RBCC Red Blood Cell Collection

ABCA1 (ABC1, CERP) [Confidence: low (only semi-automatic identification from reviews)]
ATP-binding cassette sub-family A member 1 (ATP-binding cassette transporter 1; ABC-1; ATP-binding cassette 1; Cholesterol efflux regulatory protein)

UniProt O95477
ID ABCA1_HUMAN Reviewed; 2261 AA.
AC O95477; Q5VX33; Q96S56; Q96T85; Q9NQV4; Q9UN06; Q9UN07; Q9UN08;
read moreAC Q9UN09;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2010, sequence version 3.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=ATP-binding cassette sub-family A member 1;
DE AltName: Full=ATP-binding cassette transporter 1;
DE Short=ABC-1;
DE Short=ATP-binding cassette 1;
DE AltName: Full=Cholesterol efflux regulatory protein;
GN Name=ABCA1; Synonyms=ABC1, CERP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANT ARG-1587.
RX PubMed=10884428; DOI=10.1073/pnas.97.14.7987;
RA Santamarina-Fojo S., Peterson K.M., Knapper C.L., Qiu Y.,
RA Freeman L.A., Cheng J.-F., Osorio J., Remaley A.T., Yang X.-P.,
RA Haudenschild C.C., Prades C., Chimini G., Blackmon E.E.,
RA Francois T.L., Duverger N., Rubin E.M., Rosier M., Denefle P.,
RA Fredrickson D.S., Brewer H.B. Jr.;
RT "Complete genomic sequence of the human ABCA1 gene: analysis of the
RT human and mouse ATP-binding cassette A promoter.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:7987-7992(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ARG-1587.
RC TISSUE=Skin;
RA Schwartz K., Lawn R.M., Wade D.P.;
RT "ABCA1 gene expression and apoA-I-mediated cholesterol efflux are
RT regulated by LXR.";
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ARG-1587.
RX PubMed=11352567; DOI=10.1006/geno.2000.6467;
RA Qiu Y., Cavelier L., Chiu S., Yang X., Rubin E., Cheng J.-F.;
RT "Human and mouse ABCA1 comparative sequencing and transgenesis studies
RT revealing novel regulatory sequences.";
RL Genomics 73:66-76(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Tanaka A.R., Abe-Dohmae S., Arakawa R., Sadanami K., Kidera A.,
RA Kioka N., Amachi T., Yokoyama S., Ueda K.;
RT "A new topological model of functional human ABCA1-signal peptide
RT cleavage and glycosylation of a large extracellular domain.";
RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 21-2261, AND VARIANTS THR-1555;
RP ARG-1587; PRO-1648 AND PRO-2168.
RX PubMed=10092505; DOI=10.1006/bbrc.1999.0406;
RA Langmann T., Klucken J., Reil M., Liebisch G., Luciani M.-F.,
RA Chimini G., Kaminski W.E., Schmitz G.;
RT "Molecular cloning of the human ATP-binding cassette transporter 1
RT (hABC1): evidence for sterol-dependent regulation in macrophages.";
RL Biochem. Biophys. Res. Commun. 257:29-33(1999).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 21-2261, AND VARIANTS
RP THR-1555; ARG-1587; PRO-1648 AND PRO-2168.
RX PubMed=10431238; DOI=10.1038/11921;
RA Rust S., Rosier M., Funke H., Real J., Amoura Z., Piette J.-C.,
RA Deleuze J.-F., Brewer H.B. Jr., Duverger N., Denefle P., Assmann G.;
RT "Tangier disease is caused by mutations in the gene encoding ATP-
RT binding cassette transporter 1.";
RL Nat. Genet. 22:352-355(1999).
RN [8]
RP PHOSPHORYLATION AT SER-1042 AND SER-2054.
RX PubMed=12196520; DOI=10.1074/jbc.M204923200;
RA See R.H., Caday-Malcolm R.A., Singaraja R.R., Zhou S., Silverston A.,
RA Huber M.T., Moran J., James E.R., Janoo R., Savill J.M., Rigot V.,
RA Zhang L.H., Wang M., Chimini G., Wellington C.L., Tafuri S.R.,
RA Hayden M.R.;
RT "Protein kinase A site-specific phosphorylation regulates ATP-binding
RT cassette A1 (ABCA1)-mediated phospholipid efflux.";
RL J. Biol. Chem. 277:41835-41842(2002).
RN [9]
RP REPRESSION BY ZNF202.
RX PubMed=11279031; DOI=10.1074/jbc.M100218200;
RA Porsch-Oezcueruemez M., Langmann T., Heimerl S., Borsukova H.,
RA Kaminski W.E., Drobnik W., Honer C., Schumacher C., Schmitz G.;
RT "The zinc finger protein 202 (ZNF202) is a transcriptional repressor
RT of ATP binding cassette transporter A1 (ABCA1) and ABCG1 gene
RT expression and a modulator of cellular lipid efflux.";
RL J. Biol. Chem. 276:12427-12433(2001).
RN [10]
RP INDUCTION BY LPS.
RX PubMed=12032171;
RA Kaplan R., Gan X., Menke J.G., Wright S.D., Cai T.-Q.;
RT "Bacterial lipopolysaccharide induces expression of ABCA1 but not
RT ABCG1 via an LXR-independent pathway.";
RL J. Lipid Res. 43:952-959(2002).
RN [11]
RP INTERACTION WITH MEGF10.
RX PubMed=17205124; DOI=10.1371/journal.pone.0000120;
RA Hamon Y., Trompier D., Ma Z., Venegas V., Pophillat M., Mignotte V.,
RA Zhou Z., Chimini G.;
RT "Cooperation between engulfment receptors: the case of ABCA1 and
RT MEGF10.";
RL PLoS ONE 1:E120-E120(2006).
RN [12]
RP REVIEW ON VARIANTS.
RX PubMed=12763760; DOI=10.1161/01.ATV.0000078520.89539.77;
RA Singaraja R.R., Brunham L.R., Visscher H., Kastelein J.J.P.,
RA Hayden M.R.;
RT "Efflux and atherosclerosis: the clinical and biochemical impact of
RT variations in the ABCA1 gene.";
RL Arterioscler. Thromb. Vasc. Biol. 23:1322-1332(2003).
RN [13]
RP PALMITOYLATION AT CYS-3; CYS-23; CYS-1110 AND CYS-1111, AND
RP SUBCELLULAR LOCATION.
RX PubMed=19556522; DOI=10.1161/CIRCRESAHA.108.193011;
RA Singaraja R.R., Kang M.H., Vaid K., Sanders S.S., Vilas G.L.,
RA Arstikaitis P., Coutinho J., Drisdel R.C., El-Husseini Ael D.,
RA Green W.N., Berthiaume L., Hayden M.R.;
RT "Palmitoylation of ATP-binding cassette transporter A1 is essential
RT for its trafficking and function.";
RL Circ. Res. 105:138-147(2009).
RN [14]
RP DISULFIDE BONDS, AND SUBCELLULAR LOCATION.
RX PubMed=19258317; DOI=10.1074/jbc.M900580200;
RA Hozoji M., Kimura Y., Kioka N., Ueda K.;
RT "Formation of two intramolecular disulfide bonds is necessary for
RT ApoA-I-dependent cholesterol efflux mediated by ABCA1.";
RL J. Biol. Chem. 284:11293-11300(2009).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-98 AND ASN-244, AND MASS
RP 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 [16]
RP VARIANTS HDLD2 THR-1091 AND 1893-GLU-ASP-1894 DEL.
RX PubMed=10533863; DOI=10.1016/S0140-6736(99)07026-9;
RA Marcil M., Brooks-Wilson A., Clee S.M., Roomp K., Zhang L.-H., Yu L.,
RA Collins J.A., van Dam M., Molhuizen H.O.F., Loubser O.,
RA Ouellette B.F.F., Sensen C.W., Fichter K., Mott S., Denis M.,
RA Boucher B., Pimstone S., Genest J. Jr., Kastelein J.J.P., Hayden M.R.;
RT "Mutations in the ABC1 gene in familial HDL deficiency with defective
RT cholesterol efflux.";
RL Lancet 354:1341-1346(1999).
RN [17]
RP VARIANTS HDLD1 ARG-597 AND ARG-1477, AND VARIANT HDLD2 LEU-693 DEL.
RX PubMed=10431236; DOI=10.1038/11905;
RA Brooks-Wilson A., Marcil M., Clee S.M., Zhang L.-H., Roomp K.,
RA van Dam M., Yu L., Brewer C., Collins J.A., Molhuizen H.O.F.,
RA Loubser O., Ouelette B.F.F., Fichter K., Ashbourne-Excoffon K.J.D.,
RA Sensen C.W., Scherer S., Mott S., Denis M., Martindale D.,
RA Frohlich J., Morgan K., Koop B., Pimstone S., Kastelein J.J.P.,
RA Hayden M.R.;
RT "Mutations in ABC1 in Tangier disease and familial high-density
RT lipoprotein deficiency.";
RL Nat. Genet. 22:336-345(1999).
RN [18]
RP VARIANTS HDLD1 SER-590; SER-935 AND VAL-937, AND VARIANTS ALA-399 AND
RP MET-883.
RX PubMed=10431237; DOI=10.1038/11914;
RA Bodzioch M., Orso E., Klucken J., Langmann T., Boettcher A.,
RA Diederich W., Drobnik W., Barlage S., Buechler C.,
RA Porsch-Oezcueruemez M., Kaminski W.E., Hahmann H.W., Oette K.,
RA Rothe G., Aslanidis C., Lackner K.J., Schmitz G.;
RT "The gene encoding ATP-binding cassette transporter 1 is mutated in
RT Tangier disease.";
RL Nat. Genet. 22:347-351(1999).
RN [19]
RP VARIANTS HDLD1 ARG-597; ILE-929 AND ARG-1477, AND VARIANTS HDLD2
RP LEU-693 DEL; THR-1091; 1893-GLU-ASP-1894 DEL AND LEU-2150.
RX PubMed=11086027; DOI=10.1172/JCI10727;
RA Clee S.M., Kastelein J.J.P., van Dam M., Marcil M., Roomp K.,
RA Zwarts K.Y., Collins J.A., Roelants R., Tamasawa N., Stulc T.,
RA Suda T., Ceska R., Boucher B., Rondeau C., DeSouich C.,
RA Brooks-Wilson A., Molhuizen H.O.F., Frohlich J., Genest J. Jr.,
