RBCC Red Blood Cell Collection

LPA [Confidence: low (only semi-automatic identification from reviews)]
Apolipoprotein(a); Apo(a); Lp(a); 3.4.21.-; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P08519
ID APOA_HUMAN Reviewed; 4548 AA.
AC P08519; Q5VTD7; Q9UD88;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-AUG-1988, sequence version 1.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Apolipoprotein(a);
DE Short=Apo(a);
DE Short=Lp(a);
DE EC=3.4.21.-;
DE Flags: Precursor;
GN Name=LPA;
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 POLYMORPHISM.
RX PubMed=3670400; DOI=10.1038/330132a0;
RA McLean J.W., Tomlison J.E., Kuang W.-J., Eaton D.L., Chen E.Y.,
RA Fless G.M., Scanu A.M., Lawn R.M.;
RT "cDNA sequence of human apolipoprotein(a) is homologous to
RT plasminogen.";
RL Nature 330:132-137(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4184-4208.
RC TISSUE=Lymphocyte;
RX PubMed=7848387; DOI=10.1016/0925-4439(93)90130-S;
RA Pfaffinger D., Mc Lean J., Scanu A.M.;
RT "Amplification of human APO(a) kringle 4-37 from blood lymphocyte
RT DNA.";
RL Biochim. Biophys. Acta 1225:107-109(1993).
RN [4]
RP FUNCTION AS A SERINE PROTEASE.
RX PubMed=2531657;
RA Salonen E.-M., Jauhiainen M., Zardi L., Vaheri A., Ehnholm C.;
RT "Lipoprotein(a) binds to fibronectin and has serine proteinase
RT activity capable of cleaving it.";
RL EMBO J. 8:4035-4040(1989).
RN [5]
RP REVIEW.
RX PubMed=2530631; DOI=10.1126/science.2530631;
RA Utermann G.;
RT "The mysteries of lipoprotein(a).";
RL Science 246:904-910(1989).
RN [6]
RP STRUCTURE OF N-LINKED AND O-LINKED CARBOHYDRATES, AND MASS
RP SPECTROMETRY.
RX PubMed=11294842; DOI=10.1074/jbc.M102150200;
RA Garner B., Merry A.H., Royle L., Harvey D.J., Rudd P.M., Thillet J.;
RT "Structural elucidation of the N- and O-glycans of human
RT apolipoprotein(a): role of o-glycans in conferring protease
RT resistance.";
RL J. Biol. Chem. 276:22200-22208(2001).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 4121-4208.
RX PubMed=8642595; DOI=10.1006/jmbi.1996.0122;
RA Mikol V., Lograsso P.V., Boettcher B.R.;
RT "Crystal structures of apolipoprotein(a) kringle IV37 free and
RT complexed with 6-aminohexanoic acid and with p-aminomethylbenzoic
RT acid: existence of novel and expected binding modes.";
RL J. Mol. Biol. 256:751-761(1996).
RN [8]
RP VARIANT ARG-4193.
RX PubMed=7918682; DOI=10.1016/0925-4439(94)90104-X;
RA Scanu A.M., Pfaffinger D., Lee J.C., Hinman J.;
RT "A single point mutation (Trp72-->Arg) in human apo(a) kringle 4-37
RT associated with a lysine binding defect in Lp(a).";
RL Biochim. Biophys. Acta 1227:41-45(1994).
CC -!- FUNCTION: Apo(a) is the main constituent of lipoprotein(a)
CC (Lp(a)). It has serine proteinase activity and is able of
CC autoproteolysis. Inhibits tissue-type plasminogen activator 1.
CC Lp(a) may be a ligand for megalin/Gp 330.
CC -!- SUBUNIT: Disulfide-linked to apo-B100. Binds to fibronectin and
CC decorin.
CC -!- PTM: N- and O-glycosylated. The N-glycans are complex biantennary
CC structures present in either a mono- or disialylated state. The O-
CC glycans are mostly (80%) represented by the monosialylated core
CC type I structure, NeuNAcalpha2-3Galbeta1-3GalNAc, with smaller
CC amounts of disialylated and non-sialylated O-glycans also
CC detected.
CC -!- POLYMORPHISM: The reference genome sequence encodes a variant that
CC contains 16 Kringle domains and that lack residues 533 to 3040.
CC Depending on the individual, the encoded protein contains 2-43
CC copies of kringle-type domains. The allele represented here
CC contains 38 copies of the kringle-type repeats.
CC -!- MISCELLANEOUS: Apo(a) is known to be proteolytically cleaved,
CC leading to the formation of the so-called mini-Lp(a). Apo(a)
CC fragments accumulate in atherosclerotic lesions, where they may
CC promote thrombogenesis. O-glycosylation may limit the extent of
CC proteolytic fragmentation. Homology with plasminogen kringles IV
CC and V is thought to underlie the atherogenicity of the protein,
CC because the fragments are competing with plasminogen for
CC fibrin(ogen) binding.
CC -!- SIMILARITY: Belongs to the peptidase S1 family. Plasminogen
CC subfamily.
CC -!- SIMILARITY: Contains 38 kringle domains.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
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;=APOA";
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DR EMBL; X06290; CAA29618.1; -; mRNA.
DR EMBL; AL109933; CAI22905.1; -; Genomic_DNA.
DR EMBL; AL596089; CAI22905.1; JOINED; Genomic_DNA.
DR EMBL; AL596089; CAH73590.1; -; Genomic_DNA.
DR EMBL; AL109933; CAH73590.1; JOINED; Genomic_DNA.
DR PIR; S00657; S00657.
DR UniGene; Hs.520120; -.
DR PDB; 1I71; X-ray; 1.45 A; A=3781-3863.
DR PDB; 1JFN; NMR; -; A=3665-3770.
DR PDB; 1KIV; X-ray; 2.10 A; A=4124-4201.
DR PDB; 2FEB; NMR; -; A=3885-3980.
DR PDB; 3KIV; X-ray; 1.80 A; A=4123-4201.
DR PDB; 4KIV; X-ray; 2.20 A; A=4123-4201.
DR PDBsum; 1I71; -.
DR PDBsum; 1JFN; -.
DR PDBsum; 1KIV; -.
DR PDBsum; 2FEB; -.
DR PDBsum; 3KIV; -.
DR PDBsum; 4KIV; -.
DR ProteinModelPortal; P08519; -.
DR STRING; 9606.ENSP00000321334; -.
DR DrugBank; DB00513; Aminocaproic Acid.
DR MEROPS; S01.999; -.
DR PhosphoSite; P08519; -.
DR UniCarbKB; P08519; -.
DR DMDM; 114062; -.
DR PaxDb; P08519; -.
DR PRIDE; P08519; -.
DR Ensembl; ENST00000316300; ENSP00000321334; ENSG00000198670.
DR Ensembl; ENST00000447678; ENSP00000395608; ENSG00000198670.
DR GeneCards; GC06M160952; -.
DR H-InvDB; HIX0057735; -.
DR HGNC; HGNC:6667; LPA.
DR HPA; CAB000668; -.
DR HPA; CAB016072; -.
DR HPA; CAB016678; -.
DR MIM; 152200; gene+phenotype.
DR neXtProt; NX_P08519; -.
DR PharmGKB; PA30432; -.
DR eggNOG; COG5640; -.
DR HOGENOM; HOG000170962; -.
DR HOVERGEN; HBG004270; -.
DR InParanoid; P08519; -.
DR OrthoDB; EOG75B84T; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; P08519; -.
DR GenomeRNAi; 4018; -.
DR NextBio; 15766; -.
DR PRO; PR:P08519; -.
DR ArrayExpress; P08519; -.
DR Bgee; P08519; -.
DR CleanEx; HS_LPA; -.
DR Genevestigator; P08519; -.
DR GO; GO:0034358; C:plasma lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc.
DR GO; GO:0008201; F:heparin binding; NAS:BHF-UCL.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:BHF-UCL.
DR GO; GO:0008015; P:blood circulation; TAS:ProtInc.
DR GO; GO:0006629; P:lipid metabolic process; NAS:ProtInc.
DR GO; GO:0006869; P:lipid transport; IEA:UniProtKB-KW.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0006898; P:receptor-mediated endocytosis; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 2.40.20.10; -; 38.
DR InterPro; IPR000001; Kringle.
DR InterPro; IPR013806; Kringle-like.
DR InterPro; IPR018056; Kringle_CS.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR018114; Peptidase_S1_AS.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00051; Kringle; 38.
DR Pfam; PF00089; Trypsin; 1.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR SMART; SM00130; KR; 38.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF57440; SSF57440; 38.
DR PROSITE; PS00021; KRINGLE_1; 38.
DR PROSITE; PS50070; KRINGLE_2; 38.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Atherosclerosis; Complete proteome; Disulfide bond;
KW Glycoprotein; Hydrolase; Kringle; Lipid transport; Polymorphism;
