited nature of the defect.

Weisgraber et al. (1988) found an antibody with an isotope between
residues 3350 and 3506 of apoB that distinguished abnormal LDL from
normal LDL in this disorder; the antibody MB47 bound with a higher
affinity to abnormal LDL. Thus, an assay was provided for screening
large populations for this disorder.

Goldstein (1987) stated that an abnormality in LDL was not confirmed in
his or in a second laboratory. The putatively abnormal LDL tested normal
in all of their culture systems and also tested normal when injected
into animals. Myant et al. (1976) found that the putatively abnormal LDL
behaved in a normal fashion in various in vivo and in vitro assays.
Goldstein (1987) stated further that although no documented cases of
hypercholesterolemia due to mutations in the apoB gene were known, he
'would not be surprised if such cases were discovered any time--now that
cDNA probes for the apoB of LDL are widely available.' The prophecy was
fulfilled by the demonstration of familial hypercholesterolemia due to
defective apoB-100.

Illingworth et al. (1992) found that LDL cholesterol was reduced after
administration of lovastatin in 12 hypercholesterolemic patients from 10
unrelated families with familial defective apoB100.

Hansen et al. (1997) attempted to identify determinants of phenotypic
variation in patients heterozygous for familial defective apolipoprotein
B in 205 patients: 73 from Germany, 87 from the Netherlands, and 45 from
Denmark. In addition, they attempted to assess whether the clinical
phenotype of familial defective apoB differs from that of familial
hypercholesterolemia. Besides age, sex, and geographic origin, variation
in the LDLR gene was found to be the most powerful determinant of
variation in total cholesterol and LDL cholesterol levels. Polymorphic
variation in the LDLR gene was associated with total cholesterol and LDL
variation in women. The expected association of APOE genotypes with
cholesterol concentrations was also seen. With regard to clinical
expression, familial defective APOB patients had lower total cholesterol
and LDL cholesterol levels and a lower prevalence of cardiovascular
disease than did 101 Danish patients with familial hypercholesterolemia.

MOLECULAR GENETICS

Goldstein and Brown (1974) showed that the classic form of familial
hypercholesterolemia (143890) results from defects in the cell surface
receptor that removes LDL particles from plasma (LDLR; 606945).
Innerarity et al. (1987) demonstrated the genetic heterogeneity of
autosomal dominant hypercholesterolemia by reporting
hypercholesterolemic patients with normal LDLR activity and defective
apolipoprotein B-100 (APOB; 107730) that displayed low affinity for its
receptor. This novel form of the disorder was called familial
ligand-defective apolipoprotein B-100, or type B familial
hypercholesterolemia, because mutations were identified in the APOB gene
(e.g., R3500Q; 107730.0009). Classic FH and the ligand-defective form
(type B) map to chromosomes 19 and 2, respectively.

In a 46-year-old woman of Celtic and Native American ancestry with
primary hypercholesterolemia and pronounced peripheral vascular disease,
Pullinger et al. (1995) identified heterozygosity for a missense
mutation in the APOB gene (R3531C; 107730.0017). Screening of 1,560
individuals revealed an unrelated man of Italian ancestry with coronary
heart disease and elevated triglyceride and LDL cholesterol levels who
carried the same R3531C mutation; the mutation was also detected in 8
other members of the families of the 2 patients. LDL from
R3531C-positive individuals had an affinity for the LDL receptor that
was 63% of that of control LDL, compared to 91% for unaffected family
members and 36% for patients heterozygous for the R3500Q mutation
(107730.0009).

*FIELD* RF
1. Goldstein, J. L.: Personal Communication. Dallas, Tex. 3/9/1987.

2. Goldstein, J. L.; Brown, M. S.: Binding and degradation of low
density lipoproteins by cultured human fibroblasts: comparison of
cells from a normal subject and from a patient with homozygous familial
hypercholesterolemia. J. Biol. Chem. 249: 5153-5162, 1974.

3. Hansen, P. S.; Defesche, J. C.; Kastelein, J. J. P.; Gerdes, L.
U.; Fraza, L.; Gerdes, C.; Tato, F.; Jensen, H. K.; Jensen, L. G.;
Klausen, I. C.; Faergeman, O.; Schuster, H.: Phenotypic variation
in patients heterozygous for familial defective apolipoprotein B (FDB)
in three European countries. Arteriosclerosis Thromb. Vasc. Biol. 17:
741-747, 1997.

4. Higgins, M. J. P.; Lecamwasam, D. S.; Galton, D. J.: A new type
of familial hypercholesterolemia. Lancet 306: 737-740, 1975. Note:
Originally Volume II.

5. Illingworth, D. R.; Vakar, F.; Mahley, R. W.; Weisgraber, K. H.
: Hypocholesterolaemic effects of lovastatin in familial defective
apolipoprotein B-100. Lancet 339: 598-600, 1992.

6. Innerarity, T. L.; Weisgraber, K. H.; Arnold, K. S.; Mahley, R.
W.; Krauss, R. M.; Vega, G. L.; Grundy, S. M.: Familial defective
apolipoprotein B-100: low density lipoproteins with abnormal receptor
binding. Proc. Nat. Acad. Sci. 84: 6919-6923, 1987.

7. Myant, N. B.; Reichl, D.; Thompson, G. R.; Higgins, M. J.; Galton,
D. J.: The metabolism in vivo and in vitro of plasma low-density
lipoprotein from a subject with inherited hypercholesterolaemia. Clin.
Sci. Molec. Med. 51: 463-465, 1976.

8. Pullinger, C. R.; Hennessy, L. K.; Chatterton, J. E.; Liu, W.;
Love, J. A.; Mendel, C. M.; Frost, P. H.; Malloy, M. J.; Schumaker,
V. N.; Kane, J. P.: Familial ligand-defective apolipoprotein B: identification
of a new mutation that decreases LDL receptor binding affinity. J.
Clin. Invest. 95: 1225-1234, 1995.

9. Vega, G. L.; Grundy, S. M.: In vivo evidence for reduced binding
of low density lipoproteins to receptors as a cause of primary moderate
hypercholesterolemia. J. Clin. Invest. 78: 1410-1414, 1986.

10. Weisgraber, K. H.; Innerarity, T. L.; Newhouse, Y. M.; Young,
S. G.; Arnold, K. S.; Krauss, R. M.; Vega, G. L.; Grundy, S. M.; Mahley,
R. W.: Familial defective apolipoprotein B-100: enhanced binding
of monoclonal antibody MB47 to abnormal low density lipoproteins. Proc.
Nat. Acad. Sci. 85: 9758-9762, 1988.

*FIELD* CS

Skin:
Tendinous xanthomas;
Planar xanthomas in homozygotes

Eyes:
Corneal arcus;
Xanthelasma

Cardiac:
Coronary artery disease

Lab:
Hypercholesterolemia;
Abnormal LDL

Inheritance:
Autosomal dominant

*FIELD* CN
Marla J. F. O'Neill - updated: 12/20/2013
Victor A. McKusick - updated: 7/8/1997

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

*FIELD* ED
carol: 12/20/2013
mcolton: 12/19/2013
terry: 1/21/2009
wwang: 5/21/2008
terry: 5/19/2008
wwang: 11/20/2007
alopez: 5/16/2003
alopez: 5/14/2003
alopez: 7/30/1997
mark: 7/8/1997
alopez: 6/4/1997
mark: 4/10/1995
mimadm: 9/24/1994
terry: 7/15/1994
warfield: 4/12/1994
supermim: 3/16/1992
supermim: 3/20/1990

RBCC Red Blood Cell Collection

Full text data of APOB