RA Hayden M.R.;
RT "Age and residual cholesterol efflux affect HDL cholesterol levels and
RT coronary artery disease in ABCA1 heterozygotes.";
RL J. Clin. Invest. 106:1263-1270(2000).
RN [20]
RP VARIANTS HDLD1 ASN-1289 AND HIS-1800.
RX PubMed=10706591;
RA Brousseau M.E., Schaefer E.J., Dupuis J., Eustace B.,
RA Van Eerdewegh P., Goldkamp A.L., Thurston L.M., FitzGerald M.G.,
RA Yasek-McKenna D., O'Neill G., Eberhart G.P., Weiffenbach B.,
RA Ordovas J.M., Freeman M.W., Brown R.H. Jr., Gu J.Z.;
RT "Novel mutations in the gene encoding ATP-binding cassette 1 in four
RT tangier disease kindreds.";
RL J. Lipid Res. 41:433-441(2000).
RN [21]
RP VARIANT HDLD1 ASP-1046, VARIANT HDLD2 CYS-230, AND VARIANTS LYS-219;
RP ILE-825; MET-883 AND ARG-1587.
RX PubMed=10938021;
RA Wang J., Burnett J.R., Near S., Young K., Zinman B., Hanley A.J.G.,
RA Connelly P.W., Harris S.B., Hegele R.A.;
RT "Common and rare ABCA1 variants affecting plasma HDL cholesterol.";
RL Arterioscler. Thromb. Vasc. Biol. 20:1983-1989(2000).
RN [22]
RP VARIANT HDLD1 TRP-587, AND VARIANT PRO-2168.
RX PubMed=11257260; DOI=10.1016/S0021-9150(00)00587-6;
RA Bertolini S., Pisciotta L., Seri M., Cusano R., Cantafora A.,
RA Calabresi L., Franceschini G., Ravazzolo R., Calandra S.;
RT "A point mutation in ABC1 gene in a patient with severe premature
RT coronary heart disease and mild clinical phenotype of Tangier
RT disease.";
RL Atherosclerosis 154:599-605(2001).
RN [23]
RP VARIANTS LYS-219; MET-883 AND ASP-1172.
RX PubMed=11257261; DOI=10.1016/S0021-9150(00)00722-X;
RA Brousseau M.E., Bodzioch M., Schaefer E.J., Goldkamp A.L., Kielar D.,
RA Probst M., Ordovas J.M., Aslanidis C., Lackner K.J.,
RA Bloomfield Rubins H., Collins D., Robins S.J., Wilson P.W.F.,
RA Schmitz G.;
RT "Common variants in the gene encoding ATP-binding cassette transporter
RT 1 in men with low HDL cholesterol levels and coronary heart disease.";
RL Atherosclerosis 154:607-611(2001).
RN [24]
RP VARIANT HDLD1 LEU-1506.
RX PubMed=11476961; DOI=10.1016/S0925-4439(01)00053-9;
RA Lapicka-Bodzioch K., Bodzioch M., Kruell M., Kielar D., Probst M.,
RA Kiec B., Andrikovics H., Boettcher A., Hubacek J., Aslanidis C.,
RA Suttorp N., Schmitz G.;
RT "Homogeneous assay based on 52 primer sets to scan for mutations of
RT the ABCA1 gene and its application in genetic analysis of a new
RT patient with familial high-density lipoprotein deficiency syndrome.";
RL Biochim. Biophys. Acta 1537:42-48(2001).
RN [25]
RP VARIANTS HDLD1 ASN-1289 AND TRP-2081, AND VARIANT LYS-219.
RX PubMed=11476965; DOI=10.1016/S0925-4439(01)00058-8;
RA Huang W., Moriyama K., Koga T., Hua H., Ageta M., Kawabata S.,
RA Mawatari K., Imamura T., Eto T., Kawamura M., Teramoto T., Sasaki J.;
RT "Novel mutations in ABCA1 gene in Japanese patients with Tangier
RT disease and familial high density lipoprotein deficiency with coronary
RT heart disease.";
RL Biochim. Biophys. Acta 1537:71-78(2001).
RN [26]
RP VARIANTS LYS-219; ALA-399; MET-771; PRO-774; ASN-776; ILE-825;
RP MET-883; ASP-1172; ARG-1587 AND CYS-1731.
RX PubMed=11238261;
RA Clee S.M., Zwinderman A.H., Engert J.C., Zwarts K.Y.,
RA Molhuizen H.O.F., Roomp K., Jukema J.W., van Wijland M., van Dam M.,
RA Hudson T.J., Brooks-Wilson A., Genest J. Jr., Kastelein J.J.P.,
RA Hayden M.R.;
RT "Common genetic variation in ABCA1 is associated with altered
RT lipoprotein levels and a modified risk for coronary artery disease.";
RL Circulation 103:1198-1205(2001).
RN [27]
RP VARIANT HDLD2 LEU-85.
RX PubMed=12204794; DOI=10.1016/S0021-9150(02)00106-5;
RA Hong S.H., Rhyne J., Zeller K., Miller M.;
RT "ABCA1(Alabama): a novel variant associated with HDL deficiency and
RT premature coronary artery disease.";
RL Atherosclerosis 164:245-250(2002).
RN [28]
RP VARIANTS HDLD2 TYR-1099 AND SER-2009.
RX PubMed=12009425; DOI=10.1016/S0925-4439(02)00066-2;
RA Hong S.H., Rhyne J., Zeller K., Miller M.;
RT "Novel ABCA1 compound variant associated with HDL cholesterol
RT deficiency.";
RL Biochim. Biophys. Acta 1587:60-64(2002).
RN [29]
RP VARIANT HDLD1 THR-255, AND VARIANT ATHEROSCLEROSIS ASP-1611.
RX PubMed=11785958; DOI=10.1006/bbrc.2001.6219;
RA Nishida Y., Hirano K., Tsukamoto K., Nagano M., Ikegami C., Roomp K.,
RA Ishihara M., Sakane N., Zhang Z., Tsujii K., Matsuyama A., Ohama T.,
RA Matsuura F., Ishigami M., Sakai N., Hiraoka H., Hattori H.,
RA Wellington C., Yoshida Y., Misugi S., Hayden M.R., Egashira T.,
RA Yamashita S., Matsuzawa Y.;
RT "Expression and functional analyses of novel mutations of ATP-binding
RT cassette transporter-1 in Japanese patients with high-density
RT lipoprotein deficiency.";
RL Biochem. Biophys. Res. Commun. 290:713-721(2002).
RN [30]
RP VARIANT HDLD1 LEU-590.
RX PubMed=12407001;
RA Hong S.H., Riley W., Rhyne J., Friel G., Miller M.;
RT "Lack of association between increased carotid intima-media thickening
RT and decreased HDL-cholesterol in a family with a novel ABCA1 variant,
RT G2265T.";
RL Clin. Chem. 48:2066-2070(2002).
RN [31]
RP VARIANTS HDLD1 HIS-935 AND SER-935.
RX PubMed=12111381; DOI=10.1007/s100380200044;
RA Guo Z., Inazu A., Yu W., Suzumura T., Okamoto M., Nohara A.,
RA Higashikata T., Sano R., Wakasugi K., Hayakawa T., Yoshida K.,
RA Suehiro T., Schmitz G., Mabuchi H.;
RT "Double deletions and missense mutations in the first nucleotide-
RT binding fold of the ATP-binding cassette transporter A1 (ABCA1) gene
RT in Japanese patients with Tangier disease.";
RL J. Hum. Genet. 47:325-329(2002).
RN [32]
RP VARIANT HDLD1 TRP-1680.
RX PubMed=12111371; DOI=10.1007/s100380200051;
RA Ishii J., Nagano M., Kujiraoka T., Ishihara M., Egashira T.,
RA Takada D., Tsuji M., Hattori H., Emi M.;
RT "Clinical variant of Tangier disease in Japan: mutation of the ABCA1
RT gene in hypoalphalipoproteinemia with corneal lipidosis.";
RL J. Hum. Genet. 47:366-369(2002).
RN [33]
RP VARIANT HDLD1 GLN-1851.
RX PubMed=14576201; DOI=10.1161/01.RES.0000102957.84247.8F;
RA Hong S.H., Rhyne J., Miller M.;
RT "Novel polypyrimidine variation (IVS46: del T -39._.-46) in ABCA1
RT causes exon skipping and contributes to HDL cholesterol deficiency in
RT a family with premature coronary disease.";
RL Circ. Res. 93:1006-1012(2003).
RN [34]
RP VARIANTS ILE-825 AND MET-883, AND ASSOCIATION OF VARIANTS ILE-825 AND
RP MET-883 WITH HIGHER PLASMA HDL CHOLESTEROL.
RX PubMed=12709788; DOI=10.1007/s00439-003-0943-3;
RA Tan J.H., Low P.S., Tan Y.S., Tong M.C., Saha N., Yang H., Heng C.K.;
RT "ABCA1 gene polymorphisms and their associations with coronary artery
RT disease and plasma lipids in males from three ethnic populations in
RT Singapore.";
RL Hum. Genet. 113:106-117(2003).
RN [35]
RP VARIANTS LYS-219; MET-771; ILE-825; MET-883; ASP-1172; PHE-1181 AND
RP ARG-1587.
RX PubMed=12966036; DOI=10.1093/hmg/ddg314;
RA Morabia A., Cayanis E., Costanza M.C., Ross B.M., Flaherty M.S.,
RA Alvin G.B., Das K., Gilliam T.C.;
RT "Association of extreme blood lipid profile phenotypic variation with
RT 11 reverse cholesterol transport genes and 10 non-genetic
RT cardiovascular disease risk factors.";
RL Hum. Mol. Genet. 12:2733-2743(2003).
RN [36]
RP VARIANT LYS-219.
RX PubMed=12624133; DOI=10.1136/jmg.40.3.163;
RA Cenarro A., Artieda M., Castillo S., Mozas P., Reyes G., Tejedor D.,
RA Alonso R., Mata P., Pocovi M., Civeira F.;
RT "A common variant in the ABCA1 gene is associated with a lower risk
RT for premature coronary heart disease in familial
RT hypercholesterolaemia.";
RL J. Med. Genet. 40:163-168(2003).
RN [37]
RP VARIANTS HDLD1 LEU-590; ARG-840 AND CYS-1068, AND VARIANTS MET-771;
RP SER-2163 AND ILE-2244.
RX PubMed=15262183; DOI=10.1016/j.atherosclerosis.2004.02.019;
RA Probst M.C., Thumann H., Aslanidis C., Langmann T., Buechler C.,
RA Patsch W., Baralle F.E., Dallinga-Thie G.M., Geisel J., Keller C.,
RA Menys V.C., Schmitz G.;
RT "Screening for functional sequence variations and mutations in
RT ABCA1.";
RL Atherosclerosis 175:269-279(2004).