KW Protease; Reference proteome; Repeat; Serine protease; Signal;
KW Transport.
FT SIGNAL 1 19
FT CHAIN 20 4548 Apolipoprotein(a).
FT /FTId=PRO_0000028097.
FT DOMAIN 20 130 Kringle 1.
FT DOMAIN 131 244 Kringle 2.
FT DOMAIN 245 358 Kringle 3.
FT DOMAIN 359 472 Kringle 4.
FT DOMAIN 473 586 Kringle 5.
FT DOMAIN 587 700 Kringle 6.
FT DOMAIN 701 814 Kringle 7.
FT DOMAIN 815 928 Kringle 8.
FT DOMAIN 929 1042 Kringle 9.
FT DOMAIN 1043 1156 Kringle 10.
FT DOMAIN 1157 1270 Kringle 11.
FT DOMAIN 1271 1384 Kringle 12.
FT DOMAIN 1385 1498 Kringle 13.
FT DOMAIN 1499 1612 Kringle 14.
FT DOMAIN 1613 1726 Kringle 15.
FT DOMAIN 1727 1840 Kringle 16.
FT DOMAIN 1841 1954 Kringle 17.
FT DOMAIN 1955 2068 Kringle 18.
FT DOMAIN 2069 2182 Kringle 19.
FT DOMAIN 2183 2296 Kringle 20.
FT DOMAIN 2297 2410 Kringle 21.
FT DOMAIN 2411 2524 Kringle 22.
FT DOMAIN 2525 2638 Kringle 23.
FT DOMAIN 2639 2752 Kringle 24.
FT DOMAIN 2753 2866 Kringle 25.
FT DOMAIN 2867 2980 Kringle 26.
FT DOMAIN 2981 3094 Kringle 27.
FT DOMAIN 3095 3208 Kringle 28.
FT DOMAIN 3209 3322 Kringle 29.
FT DOMAIN 3323 3436 Kringle 30.
FT DOMAIN 3437 3550 Kringle 31.
FT DOMAIN 3551 3664 Kringle 32.
FT DOMAIN 3665 3770 Kringle 33.
FT DOMAIN 3771 3884 Kringle 34.
FT DOMAIN 3885 3998 Kringle 35.
FT DOMAIN 3999 4112 Kringle 36.
FT DOMAIN 4113 4226 Kringle 37.
FT DOMAIN 4227 4327 Kringle 38.
FT DOMAIN 4328 4546 Peptidase S1.
FT ACT_SITE 4369 4369 Charge relay system.
FT ACT_SITE 4412 4412 Charge relay system.
FT ACT_SITE 4498 4498 Charge relay system.
FT CARBOHYD 61 61 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 101 101 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 215 215 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 329 329 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 443 443 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 557 557 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 671 671 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 785 785 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 899 899 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1013 1013 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1127 1127 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1241 1241 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1355 1355 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1469 1469 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1583 1583 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1697 1697 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1811 1811 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1925 1925 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2039 2039 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2153 2153 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2267 2267 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2381 2381 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2495 2495 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2609 2609 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2723 2723 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2837 2837 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2951 2951 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3065 3065 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3179 3179 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3293 3293 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3407 3407 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3521 3521 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3635 3635 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3749 3749 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3855 3855 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3889 3889 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3969 3969 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 4083 4083 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 4197 4197 N-linked (GlcNAc...) (Potential).
FT DISULFID 28 105 By similarity.
FT DISULFID 49 88 By similarity.
FT DISULFID 77 100 By similarity.
FT DISULFID 142 219 By similarity.
FT DISULFID 163 202 By similarity.
FT DISULFID 191 214 By similarity.
FT DISULFID 256 333 By similarity.
FT DISULFID 277 316 By similarity.
FT DISULFID 305 328 By similarity.
FT DISULFID 370 447 By similarity.
FT DISULFID 391 430 By similarity.
FT DISULFID 419 442 By similarity.
FT DISULFID 484 561 By similarity.
FT DISULFID 505 544 By similarity.
FT DISULFID 533 556 By similarity.
FT DISULFID 598 675 By similarity.
FT DISULFID 619 658 By similarity.
FT DISULFID 647 670 By similarity.
FT DISULFID 712 789 By similarity.
FT DISULFID 733 772 By similarity.
FT DISULFID 761 784 By similarity.
FT DISULFID 826 903 By similarity.
FT DISULFID 847 886 By similarity.
FT DISULFID 875 898 By similarity.
FT DISULFID 940 1017 By similarity.
FT DISULFID 961 1000 By similarity.
FT DISULFID 989 1012 By similarity.
FT DISULFID 1054 1131 By similarity.
FT DISULFID 1075 1114 By similarity.
FT DISULFID 1103 1126 By similarity.
FT DISULFID 1168 1245 By similarity.
FT DISULFID 1189 1228 By similarity.
FT DISULFID 1217 1240 By similarity.
FT DISULFID 1282 1359 By similarity.
FT DISULFID 1303 1342 By similarity.
FT DISULFID 1331 1354 By similarity.
FT DISULFID 1396 1473 By similarity.
FT DISULFID 1417 1456 By similarity.
FT DISULFID 1445 1468 By similarity.
FT DISULFID 1510 1587 By similarity.
FT DISULFID 1531 1570 By similarity.
FT DISULFID 1559 1582 By similarity.
FT DISULFID 1624 1701 By similarity.
FT DISULFID 1645 1684 By similarity.
FT DISULFID 1673 1696 By similarity.
FT DISULFID 1738 1815 By similarity.
FT DISULFID 1759 1798 By similarity.
FT DISULFID 1787 1810 By similarity.
FT DISULFID 1852 1929 By similarity.
FT DISULFID 1873 1912 By similarity.
FT DISULFID 1901 1924 By similarity.
FT DISULFID 1966 2043 By similarity.
FT DISULFID 1987 2026 By similarity.
FT DISULFID 2015 2038 By similarity.
FT DISULFID 2080 2157 By similarity.
FT DISULFID 2101 2140 By similarity.
FT DISULFID 2129 2152 By similarity.
FT DISULFID 2194 2271 By similarity.
FT DISULFID 2215 2254 By similarity.
FT DISULFID 2243 2266 By similarity.
FT DISULFID 2308 2385 By similarity.
FT DISULFID 2329 2368 By similarity.
FT DISULFID 2357 2380 By similarity.
FT DISULFID 2422 2499 By similarity.
FT DISULFID 2443 2482 By similarity.
FT DISULFID 2471 2494 By similarity.
FT DISULFID 2536 2613 By similarity.
FT DISULFID 2557 2596 By similarity.
FT DISULFID 2585 2608 By similarity.
FT DISULFID 2650 2727 By similarity.
FT DISULFID 2671 2710 By similarity.
FT DISULFID 2699 2722 By similarity.
FT DISULFID 2764 2841 By similarity.
FT DISULFID 2785 2824 By similarity.
FT DISULFID 2813 2836 By similarity.
FT DISULFID 2878 2955 By similarity.
FT DISULFID 2899 2938 By similarity.
FT DISULFID 2927 2950 By similarity.
FT DISULFID 2992 3069 By similarity.
FT DISULFID 3013 3052 By similarity.
FT DISULFID 3041 3064 By similarity.
FT DISULFID 3106 3183 By similarity.
FT DISULFID 3127 3166 By similarity.
FT DISULFID 3155 3178 By similarity.
FT DISULFID 3220 3297 By similarity.
FT DISULFID 3241 3280 By similarity.
FT DISULFID 3269 3292 By similarity.
FT DISULFID 3334 3411 By similarity.
FT DISULFID 3355 3394 By similarity.
FT DISULFID 3383 3406 By similarity.