RN [38]
RP VARIANTS HDLD1 LYS-284; CYS-482; HIS-1800; SER-1901 AND HIS-2196.
RX PubMed=15019541; DOI=10.1016/j.atherosclerosis.2003.11.009;
RA Pisciotta L., Hamilton-Craig I., Tarugi P., Bellocchio A., Fasano T.,
RA Alessandrini P., Bon G.B., Siepi D., Mannarino E., Cattin L.,
RA Averna M., Cefalu A.B., Cantafora A., Calandra S., Bertolini S.;
RT "Familial HDL deficiency due to ABCA1 gene mutations with or without
RT other genetic lipoprotein disorders.";
RL Atherosclerosis 172:309-320(2004).
RN [39]
RP VARIANTS HDLD1 PHE-1379 AND ASP-1704, AND CHARACTERIZATION OF VARIANTS
RP HDLD1 PHE-1379 AND ASP-1704.
RX PubMed=15158913; DOI=10.1016/j.bbadis.2004.01.007;
RA Albrecht C., Baynes K., Sardini A., Schepelmann S., Eden E.R.,
RA Davies S.W., Higgins C.F., Feher M.D., Owen J.S., Soutar A.K.;
RT "Two novel missense mutations in ABCA1 result in altered trafficking
RT and cause severe autosomal recessive HDL deficiency.";
RL Biochim. Biophys. Acta 1689:47-57(2004).
RN [40]
RP VARIANT HDLD1 HIS-1800, AND VARIANTS LYS-219; CYS-364; MET-771;
RP PRO-774; ASN-776; ILE-825; MET-883; SER-1065; ASP-1172; VAL-1216 AND
RP ARG-1587.
RX PubMed=15520867; DOI=10.1172/JCI20361;
RA Frikke-Schmidt R., Nordestgaard B.G., Jensen G.B., Tybjaerg-Hansen A.;
RT "Genetic variation in ABC transporter A1 contributes to HDL
RT cholesterol in the general population.";
RL J. Clin. Invest. 114:1343-1353(2004).
RN [41]
RP VARIANT HDLD1 HIS-1800, AND VARIANTS ALA-248; GLN-401; TRP-496;
RP SER-590; GLN-638; SER-774; GLY-815; PHE-1181; THR-1341; GLY-1376;
RP GLN-1615; THR-1670; GLN-1680 AND GLU-2243.
RX PubMed=15297675; DOI=10.1126/science.1099870;
RA Cohen J.C., Kiss R.S., Pertsemlidis A., Marcel Y.L., McPherson R.,
RA Hobbs H.H.;
RT "Multiple rare alleles contribute to low plasma levels of HDL
RT cholesterol.";
RL Science 305:869-872(2004).
RN [42]
RP VARIANT SCOTT SYNDROME GLN-1925, AND CHARACTERIZATION OF VARIANT SCOTT
RP SYNDROME GLN-1925.
RX PubMed=15790791; DOI=10.1182/blood-2004-05-2056;
RA Albrecht C., McVey J.H., Elliott J.I., Sardini A., Kasza I.,
RA Mumford A.D., Naoumova R.P., Tuddenham E.G., Szabo K., Higgins C.F.;
RT "A novel missense mutation in ABCA1 results in altered protein
RT trafficking and reduced phosphatidylserine translocation in a patient
RT with Scott syndrome.";
RL Blood 106:542-549(2005).
RN [43]
RP VARIANT ASN-776, AND ASSOCIATION OF VARIANT ASN-776 WITH INCREASED
RP RISK OF ISCHEMIC HEART DISEASE.
RX PubMed=16226177; DOI=10.1016/j.jacc.2005.06.066;
RA Frikke-Schmidt R., Nordestgaard B.G., Schnohr P., Steffensen R.,
RA Tybjaerg-Hansen A.;
RT "Mutation in ABCA1 predicted risk of ischemic heart disease in the
RT Copenhagen City Heart Study Population.";
RL J. Am. Coll. Cardiol. 46:1516-1520(2005).
RN [44]
RP VARIANT HDLD2 TRP-1897.
RX PubMed=15722566; DOI=10.1194/jlr.D400038-JLR200;
RA Fasano T., Bocchi L., Pisciotta L., Bertolini S., Calandra S.;
RT "Denaturing high-performance liquid chromatography in the detection of
RT ABCA1 gene mutations in familial HDL deficiency.";
RL J. Lipid Res. 46:817-822(2005).
RN [45]
RP VARIANTS [LARGE SCALE ANALYSIS] ASP-210; TYR-917; THR-1407 AND
RP THR-2109.
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).
CC -!- FUNCTION: cAMP-dependent and sulfonylurea-sensitive anion
CC transporter. Key gatekeeper influencing intracellular cholesterol
CC transport.
CC -!- SUBUNIT: Interacts with MEGF10.
CC -!- INTERACTION:
CC Q13424:SNTA1; NbExp=2; IntAct=EBI-784112, EBI-717191;
CC Q13884:SNTB1; NbExp=3; IntAct=EBI-784112, EBI-295843;
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Widely expressed, but most abundant in
CC macrophages.
CC -!- INDUCTION: By bacterial lipopolysaccharides (LPS). LPS regulates
CC expression through a liver X receptor (LXR) -independent
CC mechanism. Repressed by ZNF202.
CC -!- DOMAIN: Multifunctional polypeptide with two homologous halves,
CC each containing a hydrophobic membrane-anchoring domain and an ATP
CC binding cassette (ABC) domain.
CC -!- PTM: Phosphorylation on Ser-2054 regulates phospholipid efflux.
CC -!- PTM: Palmitoylation by DHHC8 is essential for membrane
CC localization.
CC -!- POLYMORPHISM: Genetic variations in ABCA1 define the high density
CC lipoprotein cholesterol level quantitative trait locus 13
CC (HDLCQ13) [MIM:600046].
CC -!- DISEASE: High density lipoprotein deficiency 1 (HDLD1)
CC [MIM:205400]: Recessive disorder characterized by absence of high
CC density lipoprotein (HDL) cholesterol from plasma, accumulation of
CC cholesteryl esters, premature coronary artery disease (CAD),
CC hepatosplenomegaly, recurrent peripheral neuropathy and
CC progressive muscle wasting and weakness. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: High density lipoprotein deficiency 2 (HDLD2)
CC [MIM:604091]: Inherited as autosomal dominant trait. It is
CC characterized by moderately low HDL cholesterol, predilection
CC toward premature coronary artery disease (CAD) and a reduction in
CC cellular cholesterol efflux. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCA
CC family.
CC -!- SIMILARITY: Contains 2 ABC transporter domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD49849.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAA10005.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ABCA1";
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;=ABCA1";
CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC
CC proteins;
CC URL="http://abcmutations.hegelab.org/proteinDetails?uniprot_id=O95477";
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; AF275948; AAF86276.1; -; Genomic_DNA.
DR EMBL; AL353685; CAH72444.1; -; Genomic_DNA.
DR EMBL; AL359846; CAH72444.1; JOINED; Genomic_DNA.
DR EMBL; AL359846; CAH73579.1; -; Genomic_DNA.
DR EMBL; AL353685; CAH73579.1; JOINED; Genomic_DNA.
DR EMBL; AF285167; AAF98175.1; -; mRNA.
DR EMBL; AF287262; AAK43526.1; -; Genomic_DNA.
DR EMBL; AB055982; BAB63210.1; -; mRNA.
DR EMBL; AJ012376; CAA10005.1; ALT_INIT; mRNA.
DR EMBL; AF165281; AAD49849.1; ALT_INIT; mRNA.
DR EMBL; AF165286; AAD49851.1; -; Genomic_DNA.
DR EMBL; AF165282; AAD49851.1; JOINED; Genomic_DNA.
DR EMBL; AF165283; AAD49851.1; JOINED; Genomic_DNA.
DR EMBL; AF165284; AAD49851.1; JOINED; Genomic_DNA.
DR EMBL; AF165285; AAD49851.1; JOINED; Genomic_DNA.
DR EMBL; AF165306; AAD49852.1; -; Genomic_DNA.
DR EMBL; AF165287; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165288; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165289; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165290; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165291; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165292; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165293; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165294; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165295; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165296; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165297; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165298; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165299; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165300; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165301; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165302; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165303; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165304; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165305; AAD49852.1; JOINED; Genomic_DNA.
DR EMBL; AF165309; AAD49854.1; -; Genomic_DNA.
DR EMBL; AF165307; AAD49854.1; JOINED; Genomic_DNA.
DR EMBL; AF165308; AAD49854.1; JOINED; Genomic_DNA.
DR EMBL; AF165310; AAD49853.1; -; Genomic_DNA.
DR RefSeq; NP_005493.2; NM_005502.3.
DR UniGene; Hs.659274; -.
DR ProteinModelPortal; O95477; -.
DR DIP; DIP-29211N; -.
DR IntAct; O95477; 15.
DR MINT; MINT-239561; -.
DR ChEMBL; CHEMBL2362986; -.
DR DrugBank; DB00171; Adenosine triphosphate.
DR DrugBank; DB01016; Glibenclamide.
DR PhosphoSite; O95477; -.
DR PaxDb; O95477; -.
DR PRIDE; O95477; -.
DR Ensembl; ENST00000374736; ENSP00000363868; ENSG00000165029.
DR GeneID; 19; -.
DR KEGG; hsa:19; -.
DR UCSC; uc004bcl.3; human.
DR CTD; 19; -.
DR GeneCards; GC09M107543; -.
DR HGNC; HGNC:29; ABCA1.
DR MIM; 205400; phenotype.
DR MIM; 600046; gene+phenotype.
DR MIM; 604091; phenotype.
DR neXtProt; NX_O95477; -.
DR Orphanet; 425; Apolipoprotein A-I deficiency.
DR Orphanet; 31150; Tangier disease.
DR PharmGKB; PA24373; -.
DR eggNOG; COG1131; -.
DR HOVERGEN; HBG050436; -.
DR InParanoid; O95477; -.
DR KO; K05641; -.
DR OMA; FSMRSWS; -.
DR OrthoDB; EOG78D7J6; -.
DR PhylomeDB; O95477; -.
DR Reactome; REACT_111217; Metabolism.
DR SignaLink; O95477; -.
DR ChiTaRS; ABCA1; human.
DR GeneWiki; ABCA1; -.
DR GenomeRNAi; 19; -.
DR NextBio; 51; -.
DR PRO; PR:O95477; -.
DR ArrayExpress; O95477; -.
DR Bgee; O95477; -.
DR Genevestigator; O95477; -.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005887; C:integral to plasma membrane; IDA:BHF-UCL.
DR GO; GO:0045121; C:membrane raft; IDA:BHF-UCL.
DR GO; GO:0045335; C:phagocytic vesicle; IDA:BHF-UCL.
DR GO; GO:0008509; F:anion transmembrane transporter activity; ISS:BHF-UCL.
DR GO; GO:0034188; F:apolipoprotein A-I receptor activity; IDA:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IDA:BHF-UCL.
DR GO; GO:0016887; F:ATPase activity; IEA:InterPro.
DR GO; GO:0015485; F:cholesterol binding; IC:BHF-UCL.
DR GO; GO:0017127; F:cholesterol transporter activity; IDA:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; IC:BHF-UCL.
DR GO; GO:0005548; F:phospholipid transporter activity; IDA:BHF-UCL.
DR GO; GO:0006200; P:ATP catabolic process; IEA:GOC.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0071300; P:cellular response to retinoic acid; IEA:Ensembl.
DR GO; GO:0033344; P:cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0042632; P:cholesterol homeostasis; IDA:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IDA:BHF-UCL.
DR GO; GO:0016197; P:endosomal transport; IDA:BHF-UCL.
DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0034380; P:high-density lipoprotein particle assembly; IMP:BHF-UCL.
DR GO; GO:0050702; P:interleukin-1 beta secretion; IMP:BHF-UCL.
DR GO; GO:0032367; P:intracellular cholesterol transport; IMP:BHF-UCL.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0007040; P:lysosome organization; IDA:BHF-UCL.
DR GO; GO:0010887; P:negative regulation of cholesterol storage; TAS:BHF-UCL.
DR GO; GO:0010745; P:negative regulation of macrophage derived foam cell differentiation; TAS:BHF-UCL.
DR GO; GO:0002790; P:peptide secretion; IEA:Ensembl.
DR GO; GO:0006911; P:phagocytosis, engulfment; IEA:Ensembl.
DR GO; GO:0033700; P:phospholipid efflux; IDA:BHF-UCL.
DR GO; GO:0055091; P:phospholipid homeostasis; IMP:BHF-UCL.
DR GO; GO:0045332; P:phospholipid translocation; IEA:Ensembl.
DR GO; GO:0060155; P:platelet dense granule organization; IMP:BHF-UCL.
DR GO; GO:0030819; P:positive regulation of cAMP biosynthetic process; IMP:BHF-UCL.
DR GO; GO:0010875; P:positive regulation of cholesterol efflux; IEA:Ensembl.
DR GO; GO:0006497; P:protein lipidation; IEA:Ensembl.
DR GO; GO:0032489; P:regulation of Cdc42 protein signal transduction; IMP:BHF-UCL.
DR GO; GO:0034616; P:response to laminar fluid shear stress; IEP:BHF-UCL.
DR GO; GO:0055098; P:response to low-density lipoprotein particle stimulus; IEP:BHF-UCL.
DR GO; GO:0043691; P:reverse cholesterol transport; IMP:BHF-UCL.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR026082; ABC_A.
DR InterPro; IPR003439; ABC_transporter-like.
DR InterPro; IPR017871; ABC_transporter_CS.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR19229; PTHR19229; 1.
DR Pfam; PF00005; ABC_tran; 2.
DR SMART; SM00382; AAA; 2.
DR SUPFAM; SSF52540; SSF52540; 2.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 1.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 1: Evidence at protein level;
KW Atherosclerosis; ATP-binding; Cholesterol metabolism;
KW Complete proteome; Disease mutation; Disulfide bond; Glycoprotein;
KW Lipid metabolism; Lipoprotein; Membrane; Nucleotide-binding;
KW Palmitate; Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Steroid metabolism; Sterol metabolism; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1 2261 ATP-binding cassette sub-family A member
FT 1.
FT /FTId=PRO_0000093288.
FT TRANSMEM 22 42 Helical; (Potential).
FT TOPO_DOM 43 639 Extracellular.
FT TRANSMEM 640 660 Helical; (Potential).
FT TRANSMEM 683 703 Helical; (Potential).
FT TRANSMEM 716 736 Helical; (Potential).
FT TRANSMEM 745 765 Helical; (Potential).
FT TRANSMEM 777 797 Helical; (Potential).
FT TRANSMEM 827 847 Helical; (Potential).
FT TRANSMEM 1041 1057 Helical; (Potential).
FT TRANSMEM 1351 1371 Helical; (Potential).
FT TOPO_DOM 1372 1656 Extracellular.
FT TRANSMEM 1657 1677 Helical; (Potential).
FT TRANSMEM 1703 1723 Helical; (Potential).
FT TRANSMEM 1735 1755 Helical; (Potential).
FT TRANSMEM 1768 1788 Helical; (Potential).
FT TRANSMEM 1802 1822 Helical; (Potential).
FT TRANSMEM 1852 1872 Helical; (Potential).
FT DOMAIN 899 1131 ABC transporter 1.
FT DOMAIN 1912 2144 ABC transporter 2.
FT NP_BIND 933 940 ATP 1 (Potential).
FT NP_BIND 1946 1953 ATP 2 (Potential).
FT MOD_RES 1042 1042 Phosphoserine; by PKA.
FT MOD_RES 1296 1296 Phosphoserine (By similarity).
FT MOD_RES 2054 2054 Phosphoserine; by PKA.
FT LIPID 3 3 S-palmitoyl cysteine.
FT LIPID 23 23 S-palmitoyl cysteine.
FT LIPID 1110 1110 S-palmitoyl cysteine.
FT LIPID 1111 1111 S-palmitoyl cysteine.
FT CARBOHYD 14 14 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 98 98 N-linked (GlcNAc...).
FT CARBOHYD 151 151 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 161 161 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 196 196 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 244 244 N-linked (GlcNAc...).
FT CARBOHYD 292 292 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 337 337 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 349 349 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 400 400 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 478 478 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 489 489 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 521 521 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 820 820 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1144 1144 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1294 1294 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1453 1453 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1504 1504 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1637 1637 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2044 2044 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2238 2238 N-linked (GlcNAc...) (Potential).
FT DISULFID 75 309
FT DISULFID 1463 1477
FT VARIANT 85 85 P -> L (in HDLD2; Alabama;
FT dbSNP:rs145183203).
FT /FTId=VAR_017529.
FT VARIANT 210 210 E -> D (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035724.
FT VARIANT 219 219 R -> K (common polymorphism; associated
FT with a decreased severity of CAD;
FT dbSNP:rs2230806).
FT /FTId=VAR_012618.
FT VARIANT 230 230 R -> C (in HDLD2; dbSNP:rs9282541).
FT /FTId=VAR_012619.
FT VARIANT 248 248 P -> A.
FT /FTId=VAR_062481.
FT VARIANT 255 255 A -> T (in HDLD1; deficient cellular
FT cholesterol efflux).
FT /FTId=VAR_012620.
FT VARIANT 284 284 E -> K (in HDLD1).
FT /FTId=VAR_062482.
FT VARIANT 364 364 S -> C.
FT /FTId=VAR_062483.
FT VARIANT 399 399 V -> A (in dbSNP:rs9282543).
FT /FTId=VAR_009145.
FT VARIANT 401 401 K -> Q.
FT /FTId=VAR_062484.
FT VARIANT 482 482 Y -> C (in HDLD1).
FT /FTId=VAR_062485.
FT VARIANT 496 496 R -> W (associated with increased plasma
FT HDL cholesterol; dbSNP:rs147675550).
FT /FTId=VAR_062486.
FT VARIANT 587 587 R -> W (in HDLD1; dbSNP:rs2853574).
FT /FTId=VAR_009146.
FT VARIANT 590 590 W -> L (in HDLD1).