FT DISULFID 3448 3525 By similarity.
FT DISULFID 3469 3508 By similarity.
FT DISULFID 3497 3520 By similarity.
FT DISULFID 3562 3639 By similarity.
FT DISULFID 3583 3622 By similarity.
FT DISULFID 3611 3634 By similarity.
FT DISULFID 3676 3753
FT DISULFID 3697 3736
FT DISULFID 3725 3748
FT DISULFID 3782 3859
FT DISULFID 3803 3842
FT DISULFID 3831 3854
FT DISULFID 3896 3973 By similarity.
FT DISULFID 3917 3956 By similarity.
FT DISULFID 3945 3968 By similarity.
FT DISULFID 4010 4087 By similarity.
FT DISULFID 4031 4070 By similarity.
FT DISULFID 4059 4082 By similarity.
FT DISULFID 4124 4201 By similarity.
FT DISULFID 4145 4184 By similarity.
FT DISULFID 4173 4196 By similarity.
FT DISULFID 4228 4307 By similarity.
FT DISULFID 4249 4290 By similarity.
FT DISULFID 4278 4302 By similarity.
FT DISULFID 4354 4370 By similarity.
FT DISULFID 4446 4504 By similarity.
FT DISULFID 4476 4483 By similarity.
FT DISULFID 4494 4522 By similarity.
FT VARIANT 3498 3498 R -> Q (in dbSNP:rs41259144).
FT /FTId=VAR_047293.
FT VARIANT 3866 3866 L -> V (in dbSNP:rs7765803).
FT /FTId=VAR_047294.
FT VARIANT 3880 3880 L -> V (in dbSNP:rs7765781).
FT /FTId=VAR_047295.
FT VARIANT 3907 3907 T -> P (in dbSNP:rs41272110).
FT /FTId=VAR_047296.
FT VARIANT 3929 3929 R -> Q (in dbSNP:rs41272112).
FT /FTId=VAR_047297.
FT VARIANT 4106 4106 M -> T (in dbSNP:rs41264308).
FT /FTId=VAR_047298.
FT VARIANT 4187 4187 M -> T (in dbSNP:rs1801693).
FT /FTId=VAR_047299.
FT VARIANT 4193 4193 W -> R (loss of lysine-sepharose
FT binding).
FT /FTId=VAR_006633.
FT VARIANT 4330 4330 G -> A (in dbSNP:rs41265936).
FT /FTId=VAR_047300.
FT VARIANT 4399 4399 I -> M (in dbSNP:rs3798220).
FT /FTId=VAR_047301.
FT VARIANT 4524 4524 R -> C (in dbSNP:rs3124784).
FT /FTId=VAR_047302.
FT STRAND 3665 3667
FT TURN 3679 3683
FT STRAND 3704 3706
FT HELIX 3712 3714
FT TURN 3716 3718
FT STRAND 3735 3740
FT STRAND 3745 3749
FT TURN 3818 3820
FT TURN 3822 3825
FT STRAND 3834 3836
FT STRAND 3841 3846
FT STRAND 3851 3855
FT STRAND 3889 3893
FT STRAND 3912 3914
FT STRAND 3924 3926
FT STRAND 3951 3953
FT STRAND 4129 4131
FT STRAND 4152 4154
FT TURN 4160 4162
FT STRAND 4183 4187
FT STRAND 4193 4197
SQ SEQUENCE 4548 AA; 501319 MW; 96921BE96A465C5F CRC64;
MEHKEVVLLL LLFLKSAAPE QSHVVQDCYH GDGQSYRGTY STTVTGRTCQ AWSSMTPHQH
NRTTENYPNA GLIMNYCRNP DAVAAPYCYT RDPGVRWEYC NLTQCSDAEG TAVAPPTVTP
VPSLEAPSEQ APTEQRPGVQ ECYHGNGQSY RGTYSTTVTG RTCQAWSSMT PHSHSRTPEY
YPNAGLIMNY CRNPDAVAAP YCYTRDPGVR WEYCNLTQCS DAEGTAVAPP TVTPVPSLEA
PSEQAPTEQR PGVQECYHGN GQSYRGTYST TVTGRTCQAW SSMTPHSHSR TPEYYPNAGL
IMNYCRNPDA VAAPYCYTRD PGVRWEYCNL TQCSDAEGTA VAPPTVTPVP SLEAPSEQAP
TEQRPGVQEC YHGNGQSYRG TYSTTVTGRT CQAWSSMTPH SHSRTPEYYP NAGLIMNYCR
NPDAVAAPYC YTRDPGVRWE YCNLTQCSDA EGTAVAPPTV TPVPSLEAPS EQAPTEQRPG
VQECYHGNGQ SYRGTYSTTV TGRTCQAWSS MTPHSHSRTP EYYPNAGLIM NYCRNPDAVA
APYCYTRDPG VRWEYCNLTQ CSDAEGTAVA PPTVTPVPSL EAPSEQAPTE QRPGVQECYH
GNGQSYRGTY STTVTGRTCQ AWSSMTPHSH SRTPEYYPNA GLIMNYCRNP DAVAAPYCYT
RDPGVRWEYC NLTQCSDAEG TAVAPPTVTP VPSLEAPSEQ APTEQRPGVQ ECYHGNGQSY
RGTYSTTVTG RTCQAWSSMT PHSHSRTPEY YPNAGLIMNY CRNPDAVAAP YCYTRDPGVR
WEYCNLTQCS DAEGTAVAPP TVTPVPSLEA PSEQAPTEQR PGVQECYHGN GQSYRGTYST
TVTGRTCQAW SSMTPHSHSR TPEYYPNAGL IMNYCRNPDA VAAPYCYTRD PGVRWEYCNL
TQCSDAEGTA VAPPTVTPVP SLEAPSEQAP TEQRPGVQEC YHGNGQSYRG TYSTTVTGRT
CQAWSSMTPH SHSRTPEYYP NAGLIMNYCR NPDAVAAPYC YTRDPGVRWE YCNLTQCSDA
EGTAVAPPTV TPVPSLEAPS EQAPTEQRPG VQECYHGNGQ SYRGTYSTTV TGRTCQAWSS
MTPHSHSRTP EYYPNAGLIM NYCRNPDAVA APYCYTRDPG VRWEYCNLTQ CSDAEGTAVA
PPTVTPVPSL EAPSEQAPTE QRPGVQECYH GNGQSYRGTY STTVTGRTCQ AWSSMTPHSH
SRTPEYYPNA GLIMNYCRNP DAVAAPYCYT RDPGVRWEYC NLTQCSDAEG TAVAPPTVTP
VPSLEAPSEQ APTEQRPGVQ ECYHGNGQSY RGTYSTTVTG RTCQAWSSMT PHSHSRTPEY
YPNAGLIMNY CRNPDAVAAP YCYTRDPGVR WEYCNLTQCS DAEGTAVAPP TVTPVPSLEA
PSEQAPTEQR PGVQECYHGN GQSYRGTYST TVTGRTCQAW SSMTPHSHSR TPEYYPNAGL
IMNYCRNPDA VAAPYCYTRD PGVRWEYCNL TQCSDAEGTA VAPPTVTPVP SLEAPSEQAP
TEQRPGVQEC YHGNGQSYRG TYSTTVTGRT CQAWSSMTPH SHSRTPEYYP NAGLIMNYCR
NPDAVAAPYC YTRDPGVRWE YCNLTQCSDA EGTAVAPPTV TPVPSLEAPS EQAPTEQRPG
VQECYHGNGQ SYRGTYSTTV TGRTCQAWSS MTPHSHSRTP EYYPNAGLIM NYCRNPDAVA
APYCYTRDPG VRWEYCNLTQ CSDAEGTAVA PPTVTPVPSL EAPSEQAPTE QRPGVQECYH
GNGQSYRGTY STTVTGRTCQ AWSSMTPHSH SRTPEYYPNA GLIMNYCRNP DAVAAPYCYT
RDPGVRWEYC NLTQCSDAEG TAVAPPTVTP VPSLEAPSEQ APTEQRPGVQ ECYHGNGQSY
RGTYSTTVTG RTCQAWSSMT PHSHSRTPEY YPNAGLIMNY CRNPDAVAAP YCYTRDPGVR
WEYCNLTQCS DAEGTAVAPP TVTPVPSLEA PSEQAPTEQR PGVQECYHGN GQSYRGTYST
TVTGRTCQAW SSMTPHSHSR TPEYYPNAGL IMNYCRNPDA VAAPYCYTRD PGVRWEYCNL
TQCSDAEGTA VAPPTVTPVP SLEAPSEQAP TEQRPGVQEC YHGNGQSYRG TYSTTVTGRT
CQAWSSMTPH SHSRTPEYYP NAGLIMNYCR NPDAVAAPYC YTRDPGVRWE YCNLTQCSDA
EGTAVAPPTV TPVPSLEAPS EQAPTEQRPG VQECYHGNGQ SYRGTYSTTV TGRTCQAWSS
MTPHSHSRTP EYYPNAGLIM NYCRNPDAVA APYCYTRDPG VRWEYCNLTQ CSDAEGTAVA
PPTVTPVPSL EAPSEQAPTE QRPGVQECYH GNGQSYRGTY STTVTGRTCQ AWSSMTPHSH
SRTPEYYPNA GLIMNYCRNP DAVAAPYCYT RDPGVRWEYC NLTQCSDAEG TAVAPPTVTP
VPSLEAPSEQ APTEQRPGVQ ECYHGNGQSY RGTYSTTVTG RTCQAWSSMT PHSHSRTPEY
YPNAGLIMNY CRNPDAVAAP YCYTRDPGVR WEYCNLTQCS DAEGTAVAPP TVTPVPSLEA
PSEQAPTEQR PGVQECYHGN GQSYRGTYST TVTGRTCQAW SSMTPHSHSR TPEYYPNAGL
IMNYCRNPDA VAAPYCYTRD PGVRWEYCNL TQCSDAEGTA VAPPTVTPVP SLEAPSEQAP
TEQRPGVQEC YHGNGQSYRG TYSTTVTGRT CQAWSSMTPH SHSRTPEYYP NAGLIMNYCR
NPDAVAAPYC YTRDPGVRWE YCNLTQCSDA EGTAVAPPTV TPVPSLEAPS EQAPTEQRPG
VQECYHGNGQ SYRGTYSTTV TGRTCQAWSS MTPHSHSRTP EYYPNAGLIM NYCRNPDAVA
APYCYTRDPG VRWEYCNLTQ CSDAEGTAVA PPTVTPVPSL EAPSEQAPTE QRPGVQECYH
GNGQSYRGTY STTVTGRTCQ AWSSMTPHSH SRTPEYYPNA GLIMNYCRNP DAVAAPYCYT
RDPGVRWEYC NLTQCSDAEG TAVAPPTVTP VPSLEAPSEQ APTEQRPGVQ ECYHGNGQSY
RGTYSTTVTG RTCQAWSSMT PHSHSRTPEY YPNAGLIMNY CRNPDAVAAP YCYTRDPGVR
WEYCNLTQCS DAEGTAVAPP TVTPVPSLEA PSEQAPTEQR PGVQECYHGN GQSYRGTYST
TVTGRTCQAW SSMTPHSHSR TPEYYPNAGL IMNYCRNPDA VAAPYCYTRD PGVRWEYCNL
TQCSDAEGTA VAPPTVTPVP SLEAPSEQAP TEQRPGVQEC YHGNGQSYRG TYSTTVTGRT
CQAWSSMTPH SHSRTPEYYP NAGLIMNYCR NPDAVAAPYC YTRDPGVRWE YCNLTQCSDA
EGTAVAPPTV TPVPSLEAPS EQAPTEQRPG VQECYHGNGQ SYRGTYSTTV TGRTCQAWSS
MTPHSHSRTP EYYPNAGLIM NYCRNPDPVA APYCYTRDPS VRWEYCNLTQ CSDAEGTAVA
PPTITPIPSL EAPSEQAPTE QRPGVQECYH GNGQSYQGTY FITVTGRTCQ AWSSMTPHSH
SRTPAYYPNA GLIKNYCRNP DPVAAPWCYT TDPSVRWEYC NLTRCSDAEW TAFVPPNVIL
APSLEAFFEQ ALTEETPGVQ DCYYHYGQSY RGTYSTTVTG RTCQAWSSMT PHQHSRTPEN
YPNAGLTRNY CRNPDAEIRP WCYTMDPSVR WEYCNLTQCL VTESSVLATL TVVPDPSTEA
SSEEAPTEQS PGVQDCYHGD GQSYRGSFST TVTGRTCQSW SSMTPHWHQR TTEYYPNGGL
TRNYCRNPDA EISPWCYTMD PNVRWEYCNL TQCPVTESSV LATSTAVSEQ APTEQSPTVQ
DCYHGDGQSY RGSFSTTVTG RTCQSWSSMT PHWHQRTTEY YPNGGLTRNY CRNPDAEIRP
WCYTMDPSVR WEYCNLTQCP VMESTLLTTP TVVPVPSTEL PSEEAPTENS TGVQDCYRGD
GQSYRGTLST TITGRTCQSW SSMTPHWHRR IPLYYPNAGL TRNYCRNPDA EIRPWCYTMD
PSVRWEYCNL TRCPVTESSV LTTPTVAPVP STEAPSEQAP PEKSPVVQDC YHGDGRSYRG
ISSTTVTGRT CQSWSSMIPH WHQRTPENYP NAGLTENYCR NPDSGKQPWC YTTDPCVRWE
YCNLTQCSET ESGVLETPTV VPVPSMEAHS EAAPTEQTPV VRQCYHGNGQ SYRGTFSTTV
TGRTCQSWSS MTPHRHQRTP ENYPNDGLTM NYCRNPDADT GPWCFTMDPS IRWEYCNLTR
CSDTEGTVVA PPTVIQVPSL GPPSEQDCMF GNGKGYRGKK ATTVTGTPCQ EWAAQEPHRH
STFIPGTNKW AGLEKNYCRN PDGDINGPWC YTMNPRKLFD YCDIPLCASS SFDCGKPQVE
PKKCPGSIVG GCVAHPHSWP WQVSLRTRFG KHFCGGTLIS PEWVLTAAHC LKKSSRPSSY
KVILGAHQEV NLESHVQEIE VSRLFLEPTQ ADIALLKLSR PAVITDKVMP ACLPSPDYMV
TARTECYITG WGETQGTFGT GLLKEAQLLV IENEVCNHYK YICAEHLARG TDSCQGDSGG
PLVCFEKDKY ILQGVTSWGL GCARPNKPGV YARVSRFVTW IEGMMRNN
//