FT /FTId=VAR_062487.
FT VARIANT 590 590 W -> S (in HDLD1).
FT /FTId=VAR_009147.
FT VARIANT 597 597 Q -> R (in HDLD1; dbSNP:rs2853578).
FT /FTId=VAR_009148.
FT VARIANT 638 638 R -> Q (associated with reduced plasma
FT HDL cholesterol).
FT /FTId=VAR_062488.
FT VARIANT 693 693 Missing (in HDLD2).
FT /FTId=VAR_009149.
FT VARIANT 771 771 V -> M (associated with HDL cholesterol;
FT dbSNP:rs2066718).
FT /FTId=VAR_012621.
FT VARIANT 774 774 T -> P (in dbSNP:rs35819696).
FT /FTId=VAR_012622.
FT VARIANT 774 774 T -> S.
FT /FTId=VAR_062489.
FT VARIANT 776 776 K -> N (may be associated with increased
FT risk of ischemic heart disease;
FT dbSNP:rs138880920).
FT /FTId=VAR_012623.
FT VARIANT 815 815 E -> G (associated with reduced plasma
FT HDL cholesterol; dbSNP:rs145582736).
FT /FTId=VAR_062490.
FT VARIANT 825 825 V -> I (associated with higher plasma
FT cholesterol; dbSNP:rs2066715).
FT /FTId=VAR_012624.
FT VARIANT 840 840 W -> R (in HDLD1).
FT /FTId=VAR_062491.
FT VARIANT 883 883 I -> M (associated with higher plasma
FT cholesterol; dbSNP:rs2066714).
FT /FTId=VAR_012625.
FT VARIANT 917 917 D -> Y (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035725.
FT VARIANT 929 929 T -> I (in HDLD1).
FT /FTId=VAR_012626.
FT VARIANT 935 935 N -> H (in HDLD1; dbSNP:rs28937314).
FT /FTId=VAR_037968.
FT VARIANT 935 935 N -> S (in HDLD1; dbSNP:rs28937313).
FT /FTId=VAR_009150.
FT VARIANT 937 937 A -> V (in HDLD1).
FT /FTId=VAR_009151.
FT VARIANT 1046 1046 A -> D (in HDLD1).
FT /FTId=VAR_012627.
FT VARIANT 1054 1054 V -> I (in dbSNP:rs13306072).
FT /FTId=VAR_037969.
FT VARIANT 1065 1065 P -> S.
FT /FTId=VAR_062492.
FT VARIANT 1068 1068 R -> C (in HDLD1).
FT /FTId=VAR_062493.
FT VARIANT 1091 1091 M -> T (in HDLD2).
FT /FTId=VAR_012628.
FT VARIANT 1099 1099 D -> Y (in HDLD2; dbSNP:rs28933692).
FT /FTId=VAR_017530.
FT VARIANT 1172 1172 E -> D (associated with premature
FT coronary heart disease;
FT dbSNP:rs33918808).
FT /FTId=VAR_012629.
FT VARIANT 1181 1181 S -> F (associated with reduced plasma
FT HDL cholesterol; dbSNP:rs76881554).
FT /FTId=VAR_017016.
FT VARIANT 1216 1216 G -> V.
FT /FTId=VAR_062494.
FT VARIANT 1289 1289 D -> N (in HDLD1).
FT /FTId=VAR_009152.
FT VARIANT 1341 1341 R -> T (associated with reduced plasma
FT HDL cholesterol; dbSNP:rs147743782).
FT /FTId=VAR_062495.
FT VARIANT 1376 1376 S -> G.
FT /FTId=VAR_062496.
FT VARIANT 1379 1379 L -> F (in HDLD1; the mutant protein is
FT retained in the endoplasmic reticulum
FT while the wild-type protein is located at
FT the plasma membrane).
FT /FTId=VAR_062497.
FT VARIANT 1407 1407 A -> T (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035726.
FT VARIANT 1477 1477 C -> R (in HDLD1).
FT /FTId=VAR_009153.
FT VARIANT 1506 1506 S -> L (in HDLD1).
FT /FTId=VAR_012630.
FT VARIANT 1517 1517 I -> R (in HDLD1).
FT /FTId=VAR_009154.
FT VARIANT 1555 1555 I -> T (in dbSNP:rs1997618).
FT /FTId=VAR_012638.
FT VARIANT 1587 1587 K -> R (associated with HDL cholesterol;
FT dbSNP:rs2230808).
FT /FTId=VAR_012631.
FT VARIANT 1611 1611 N -> D (probable disease-associated
FT mutation; associated with
FT atherosclerosis; deficient cellular
FT cholesterol efflux).
FT /FTId=VAR_012632.
FT VARIANT 1615 1615 R -> Q (associated with reduced plasma
FT HDL cholesterol).
FT /FTId=VAR_062498.
FT VARIANT 1648 1648 L -> P (in dbSNP:rs1883024).
FT /FTId=VAR_012639.
FT VARIANT 1670 1670 A -> T (associated with reduced plasma
FT HDL cholesterol).
FT /FTId=VAR_062499.
FT VARIANT 1680 1680 R -> Q (associated with increased plasma
FT HDL cholesterol; dbSNP:rs150125857).
FT /FTId=VAR_062500.
FT VARIANT 1680 1680 R -> W (in HDLD1; dbSNP:rs137854498).
FT /FTId=VAR_037970.
FT VARIANT 1704 1704 V -> D (in HDLD1; the mutant protein is
FT retained in the endoplasmic reticulum
FT while the wild-type protein is located at
FT the plasma membrane).
FT /FTId=VAR_062501.
FT VARIANT 1731 1731 S -> C.
FT /FTId=VAR_012633.
FT VARIANT 1800 1800 N -> H (in HDLD1).
FT /FTId=VAR_009155.
FT VARIANT 1851 1851 R -> Q (in HDLD1).
FT /FTId=VAR_062502.
FT VARIANT 1893 1894 Missing (in HDLD2).
FT /FTId=VAR_012634.
FT VARIANT 1897 1897 R -> W (in HDLD2; uncertain pathological
FT significance).
FT /FTId=VAR_062503.
FT VARIANT 1901 1901 R -> S (in HDLD1).
FT /FTId=VAR_062504.
FT VARIANT 1925 1925 R -> Q (in Scott syndrome; shows impaired
FT trafficking of the mutant protein to the
FT plasma membrane; dbSNP:rs142688906).
FT /FTId=VAR_062505.
FT VARIANT 2009 2009 F -> S (in HDLD2).
FT /FTId=VAR_037971.
FT VARIANT 2081 2081 R -> W (in HDLD1).
FT /FTId=VAR_012635.
FT VARIANT 2109 2109 A -> T (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035727.
FT VARIANT 2150 2150 P -> L (in HDLD2).
FT /FTId=VAR_012636.
FT VARIANT 2163 2163 F -> S (could be associated with reduced
FT plasma HDL cholesterol).
FT /FTId=VAR_062506.
FT VARIANT 2168 2168 L -> P (in dbSNP:rs2853577).
FT /FTId=VAR_012637.
FT VARIANT 2196 2196 Q -> H (in HDLD1).
FT /FTId=VAR_062507.
FT VARIANT 2243 2243 D -> E (in dbSNP:rs34879708).
FT /FTId=VAR_062508.
FT VARIANT 2244 2244 V -> I (could be associated with reduced
FT plasma HDL cholesterol;
FT dbSNP:rs144588452).
FT /FTId=VAR_062509.
FT CONFLICT 793 793 Y -> C (in Ref. 3; AAK43526).
FT CONFLICT 831 831 D -> N (in Ref. 3; AAK43526).
FT CONFLICT 1005 1005 E -> K (in Ref. 3; AAK43526).
FT CONFLICT 1745 1746 Missing (in Ref. 7; AAD49852).
SQ SEQUENCE 2261 AA; 254302 MW; 21A2CF8F3F518D6D CRC64;
MACWPQLRLL LWKNLTFRRR QTCQLLLEVA WPLFIFLILI SVRLSYPPYE QHECHFPNKA
MPSAGTLPWV QGIICNANNP CFRYPTPGEA PGVVGNFNKS IVARLFSDAR RLLLYSQKDT
SMKDMRKVLR TLQQIKKSSS NLKLQDFLVD NETFSGFLYH NLSLPKSTVD KMLRADVILH
KVFLQGYQLH LTSLCNGSKS EEMIQLGDQE VSELCGLPRE KLAAAERVLR SNMDILKPIL
RTLNSTSPFP SKELAEATKT LLHSLGTLAQ ELFSMRSWSD MRQEVMFLTN VNSSSSSTQI
YQAVSRIVCG HPEGGGLKIK SLNWYEDNNY KALFGGNGTE EDAETFYDNS TTPYCNDLMK
NLESSPLSRI IWKALKPLLV GKILYTPDTP ATRQVMAEVN KTFQELAVFH DLEGMWEELS
PKIWTFMENS QEMDLVRMLL DSRDNDHFWE QQLDGLDWTA QDIVAFLAKH PEDVQSSNGS
VYTWREAFNE TNQAIRTISR FMECVNLNKL EPIATEVWLI NKSMELLDER KFWAGIVFTG
ITPGSIELPH HVKYKIRMDI DNVERTNKIK DGYWDPGPRA DPFEDMRYVW GGFAYLQDVV
EQAIIRVLTG TEKKTGVYMQ QMPYPCYVDD IFLRVMSRSM PLFMTLAWIY SVAVIIKGIV
YEKEARLKET MRIMGLDNSI LWFSWFISSL IPLLVSAGLL VVILKLGNLL PYSDPSVVFV
FLSVFAVVTI LQCFLISTLF SRANLAAACG GIIYFTLYLP YVLCVAWQDY VGFTLKIFAS
LLSPVAFGFG CEYFALFEEQ GIGVQWDNLF ESPVEEDGFN LTTSVSMMLF DTFLYGVMTW
YIEAVFPGQY GIPRPWYFPC TKSYWFGEES DEKSHPGSNQ KRISEICMEE EPTHLKLGVS
IQNLVKVYRD GMKVAVDGLA LNFYEGQITS FLGHNGAGKT TTMSILTGLF PPTSGTAYIL
GKDIRSEMST IRQNLGVCPQ HNVLFDMLTV EEHIWFYARL KGLSEKHVKA EMEQMALDVG
LPSSKLKSKT SQLSGGMQRK LSVALAFVGG SKVVILDEPT AGVDPYSRRG IWELLLKYRQ
GRTIILSTHH MDEADVLGDR IAIISHGKLC CVGSSLFLKN QLGTGYYLTL VKKDVESSLS
SCRNSSSTVS YLKKEDSVSQ SSSDAGLGSD HESDTLTIDV SAISNLIRKH VSEARLVEDI
GHELTYVLPY EAAKEGAFVE LFHEIDDRLS DLGISSYGIS ETTLEEIFLK VAEESGVDAE
TSDGTLPARR NRRAFGDKQS CLRPFTEDDA ADPNDSDIDP ESRETDLLSG MDGKGSYQVK
GWKLTQQQFV ALLWKRLLIA RRSRKGFFAQ IVLPAVFVCI ALVFSLIVPP FGKYPSLELQ
PWMYNEQYTF VSNDAPEDTG TLELLNALTK DPGFGTRCME GNPIPDTPCQ AGEEEWTTAP
VPQTIMDLFQ NGNWTMQNPS PACQCSSDKI KKMLPVCPPG AGGLPPPQRK QNTADILQDL
TGRNISDYLV KTYVQIIAKS LKNKIWVNEF RYGGFSLGVS NTQALPPSQE VNDAIKQMKK
HLKLAKDSSA DRFLNSLGRF MTGLDTKNNV KVWFNNKGWH AISSFLNVIN NAILRANLQK
GENPSHYGIT AFNHPLNLTK QQLSEVALMT TSVDVLVSIC VIFAMSFVPA SFVVFLIQER
VSKAKHLQFI SGVKPVIYWL SNFVWDMCNY VVPATLVIII FICFQQKSYV SSTNLPVLAL
LLLLYGWSIT PLMYPASFVF KIPSTAYVVL TSVNLFIGIN GSVATFVLEL FTDNKLNNIN
DILKSVFLIF PHFCLGRGLI DMVKNQAMAD ALERFGENRF VSPLSWDLVG RNLFAMAVEG
VVFFLITVLI QYRFFIRPRP VNAKLSPLND EDEDVRRERQ RILDGGGQND ILEIKELTKI
YRRKRKPAVD RICVGIPPGE CFGLLGVNGA GKSSTFKMLT GDTTVTRGDA FLNKNSILSN
IHEVHQNMGY CPQFDAITEL LTGREHVEFF ALLRGVPEKE VGKVGEWAIR KLGLVKYGEK
YAGNYSGGNK RKLSTAMALI GGPPVVFLDE PTTGMDPKAR RFLWNCALSV VKEGRSVVLT
SHSMEECEAL CTRMAIMVNG RFRCLGSVQH LKNRFGDGYT IVVRIAGSNP DLKPVQDFFG
LAFPGSVLKE KHRNMLQYQL PSSLSSLARI FSILSQSKKR LHIEDYSVSQ TTLDQVFVNF
AKDQSDDDHL KDLSLHKNQT VVDVAVLTSF LQDEKVKESY V
//