MIM 152200
*RECORD*
*FIELD* NO
152200
*FIELD* TI
+152200 APOLIPOPROTEIN(a); LPA
LIPOPROTEIN(a), INCLUDED; Lp(a), INCLUDED;;
LIPOPROTEIN TYPES--Lp SYSTEM Lp(a) HYPERLIPOPROTEINEMIA, INCLUDED;;
read moreSINKING PRE-BETA-LIPOPROTEIN, INCLUDED; SPB, INCLUDED;;
LIPOPROTEIN(a) DEFICIENCY, CONGENITAL, INCLUDED;;
Lp(a) DEFICIENCY, CONGENITAL, INCLUDED;;
CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
Berg and Mohr (1963) discovered a new serum protein system, called Lp
(for lipoprotein), by the intravenous injection of rabbits with human
serum beta-lipoprotein isolated from 1 individual. The resulting
antibody distinguishes 2 distinct types of human beta-lipoprotein. Berg
and Mohr (1963) demonstrated regular dominant inheritance. The Lp(a)
allele has a frequency of 0.19 in Norwegians. The authors concluded that
this system is independent of the Ag system of Blumberg (which
subsequently proved to be a variation in the APOB gene; see 107730).
Berg (1967) suggested that at least 4 lipoprotein systems exist: Ag, Lp,
Ld, and Lt. Schultz and Shreffler (1972) espoused a polygenic
determination of Lp antigen, whereas Berg (1972) defended his monolocus
hypothesis. Dahlen and Berg (1976) found that over a period of time mean
fasting cholesterol and triglyceride concentrations in blood rose in
Lp(a+) persons but not in Lp(a-) persons. Berg et al. (1979) found an
association between phenotype Lp(a+) and coronary heart disease. Hewitt
et al. (1982) confirmed the correlation between the Lp(a) antigen and
the presence of a sinking pre-beta component of low density lipoprotein
fraction of serum cholesterol (Breckenridge and Maguire, 1981). Studying
a large Utah pedigree, Hasstedt et al. (1983) concluded that 'a dominant
major gene with polygenic background' determines the quantitative plasma
Lp(a) level. The Lp(a) glycoprotein is joined to apoB-100 (APOB) by one
or more disulfide bridges. Utermann et al. (1987) studied the
glycoprotein directly by sodium dodecyl sulfate-gel electrophoresis.
Family studies were compatible with the concept that Lp(a) glycoprotein
phenotypes are controlled by a series of autosomal alleles at a single
locus. A highly significant association was found between
electrophoretic phenotype and concentration of Lp(a) lipoprotein. This
suggested that the same gene locus is involved in determining the Lp(a)
glycoprotein phenotypes and the Lp(a) lipoprotein concentrations in
plasma and was the first indication for structural differences
underlying the quantitative genetic Lp(a)-trait. Because in other
respects it resembles LDL, the atherogenicity of Lp(a) is probably due
to the presence of the apolipoprotein(a) component (apoa). Kane and
Havel (1989) discussed Lp(a) hyperlipoproteinemia as a separate
disorder. Also see Utermann (1989).

Namboodiri et al. (1977) concluded that Lp and esterase D (ESD; 133280)
are closely linked; the maximum lod score was 2.32 at a recombination
fraction of 0.0. Ott and Falk (1982), however, reanalyzed the data of
Namboodiri et al. (1977) in connection with a theoretic consideration of
the confounding effects of epistatic association on linkage. Namboodiri
et al. (1977) had noted a strong association between the phenotypes a-
and a+ at the Lp locus and the phenotypes 2-1 and 1-1 at the ESD locus
(no 2-2 persons were found in the pedigree). The reanalysis resulted in
a considerable drop in the lod score for linkage. Greger et al. (1988)
excluded linkage of LPA not only with ESD but also with the
retinoblastoma locus (RB; 180200), which is closely situated on
chromosome 13.

McLean et al. (1987) sequenced a cloned human LPA cDNA and showed
striking similarities to human plasminogen (PLG; 173350). Consistent
with this close similarity in nucleotide sequence and amino acid
sequence is the finding of close linkage of the LPA locus and the PLG
locus on 6q26-q27 in family studies (Weitkamp et al., 1988). The locus
that determines quantitative variation in Lp(a) lipoprotein was linked
to PLG; peak lod score = 12.73. Weitkamp (1988) was suspicious that
apparent recombinants may in fact have represented typing problems
because of the ambiguities in the Lp(a) system. Indeed, in some of the
molecular genetics work determining the assignment of plasminogen, a DNA
probe defining the LPA locus, rather than a plasminogen probe, may in
fact have been used. Frank et al. (1988) showed that the LPA locus is on
chromosome 6 by blot hybridization analysis of DNA from a panel of
mouse-human somatic cell hybrids. In situ hybridization yielded a single
peak of grain density located at 6q26-q27. Apolipoprotein(a) has been
reported only in Old World primates and in one species of hedgehog; it
has not been found in New World primates, rabbits, rats, cattle, mice,
or the marsupial Monodelphis domestica. By a linkage study using
polymorphisms at the LPA and PLG loci, VandeBerg et al. (1991)
demonstrated that the 2 loci are tightly linked in the baboon; the
maximum lod score was 30.2 with no recombinants. This was said to be the
first genetic linkage identified in a nonhuman primate species by family
studies. It would be of interest to determine whether the 2 loci are
also tightly linked in hedgehogs. It is possible that LPA arose
independently on 2 different occasions during mammalian evolution, by
duplication of the PLG locus.

Apolipoprotein(a) is a very large molecule, larger than plasminogen; it
contains duplications of many kringles present in small numbers in
plasminogen. Utermann et al. (1988) demonstrated that the size
heterogeneity of the Lp(a) glycoprotein is genetically controlled. In a
large family with early coronary artery disease and high plasma levels
of Lp(a), Drayna et al. (1988) found tight linkage between LPA size
isoforms and a DNA polymorphism in the plasminogen gene. No linkage was
found with alleles of the apoB DNA polymorphism. See review by Scanu
(1988). In studies of three 2-generation families, Lindahl et al. (1989)
found no recombination in 18 meioses, indicating again very close
linkage of LPA and the plasminogen locus. Berg (1989) demonstrated close
linkage between the LPA locus and the SacI restriction site polymorphism
at the PLG locus. Gavish et al. (1989) showed that the variable number
of kringle 4-like domains encoded by the LPA gene is the main factor
determining the size of the lipoprotein(a) and its plasma concentration.
In a review, Kondo and Berg (1990) pointed out that the Lp(a) antigen
resides in a polypeptide chain that is attached to apolipoprotein B by a
disulfide bridge. They studied a variant 2-kb DNA fragment of the LPA
gene detectable after digestion with the restriction enzyme MspI. It is
related to the 'kringle 4' region of the LPA gene. A proportion of
people appeared to lack (or have an undetectable level of) the 2-kb
fragment and there were quantitative differences between samples from
persons who had the fragment. Presence and amount of the fragment
segregated as a mendelian trait. The variation probably reflects
differences between individuals in the number of 'kringle 4' repeats at
the LPA locus.