MIM 205400
*RECORD*
*FIELD* NO
205400
*FIELD* TI
#205400 TANGIER DISEASE; TGD
;;HIGH DENSITY LIPOPROTEIN DEFICIENCY, TYPE 1; HDLDT1;;
read moreHIGH DENSITY LIPOPROTEIN DEFICIENCY, TANGIER TYPE;;
ANALPHALIPOPROTEINEMIA
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder can be caused by mutation in the ATP-binding cassette-1 gene
(ABCA1; 600046).

A more common form of genetic HDL deficiency, familial HDL deficiency
(604091), is allelic to Tangier disease.

DESCRIPTION

Tangier disease is an autosomal recessive disorder characterized by
markedly reduced levels of plasma high density lipoproteins (HDL)
resulting in tissue accumulation of cholesterol esters. Clinical
features include very large, yellow-orange tonsils, enlarged liver,
spleen and lymph nodes, hypocholesterolemia, and abnormal chylomicron
remnants (Brooks-Wilson et al., 1999).

CLINICAL FEATURES

Tangier disease was originally described and named on the basis of a
kindred living in Tangier Island in the Chesapeake Bay (Fredrickson et
al., 1961), most of whom were descendants of first settlers of 1686.
Other affected families have been discovered in Missouri and Kentucky.
The 2 hallmarks of the disease, enlarged lipid-laden tonsils and low
serum HDL, were based on the initial description of the original
kindred. Engel et al. (1967) observed that patients with Tangier disease
had recurrent peripheral neuropathy, intestinal lipid storage, and
decreased serum alpha-lipoproteins. Obligate heterozygotes also had
decreased serum alpha-lipoproteins.

Kocen et al. (1967) described a 37-year-old British air force corporal
with Tangier disease who showed widespread loss of pain and temperature
sensation and progressive muscle wasting and weakness. They commented
that, whereas the characteristic pharyngeal appearance had been the
presenting feature in children, adolescents tended to present with
relapsing peripheral neuropathy, and adults with hypersplenism or
precocious coronary artery disease.

Hypocholesterolemia was a tip-off to the diagnosis in a 38-year-old
patient with Tangier disease described by Brook et al. (1977). Assmann
et al. (1977) reported cases in Germany.

Pietrini et al. (1985) reported a case they alleged to be the
thirty-third in the 'world literature' and the second in Italy. A
complete tabulation of the 33 cases was given. Age at diagnosis varied
from 2 years to 67 years. The patient of Pietrini et al. (1985) had
widespread neuropathy with facial diplegia, bilateral wasting of the
hand muscles, and dissociated loss of pain and temperature sensation
sparing the distal parts of the limbs, known as a 'syringomyelia-like'
syndrome. First neurologic symptoms appeared at age 37; he burned the
base of the neck by application of an excessively hot heating pad and
noted induced sensation to heat and pain in some areas of the shoulder
and later in the hand and arm. Levels of apoA-I (107680) and HDL
cholesterol were very low and triglycerides were high.

Pressly et al. (1987) described a 66-year-old man with Tangier disease
and discussed the ocular complications, including corneal clouding,
decreased corneal sensation, cicatricial ectropion, and slowly
progressive visual impairment. The authors noted that ectropion and
incomplete eyelid closure may precede corneal clouding. The combination
of exposure keratopathy and corneal infiltration was responsible for the
visual impairment in their patient.

Dyck et al. (1978) studied a 67-year-old woman with typical biochemical
features of Tangier disease and a syringomyelia-like syndrome that has
been observed in other patients with adult onset. Over a period of 17
years, she had developed progressive facial diplegia, bilateral wasting
of hand muscles, and loss of sensation over cranial, cervical, and
brachial dermatomes.

Schaefer et al. (1980) presented data consistent with increased risk for
premature vascular disease in Tangier disease. However, the strikingly
accelerated atherosclerosis of familial hypercholesterolemia (143890)
was not seen, possibly because of the normal or reduced LDL cholesterol
levels.