Sandholzer et al. (1991) found that the mean level of Lp(a) varied
widely in 7 ethnic groups studied: from a mean of 7.2 mg/dl in Chinese
to a mean of 45.7 in Sudanese. They found, furthermore, that differences
in apo(a) allele frequencies alone did not explain the differences in
Lp(a) levels among populations. Kamboh et al. (1991) demonstrated that
Lp(a) is a highly polymorphic protein. The average heterozygosity at the
LPA structural locus is 94%. Plasma lipoprotein(a) shows wide
quantitative variation among individuals. These variations in
concentration are heritable and inversely related to the number of
kringle 4 repeats in the LPA gene. Boerwinkle et al. (1992) compared
Lp(a) concentrations and LPA genotypes in 48 nuclear Caucasian families.
Genotypes were determined by a pulsed field gel electrophoresis method
that distinguished 19 genotypes at the LPA locus. They showed that the
LPA gene itself accounts for almost all genetic variability in plasma
Lp(a) levels. Among 72 sibs who shared both LPA alleles, the correlation
coefficient for plasma concentration was 0.95, whereas in 52 sibs who
shared no LPA alleles, the correlation coefficient was -0.23. The LPA
gene was estimated to be responsible for 91% of the variance of plasma
concentration. The number of kringle 4 repeats in the LPA gene accounted
for 69% of the variation; yet-to-be defined cis-acting sequences at the
LPA locus accounted for the remaining 22% of interindividual variation.
During the course of the studies, Boerwinkle et al. (1992) observed the
de novo generation of an LPA allele, an event that occurred once in 376
meioses. Marcovina et al. (1993) identified 34 isoforms of
apolipoprotein(a) in a sample of 806 American whites and 701 American
blacks, using a high resolution SDS-agarose gel electrophoretic method
followed by immunoblotting. The frequency of the various isoforms
differed between blacks and whites. Lackner et al. (1993) cloned and
characterized the region of the LPA gene responsible for its
extraordinary size polymorphism; this glycoprotein varies in size over a
range of approximately 500 kD. Lackner et al. (1993) found that the LPA
alleles of different lengths contain varying numbers of a subset of a
tandemly repeated, 5.5-kb, kringle IV encoding sequence. A total of 34
LPA alleles and corresponding glycoproteins could be distinguished using
pulsed field gel electrophoresis and genomic blotting and
immunoblotting. Molecular analysis of a newly generated LPA allele of
different length suggested that the high degree of length polymorphism
is in part due to recombination between sister chromatids.

By a combination of pulsed field gel electrophoresis and genome walking
experiments, Malgaretti et al. (1992) cloned in YAC vectors DNA
fragments comprising the linked LPA and PLG genes. They identified the
5-prime portion and flanking regions of the LPA gene.

Rath and Pauling (1990) hypothesized that Lp(a) is a surrogate for
ascorbate in humans and other species that do not synthesize vitamin C
(240400) and 'marshaled the evidence bearing on this hypothesis.' They
pointed out that the guinea pig, for which vitamin C is essential,
develops atherosclerotic deposits in arteries, as does the rabbit and
other animals, but these occur on an ascorbate-deficient diet without
additional cholesterol. Lp(a) shares with ascorbate the acceleration of
wound healing and other cell-repair mechanisms, the strengthening of the
extracellular matrix (e.g., in blood vessels), and the prevention of
lipid peroxidation. Since apo(a) is associated with low-density
lipoprotein by disulfide bridges, and since in vitro N-acetylcysteine
(NAC) dissociates this complex, Gavish and Breslow (1991) administered
NAC to 2 patients with high Lp(a) levels and found reductions of an
order not hitherto achieved by either drugs or diet. Knapp et al. (1993)
followed up on the observation that Lp(a) levels are approximately twice
as high in black adults and children compared with whites by studying
the levels in 113 white men (average age = 71 years +/- 6) and 83 black
men (average age = 72 years +/- 9). The distribution was skewed in both
whites and blacks. The skewed distribution in elderly black men was in
contrast to the bell-shaped distribution commonly reported for younger
blacks. The data suggested a shift to lower values among elderly as
compared to younger men, with the greatest shift occurring among the
black men. For black men who had survived to the seventh, eighth, and
ninth decades of life, Lp(a) levels approached the lower levels of white
men.

Nowak-Gottl et al. (1997) studied 72 children with arterial or venous
thrombosis and found that 13 had elevated serum Lp(a) levels. Of these,
3 were also heterozygous for the factor V Leiden mutation (612309.0001)
and 1 also had protein C deficiency (176860). The authors concluded that
familial raised Lp(a) levels play an important role in childhood
thrombosis. Debus et al. (1998) examined the possible role of Lp(a) in
the etiology of perinatal porencephalic cysts resulting from presumed
cerebrovascular occlusion. Elevated Lp(a) levels were seen in 5 of 24
children with such cysts. Two of these children were also heterozygous
for the factor V Leiden mutation; in both cases there was a positive
family history of thrombosis. Debus et al. (1998) commented that an
elevated Lp(a) level is an important etiologic factor in perinatal
cerebroarterial occlusion and that other potential interacting factors,
such as infection, placental insufficiency, and fetal cardiac
arrhythmias, should also be considered as causative factors.

Apolipoprotein(a) varies in size over a range of approximately 500 kD
due to interallelic differences in the number of tandemly repeated
kringle 4 (K4)-encoding 5.5-kb sequences in the LPA gene. Only 1 of the
10 different types of K4 repeats in the LPA gene, the so-called type 2
K4 repeats, vary in number between LPA alleles. Mancini et al. (1995)
showed that there is microheterogeneity within the sequence of the type
2 K4 repeat. Digestion with the restriction enzyme DraIII and genomic
blotting revealed that a subset of the type 2 K4-encoding sequences
contain a DraIII site, which Mancini et al. (1995) referred to as K4-D.
The proportion of LPA alleles that had at least one K4-D repeat ranged
from 25% in Caucasians to 50% in Chinese. K4-D repeats were clustered at
the end(s) of the type 2 K4 tandem array and the number in patterns of
the K4-D repeats were in linkage disequilibrium with flanking sequence
polymorphisms; these features were remarkably similar to the
minisatellite variant repeats (MVRs) found in variable number of tandem
repeat sequences (VNTRs). In addition, a DraIII pattern that comprised
9% of the sample was found to be invariably associated with low plasma
levels of Lp(a) in Caucasians.

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

Ichinose (1995) and Ichinose and Kuriyama (1995) demonstrated, by
nucleotide sequence analysis of the LPA gene, the presence of
polymorphisms in its 5-prime flanking region: G/A at position -773, C/T
at position +93, and G/A at position +121, relative to the transcription
start site. Since the nucleotide substitutions can be distinguished by
the presence or absence of restriction sites for TaqI, MaeII, and HhaI
endonucleases, respectively, the LPA alleles among individuals could be
classified by restriction digestion analysis into 4 types, A through D.
To elucidate whether these polymorphisms affect the expression of the
gene, Suzuki et al. (1997) measured plasma Lp(a) concentrations in vivo
by ELISA and examined expression of the gene by an in vitro assay using
its 5-prime flanking region. Homozygotes of type C had significantly
higher Lp(a) levels than those of type D. The relative expression of
type C was also about 3 times higher than that of type D, which was
consistent with the in vivo results. Deletion analysis revealed that the
substitution of C by T at position +93 led to negative regulation in
expression of the gene, while a change of G to A at position +121 led to
positive regulation. These results indicated that the polymorphisms in
the 5-prime flanking region of the LPA gene affect the efficiency of its
expression and, in part, play a role in regulating plasma Lp(a) levels.
(The 4 alleles, designated A, B, C, and D by Suzuki et al. (1997),
showed the following pattern of presence or absence of the restriction
site at the 3 positions (-773, +93, +121): A = +/+/+; B = -/+/+; C =
-/+/-; D = -/-/+.)