Cheung et al. (1993) described a 48-year-old Caucasian female of central
European origin with very low apoprotein A-I and A-II (107670) and low
HDL cholesterol. She had most of the clinical features typical of
Tangier disease, including early corneal opacities, yellow-streaked
tonsils, hepatomegaly, and variable degrees of peripheral neuropathy,
but no splenomegaly. She had a myocardial infarction at the age of 46.

Schippling et al. (2008) reported a 49-year-old Afghan Caucasian patient
with Tangier syndrome who presented with a 15-year history of a
progressive syringomyelia-like syndrome with episodes of appendicular
stabbing pain. He had tonsillectomy at age 14. Physical examination
revealed marked distal atrophic weakness with absent tendon reflexes,
loss of pain and temperature sensation, trophic changes of nails and
skin, distal loss of facial hair, and mild splenomegaly. He had proximal
internal carotid artery stenosis (60% left, 50% right) on color coded
duplex sonography, left ventricular hypertrophy with reduced left
ventricular function on echocardiography, and severe coronary artery
disease with proximal LAD stenosis on coronary angiography. Laboratory
studies showed undetectable serum HDL and decreased total cholesterol
and apoA-I. Electrophysiologic studies demonstrated a predominantly
axonal sensorimotor polyneuropathy with signs of chronic and active
denervation and mild to moderate demyelination. Sural nerve biopsy
showed de- and remyelination, endoneurial fibrosis, and deposition of
fat droplets in axons and Schwann cells. Relatively low levels of HDL
were also found in the patient's mother and the 2 daughters, consistent
with heterozygosity. Genetic analysis identified a homozygous truncating
mutation in the ABCA1 gene, consistent with complete loss of protein
function.

PATHOGENESIS

Schmitz et al. (1985) showed that in macrophages, subsequent to
receptor-mediated binding, HDL is internalized and then resecreted.
Studying human monocytes from normal subjects and from patients with
Tangier disease, Schmitz et al. (1985) found that HDL was internalized
but only a minor amount, most of which was degraded, was resecreted from
Tangier monocytes. They postulated that Tangier disease is a disorder of
intracellular membrane traffic in which HDL is diverted into the
lysosomal compartment and degraded instead of being secreted through its
regular transcellular route.

In contrast to 2 other monogenic HDL deficiencies in which defects in
the plasma proteins APOA1 and LCAT (606967) interfere primarily with the
formation of HDL, Tangier disease shows a defect in cell signaling and
the mobilization of cellular lipids (Rust et al., 1998).

Studies of cultured cells from the original Tangier kindred and others
were pivotal in confirming the importance of the apolipoprotein-mediated
pathway in cholesterol and phospholipid cellular efflux in the reverse
cholesterol transport pathway (Remaley et al., 1999).

MAPPING

Rust et al. (1998) mapped the Tangier disease phenotype to chromosome
9q31 using a genomewide graphical linkage exclusion strategy in 1 large
pedigree complemented by classic lod score calculations at that region
in a total of 3 pedigrees. The results yielded a combined lod score of
10.05 at D9S1784. The studies of a mentally retarded boy with a
heterozygous de novo deletion of 9q22-q32 showed an HDL cholesterol
level below the 2.5 percentile. The HDL cholesterol in the parents of
the boy was normal. The findings in this boy were taken to support
assignment of the Tangier disease locus, and suggested that the disorder
results from a loss-of-function defect.

MOLECULAR GENETICS

- Exclusion of a Defect in the Apolipoprotein A-I Gene

HDL is the designation of lipoproteins derived from density properties
revealed by ultracentrifugation; alphalipoprotein is the designation
based on mobility in an electrophoretic system. The apoproteins of the
lipoproteins are named by their C-terminal amino acid (Schaefer et al.,
1978) Lux et al. (1972) demonstrated a marked reduction in 1 of the 2
major apoproteins of high density lipoprotein, 'Apo-Gln-I' (Apo-I).
Since no immunochemical difference could be demonstrated between this
apoprotein of Tangier disease and that of normals, they concluded that
Tangier disease could be caused by a mutation in a gene that regulates
the synthesis of Apo-Gln-I.

Schaefer et al. (1978, 1981) presented evidence suggesting that the
deficiency of apolipoproteins in Tangier disease was largely due to
increased rapid catabolism. Heterozygotes showed normal catabolism. Kay
et al. (1982) concluded that apoA-I in Tangier disease is abnormal in
amino acid composition, electrophoretic mobility, apparent molecular
weight on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, and
heterogeneity of isoforms on isoelectric focusing. Schmitz et al. (1983)
suggested that the underlying defect in Tangier disease is a faulty
conversion of pro-apoA-I to mature apoA-I, either because of a defect in
the converting enzyme activity or a specific structural defect in
Tangier apoA-I. Thus, the failure of Tangier pro-apoA-I to associate
with HDL may be at least partially responsible for the HDL deficiency in
Tangier subjects.

By restriction enzyme analysis, Rees et al. (1984) could demonstrate no
major deletion or insertion in the apoA-I gene in a patient with Tangier
disease. Law and Brewer (1985) derived the complete amino acid sequence
from the nucleic acid sequence of a cloned apoA-I cDNA from liver of a
patient with Tangier disease. The structure of Tangier preproapoA-I was
identical to the normal preproapoA-I except for a single base
substitution (G-to-T) which resulted in the isosteric substitution of
aspartic acid for glutamic acid at position 120. These results were
interpreted as indicating that there is no major structural defect in
Tangier apoA-I and that the rapid rate of catabolism must be from a
posttranslational defect in apoA-I metabolism. Specifically, a
structural defect at the propeptide cleavage site, as suggested by
Zannis et al. (1982), was excluded. Makrides et al. (1988) likewise
concluded that the APOA1 gene is structurally normal in patients with
Tangier disease. They isolated and characterized the gene from a
lambda-L47.1 genomic library constructed with DNA from lymphocytes of a
Tangier disease patient. The DNA-derived protein sequence of Tangier
apoA-I was found to be identical to normal apoA-I. Transfection into
mouse cells resulted in synthesis of a protein that was
indistinguishable from the apoA-I secreted by cultured normal human
cells.

- Mutations in the ABCA1 Gene

In 2 probands with Tangier disease, Brooks-Wilson et al. (1999)
identified compound heterozygous or homozygous mutations in the ABCA1
gene (600046.0001-600046.0003). One of the patients had presented with
acute myocardial infarction at 38 years of age; the second patient was
born of consanguineous parents and had been reported by Frohlich et al.
(1987).

Bodzioch et al. (1999) analyzed 5 kindreds with Tangier disease and
identified 7 different mutations in the ABCA1 gene, including 3 that
were predicted to impair the function of the gene product (see, e.g.,
600046.0005-600046.0008). Rust et al. (1999) likewise identified
mutations in the ABCA1 gene in Tangier disease
(600046.0009-600046.0010).

Remaley et al. (1999) demonstrated that in the original Tangier disease
family (Fredrickson et al., 1961) the disorder was caused by
homozygosity for a dinucleotide deletion in exon 22 of the ABCA1 gene
(600046.0011).

POPULATION GENETICS

Young and Fielding (1999) stated that the inhabitants of Tangier Island
in the Chesapeake Bay 'still speak a unique Elizabethan dialect, and
three-quarters of them bear one of four surnames from the original group
of founders.'

HISTORY

By identifying heterozygotes for Tangier disease, Suarez et al. (1982)
excluded close linkage to RH, MN, GPT, and GLO.

*FIELD* SA
Assmann et al. (1977); Assmann et al. (1977); Clifton-Bligh et al.
(1972); Ferrans and Fredrickson (1975); Fredrickson (1964); Fredrickson
et al. (1972); Greten et al. (1974); Pollock et al. (1983); Schmitz
et al. (1985); Utermann et al. (1975)
*FIELD* RF
1. Assmann, G.; Herbert, P. N.; Fredrickson, D. S.; Forte, T.: Isolation
and characterization of an abnormal high density lipoprotein in Tangier
disease. J. Clin. Invest. 60: 242-252, 1977.

2. Assmann, G.; Simantke, O.; Schaefer, H.-E.; Smootz, E.: Characterization
of high density lipoproteins in patients heterozygous for Tangier
disease. J. Clin. Invest. 60: 1025-1035, 1977.

3. Assmann, G.; Smootz, E.; Adler, K.; Capurso, A.; Oette, K.: The
lipoprotein abnormality in Tangier disease: quantitation of A apoproteins. J.
Clin. Invest. 59: 565-575, 1977.

4. Bodzioch, M.; Orso, E.; Klucken, J.; Langmann, T.; Bottcher, A.;
Diederich, W.; Drobnik, W.; Barlage, S.; Buchler, C.; Porsch-Ozcurumez,
M.; Kaminski, W. E.; Hahmann, H. W.; Oette, K.; Rothe, G.; Aslanidis,
C.; Lackner, K. J.; Schmitz, G.: The gene encoding ATP-binding cassette
transporter 1 is mutated in Tangier disease. Nature Genet. 22: 347-351,
1999.

5. Brook, J. G.; Lees, R. S.; Yules, J. H.; Cusack, B.: Tangier disease
(alpha-lipoprotein deficiency). JAMA 238: 332-334, 1977.