Ogorelkova et al. (1999) demonstrated that a G-to-A transition at the +1
donor splice site of the K4 type 8 intron of the LPA gene (152200.0003)
is associated with congenital deficiency of Lp(a) in plasma and occurs
with a high frequency (approximately 6%) in Caucasians but not in
Africans. This mutation alone accounts for a quarter of all 'null' LPA
alleles in Caucasians. RT-PCR analysis based on LPA illegitimate
transcription in lymphoblastoid cells demonstrated that the donor splice
site mutation results in alternative splicing of the K4 type 8 intron
and encodes a truncated form of apo(a). Expression of the alternatively
spliced cDNA analog in cultured HepG2 cells showed that the truncated
apo(a) form is secreted but is unable to form the covalent Lp(a)
complex. Taken together, the data indicated that a failure in complex
formation followed by fast degradation in plasma of the truncated free
apo(a) is one mechanism which underlies the null Lp(a) type associated
with the donor splice site mutation. Patients with congenital Lp(a)
deficiency appeared to be healthy. Ogorelkova et al. (1999) suggested
that Lp(a) may exert its normal function only in certain situations,
e.g., when challenged by environmental factors such as pathogens. In
such situations, low or absent Lp(a) may represent a susceptibility
state, and high Lp(a) may be protective. Hence, association of
congenital Lp(a) deficiency with a specific clinical phenotype may be
difficult to detect and may not or only rarely occur in some ethnic
groups or geographic areas. Such a scenario would explain the low Lp(a)
levels and the presence of the splice site mutation in Caucasians as
opposed to Africans. It appeared that the splice site mutation occurred
after the separation of African and non-African populations.

Ogorelkova et al. (2001) identified 14 single-nucleotide polymorphisms
(SNPs) in apo(a) K4 types 6, 8, 9, and 10; no sequence variants common
to Africans and Caucasians were found. A substitution in K4 type 6 and
another in K4 type 8 were associated with Lp(a) levels significantly
below average in Africans. In contrast, a substitution in K4 type 9,
which occurred with a frequency of 8% in Khoi San Africans, resulted in
a significantly increased Lp(a) concentration. The authors concluded
that several SNPs in the coding sequence of apo(a) may affect Lp(a)
levels.

Caplice et al. (2001) showed that Lp(a) binds and inactivates tissue
factor pathway inhibitor (TFPI; 152350) in vitro. They found that apo(a)
binds to a region spanning the last 37 amino acids of the C terminus of
TFPI. In human atherosclerotic plaque, apo(a) and TFPI immunostaining
coexisted in smooth muscle cell-rich areas of the intima. These data
suggested a novel mechanism whereby Lp(a), through its apo(a) moiety,
may promote thrombosis by binding and inactivating TFPI.

Ariyo et al. (2003) found that among older adults in the United States,
an elevated level of Lp(a) lipoprotein was an independent predictor of
stroke, death from vascular disease, and death from any cause in men but
not in women. The conclusion was based on studies of 3,972 adults 65
years of age or older: 2,375 women and 1,597 men who were free of
vascular disease and were followed for a median of 7.4 years.

Scanu (2003) explained the heterogeneity of Lp(a) lipoprotein particles
as compared with particles of low density lipoprotein (LDL). Small and
large particles of LDL differ mainly in the cholesteryl ester content of
the lipid core (the greater the content of cholesteryl ester, the larger
the particle), which in the case of both large LDL and small LDL is
surrounded by a monolayer of unesterified cholesterol, phospholipids,
and apolipoprotein B100. The small and large LDL particles become small
and large Lp(a) lipoproteins as a result of the linkage of
apolipoprotein(a) to the apolipoprotein B100 ring that surrounds the LDL
particle with a single disulfide bond. Apolipoprotein(a) is made of 10
different types of kringles followed by kringle V and a nonfunctional
protease domain. Apolipoprotein(a) varies in length as a function of the
number of repeats of kringle IV type 2. The length of apolipoprotein(a)
is genetically determined; its variability has an effect on the density
of Lp(a) lipoprotein.

Parson et al. (2004) described a C-to-T transversion at nucleotide 61 in
exon 1 of the kringle IV type 2 domain of the LPA gene, predicted to
result in an arg21-to-ter (R21X) truncated protein (152200.0004). The
allele frequency of this single-nucleotide polymorphism was 0.02. Parson
et al. (2004) stated that this mutation represented the second apparent
apo(a) null allele in humans (the first being that described by
Ogorelkova et al. (1999), 152200.0003).

In an aboriginal African population from Gabon in central Africa
consisting of 31 families with 54 children, Schmidt et al. (2006)
determined that the correlation of plasma lipoprotein(a) levels
associated with LPA alleles resulted in a heritability estimate of
0.801. The authors concluded that LPA is the major quantitative trait
locus for plasma lipoprotein(a) in this population.

Chretien et al. (2006) investigated the basis of the 2-fold higher Lp(a)
levels in African populations compared with non-African populations by
comparing sequence variations in the LPA gene. They studied 534 European
Americans and 249 African Americans. Isoform-adjusted Lp(a) level was
2.23-fold higher among African Americans. Three SNPs were independently
associated with Lp(a) level in both populations. The Lp(a)-increasing
SNP (-21G/A, which increases promoter activity) was more common in
African Americans, whereas the Lp(a)-lowering SNPs (T3888P and
G+1/inKIV-8A, which inhibit Lp(a) assembly) were more common in European
Americans, but all had a frequency of less than 20% in one or both
populations. Chretien et al. (2006) concluded that multiple
low-prevalence alleles in LPA can account for the large
between-population difference in serum Lp(a) levels between European
Americans and African Americans.

Lopez et al. (2008) measured Lp(a) levels and performed genomewide
linkage analysis in 387 individuals from 21 extended Spanish families
and found the strongest evidence of linkage with Lp(a) levels at
chromosome 6q25.2-q27, at the locus for the structural LPA gene (lod
score, 13.8). The overall heritability of Lp(a) concentration was
estimated at 0.79, indicating that approximately 79% of the phenotypic
variation in the trait is due to the additive effect of genes.

- Association with Coronary Artery Disease

In 3,145 individuals with coronary artery disease (CAD) and 3,352
controls, Clarke et al. (2009) performed a genomewide association study
involving 48,742 SNPs in 2,100 candidate genes and found the strongest
association at the LPA locus on chromosome 6q26-q27, with a corrected p
of less than 0.05 for 27 SNPs, 16 of which were also significantly
associated with Lp(a) level. Clarke et al. (2009) noted that the 2 SNPs
most strongly associated with Lp(a) level, dbSNP rs3798220 and dbSNP
rs10455872, were also the most strongly associated with increased risk
of CAD (odds ratio (OR) of 1.92 and 1.70, respectively). In addition,
the rare alleles of both dbSNP rs3798220 and dbSNP rs10455872 were each
correlated with a smaller Lp(a) isoform and a lower copy number.
Metaanalysis showed increased risk of CAD for 1 LPA variant allele (OR,
1.51) and 2 or more variant alleles (OR, 2.57).

- Association with Aortic Valve Calcification

For discussion of a possible association between variation in the LPA
gene and calcification of the aortic valve, see AOVD1 (109730).

ANIMAL MODEL

Elevated plasma levels of Lp(a) are associated with increased risk for
atherosclerosis and its manifestations--myocardial infarction, stroke
and restenosis. As the plasma concentration of Lp(a) is strongly
influenced by heritable factors and is refractory to most drug and
dietary manipulation, the effects of modulating it are difficult to
mimic experimentally. In addition, the absence of apolipoprotein(a) from
virtually all species other than primates precludes the use of
convenient animal models. However, Lawn et al. (1992) demonstrated that
transgenic mice expressing human apolipoprotein(a) are more susceptible
than control mice to the development of lipid-staining lesions in the
aorta, and that apolipoprotein(a) colocalizes with lipid deposition in
the artery walls. As an extension of these studies, Grainger et al.
(1994) established that the major in vivo action of apolipoprotein(a) is
inhibition of conversion of plasminogen to plasmin, resulting in a
decreased activation of latent transforming growth factor-beta (TGFB;
190180). TGFBs are negative regulators of smooth muscle cell migration
and proliferation, pointing to a possible mechanism for
apolipoprotein(a) induction of atherosclerotic lesions.

Lou et al. (1998) crossed apo(a) transgenic mice with fibrinogen
knockout mice to generate fibrinogen-deficient apo(a) transgenic mice
and control mice. In the vessel wall of apo(a) transgenic mice,
fibrinogen deposition was found to be essentially colocalized with focal
apo(a) deposition and fatty streak-type atherosclerotic lesions.
Fibrinogen deficiency in apo(a) transgenic mice decreased the average
accumulation of apo(a) in vessel walls by 78% and the average lesion
(fatty streak type) development by 81%. Fibrinogen deficiency in
wildtype mice did not significantly reduce lesion development. The
results suggested that fibrinogen provides one of the major sites to
which apo(a) binds to the vessel wall and participates in the generation
of atherosclerosis.

Lipoprotein(a) (Lp(a)) is formed by the disulfide linkage of
apolipoprotein B100 (APOB; 107730) of a low-density lipoprotein particle
to apolipoprotein(a). Previous studies had suggested that one of the
C-terminal cysteine residues of apo-B100 is involved in the disulfide
linkage of apo-B100 to apo(a). To identify the apo-B100 cysteine
residues involved in the formation of Lp(a), McCormick et al. (1995)
constructed a YAC spanning the human APOB gene and used gene-targeting
techniques to change cysteine-4326 to glycine. The mutated YAC DNA was
used to generate transgenic mice expressing the mutant human APOB
(cys4326-to-gly). Unlike the wildtype human APOB, the mutant human APOB
completely lacked the ability to bind to apo(a) and form Lp(a). The
study succeeded in demonstrating that the cysteine residue was involved
in the disulfide linkage and showed that gene targeting in YACs,
followed by the generation of transgenic mice, is a useful approach for
analyzing the structure of large proteins encoded by large genes.

*FIELD* AV
.0001
APOLIPOPROTEIN(a), TYPE C POLYMORPHISM
LPA, -773A, +93C, +121A

Ichinose and Kuriyama (1995) used the designation C for the polymorphism
in the 5-prime flanking region of the LPA gene -773A, +93C, +121A. They
found that homozygotes of type C had significantly higher Lp(a) levels
than those of type D. In vitro studies indicated that the relative
expression of type C was also about 3 times higher than that of type D,
which was consistent with the in vivo results.

.0002
APOLIPOPROTEIN(a), TYPE D POLYMORPHISM
LPA, -773G, +93T, +121G

Ichinose and Kuriyama (1995) used the designation D for the LPA allele
of the following haplotype: -773G, +93T, +121G. Homozygotes of type D
had significantly lower Lp(a) levels than those of type C.

.0003
LIPOPROTEIN(a) DEFICIENCY, CONGENITAL
LPA, IVS K4 TYPE 8 DS, G-A, +1

Ogorelkova et al. (1999) identified a G-to-A transition in the donor
splice site (position 1) of the 6-kb intron separating the 2 exons of
the kringle IV (K4) type 8 repeat of the LPA gene, resulting in
deficiency of lipoprotein(a) (Lp(a)). The frequency of this splice site
mutation was 0.053 in a Tyrolean sample of 113 individuals, and the
mutation was not found in 200 Africans. In a sample of 126 Finns, the
frequency of the mutation was 0.0635. The alleles of this splice site
polymorphism were in Hardy-Weinberg equilibrium in both Tyroleans and
Finns. Approximately 11% of Europeans are heterozygous and 0.3%
homozygous for this G-to-A splice site mutation. Persons with congenital
deficiency of Lp(a) appeared to be clinically healthy.

.0004
LIPOPROTEIN(a) DEFICIENCY, CONGENITAL
LPA, ARG21TER

Parson et al. (2004) described a C-to-T transversion at nucleotide 61 in
exon 1 of the kringle IV type 2 domain of the LPA gene, predicted to
result in an arg21-to-ter (R21X) truncated protein (GenBank GENBANK
L14005.1). The allele frequency of this single-nucleotide polymorphism
was 0.02.

*FIELD* SA
Butler (1967)
*FIELD* RF
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*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Risk factor for coronary heart disease;
[Vascular];
Risk factor for carotid atherosclerosis

LABORATORY ABNORMALITIES:
Elevated plasma levels of Lp(a)

MOLECULAR BASIS:
Caused by mutations in the apolipoprotein Lp(a) gene (LPA, 152200.0001)

*FIELD* CN
Ada Hamosh - reviewed: 11/09/2000
Kelly A. Przylepa - revised: 3/16/2000

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

*FIELD* ED
joanna: 11/09/2000
kayiaros: 3/16/2000

*FIELD* CN
Marla J. F. O'Neill - updated: 1/12/2010
Marla J. F. O'Neill - updated: 10/5/2009
Victor A. McKusick - updated: 5/31/2007
Cassandra L. Kniffin - updated: 2/10/2006
Victor A. McKusick - updated: 1/10/2005
Victor A. McKusick - updated: 1/8/2004
Victor A. McKusick - updated: 2/26/2002
Victor A. McKusick - updated: 10/25/1999
Victor A. McKusick - updated: 11/2/1998
Paul Brennan - updated: 6/3/1998
Victor A. McKusick - updated: 4/29/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 05/23/2013
carol: 3/21/2013
terry: 6/4/2012
carol: 6/17/2011
wwang: 1/13/2010
terry: 1/12/2010
wwang: 10/22/2009
terry: 10/5/2009
carol: 10/8/2008
alopez: 6/4/2007
terry: 5/31/2007
wwang: 2/23/2006
ckniffin: 2/10/2006
alopez: 2/10/2005
wwang: 1/25/2005
terry: 1/10/2005
carol: 3/17/2004
tkritzer: 1/20/2004
terry: 1/8/2004
alopez: 11/10/2003
mgross: 3/6/2002
terry: 2/26/2002
cwells: 7/27/2001
cwells: 7/23/2001
mgross: 11/5/1999
terry: 10/25/1999
carol: 11/6/1998
terry: 11/2/1998
carol: 6/4/1998
terry: 6/3/1998
mark: 2/7/1998
mark: 6/14/1997
alopez: 6/2/1997
alopez: 4/29/1997
terry: 4/25/1997
mark: 11/10/1995
mimadm: 11/5/1994
davew: 8/19/1994
terry: 5/11/1994
warfield: 4/12/1994
pfoster: 3/31/1994