6. Brooks-Wilson, A.; Marcil, M.; Clee, S. M.; Zhang, L.-H.; Roomp,
K.; van Dam, M.; Yu, L.; Brewer, C.; Collins, J. A.; Molhuizen, H.
O. F.; Loubser, O.; Ouelette, B. F. F.; and 14 others: Mutations
in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nature
Genet. 22: 336-345, 1999.

7. Cheung, M. C.; Mendez, A. J.; Wolf, A. C.; Knopp, R. H.: Characterization
of apolipoprotein A-I- and A-II-containing lipoproteins in a new case
of high density lipoprotein deficiency resembling Tangier disease
and their effects on intracellular cholesterol efflux. J. Clin. Invest. 91:
522-529, 1993.

8. Clifton-Bligh, P.; Nestel, P. J.; Whyte, H. M.: Tangier disease:
report of a case and studies of lipid metabolism. New Eng. J. Med. 286:
567-571, 1972.

9. Dyck, P. J.; Ellefson, R. D.; Yao, J. K.; Herbert, P. N.: Adult-onset
of Tangier disease: 1. Morphometric and pathologic studies suggesting
delayed degradation of neutral lipids after fiber degeneration. J.
Neuropath. Exp. Neurol. 37: 119-137, 1978.

10. Engel, W. K.; Dorman, J. D.; Levy, R. I.; Fredrickson, D. S.:
Neuropathy in Tangier disease. Alpha-lipoprotein deficiency manifesting
as familial recurrent neuropathy and intestinal lipid storage. Arch.
Neurol. 17: 1-9, 1967.

11. Ferrans, V. J.; Fredrickson, D. S.: The pathology of Tangier
disease: a light and electron microscopic study. Am. J. Path. 78:
101-158, 1975.

12. Fredrickson, D. S.: The inheritance of high density lipoprotein
deficiency (Tangier disease). J. Clin. Invest. 43: 228-236, 1964.

13. Fredrickson, D. S.; Altrocchi, P. H.; Avioli, L. V.; Goodman,
D. S.; Goodman, H. C.: Tangier disease. Ann. Intern. Med. 55: 1016-1031,
1961.

14. Fredrickson, D. S.; Gotto, A. M.; Levy, R. I.: Lipoprotein deficiency.In:
Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.: The Metabolic
Basis of Inherited Disease. New York: McGraw-Hill (pub.) (3rd
ed.): 1972. Pp. 493-530.

15. Frohlich, J.; Fong, B.; Julien, P; Despres, J. P.; Angel, A.;
Hayden, M.; McLeod, R.; Chow, C.; Davison, R. H.; Pritchard, H.:
Interaction of high density lipoprotein with adipocytes in a new patient
with Tangier disease. Clin. Invest. Med. 10: 377-382, 1987.

16. Greten, H.; Hannemann, T.; Gusek, W.; Vivell, O.: Lipoproteins
and lipolytic plasma enzymes in a case of Tangier disease. New Eng.
J. Med. 291: 548-552, 1974.

17. Kay, L. L.; Ronan, R.; Schaefer, E. J.; Brewer, H. B., Jr.: Tangier
disease: a structural defect in apolipoprotein A-I (apoA-I-Tangier). Proc.
Nat. Acad. Sci. 79: 2485-2489, 1982.

18. Kocen, R. S.; Lloyd, J. K.; Lascelles, P. T.; Fosbrooke, A. S.;
Williams, D.: Familial alpha-lipoprotein deficiency (Tangier disease)
with neurological abnormalities. Lancet 289: 1341-1345, 1967. Note:
Originally Volume I.

19. Law, S. W.; Brewer, H. B., Jr.: Tangier disease: the complete
mRNA sequence encoding for preproapo-A-I. J. Biol. Chem. 260: 12810-12814,
1985.

20. Lux, S. E.; Levy, R. I.; Gotto, A. M.; Fredrickson, D. S.: Studies
on the protein defect in Tangier disease. Isolation and characterization
of an abnormal high density lipoprotein. J. Clin. Invest. 51: 2505-2519,
1972.

21. Makrides, S. C.; Ruiz-Opazo, N.; Hayden, M.; Nussbaum, A. L.;
Breslow, J. L.; Zannis, V. I.: Sequence and expression of Tangier
apoA-I gene. Europ. J. Biochem. 173: 465-471, 1988.

22. Pietrini, V.; Rizzuto, N.; Vergani, C.; Zen, F.; Ferro Milone,
F.: Neuropathy in Tangier disease: a clinicopathologic study and
a review of the literature. Acta Neurol. Scand. 72: 495-505, 1985.

23. Pollock, M.; Nukada, H.; Frith, R. W.; Simcock, J. P.; Allpress,
S.: Peripheral neuropathy in Tangier disease. Brain 106: 911-928,
1983.

24. Pressly, T. A.; Scott, W. J.; Ide, C. H.; Winkler, A.; Reams,
G. P.: Ocular complications of Tangier disease. Am. J. Med. 83:
991-994, 1987.

25. Rees, A.; Stocks, J.; Schoulders, C.; Carlson, L. A.; Baralle,
F. E.; Galton, D. J.: Restriction enzyme analysis of the apolipoprotein
A-I gene in fish eye disease and Tangier disease. Acta Med. Scand. 215:
235-237, 1984.

26. Remaley, A. T.; Rust, S.; Rosier, M.; Knapper, C.; Naudin, L.;
Broccardo, C.; Peterson, K. M.; Koch, C.; Arnould, I.; Prades, C.;
Duverger, N.; Funke, H.; Assman, G.; Dinger, M.; Dean, M.; Chimini,
G.; Santamarina-Fojo, S.; Fredrickson, D. S.; Denefle, P.; Brewer,
H. B., Jr.: Human ATP-binding cassette transporter 1 (ABC1): genomic
organization and identification of the genetic defect in the original
Tangier disease kindred. Proc. Nat. Acad. Sci. 96: 12685-12690,
1999.

27. Rust, S.; Rosier, M.; Funke, H.; Real, J.; Amoura, Z.; Piette,
J.-C.; Deleuze, J.-F.; Brewer, H. B.; Duverger, N.; Denefle, P.; Assmann,
G.: Tangier disease is caused by mutations in the gene encoding ATP-binding
cassette transporter 1. Nature Genet. 22: 352-355, 1999.

28. Rust, S.; Walter, M.; Funke, H.; von Eckardstein, A.; Cullen,
P.; Kroes, H. Y.; Hordijk, R.; Geisel, J.; Kastelein, J.; Molhuizen,
H. O. F.; Schreiner, M.; Mischke, A.; Hahmann, H. W.; Assmann, G.
: Assignment of Tangier disease to chromosome 9q31 by a graphical
linkage exclusion strategy. Nature Genet. 20: 96-98, 1998. Note:
Erratum: Nature Genet. 20: 312 only, 1998.

29. Schaefer, E. J.; Anderson, D. W.; Zech, L. A.; Lindgren, F. T.;
Bronzert, T. B.; Rubalcaba, E. A.; Brewer, H. B., Jr.: Metabolism
of high density lipoprotein subfractions and constituents in Tangier
disease following the infusion of high density lipoproteins. J. Lipid
Res. 22: 217-228, 1981.

30. Schaefer, E. J.; Blum, C. B.; Levy, R. I.; Jenkins, L. L.; Alaupovic,
P.; Foster, D. M.; Brewer, H. B., Jr.: Metabolism of high-density
lipoprotein apolipoproteins in Tangier disease. New Eng. J. Med. 299:
905-910, 1978.

31. Schaefer, E. J.; Zech, L. A.; Schwartz, D. E.; Brewer, H. B.:
Coronary heart disease prevalence and other clinical features in familial
high-density lipoprotein deficiency (Tangier disease). Ann. Intern.
Med. 93: 261-266, 1980.

32. Schippling, S.; Orth, M.; Beisiegel, U.; Rosenkranz, T.; Vogel,
P.; Munchau, A.; Hagel, C.; Seedorf, U.: Severe Tangier disease with
a novel ABCA1 gene mutation. Neurology 71: 1454-1455, 2008.

33. Schmitz, G.; Assmann, G.; Rall, S. C., Jr.; Mahley, R. W.: Tangier
disease: defective recombination of a specific Tangier apolipoprotein
A-I isoform (pro-apo A-I) with high density lipoproteins. Proc. Nat.
Acad. Sci. 80: 6081-6085, 1983.

34. Schmitz, G.; Assmann, G.; Robenek, H.; Brennhausen, B.: Tangier
disease: a disorder of intracellular membrane traffic. Proc. Nat.
Acad. Sci. 82: 6305-6309, 1985.

35. Schmitz, G.; Robenek, H.; Lohmann, U.; Assmann, G.: Interaction
of high density lipoproteins with cholesteryl ester-laden macrophages:
biochemical and morphological characterization of cell surface receptor
binding, endocytosis and resecretion of high density lipoproteins
by macrophages. EMBO J. 4: 613-622, 1985.

36. Suarez, B. K.; Schonfeld, G.; Sparkes, R. S.: Tangier disease:
heterozygote detection and linkage analysis. Hum. Genet. 60: 150-156,
1982.

37. Utermann, G.; Menzel, H. J.; Schoenborn, W.: Plasma lipoprotein
abnormalities in a case of primary high-density-lipoprotein (HDL)
deficiency. Clin. Genet. 8: 258-268, 1975.

38. Young, S. G.; Fielding, C. J.: The ABCs of cholesterol efflux. Nature
Genet. 22: 316-318, 1999.

39. Zannis, V. I.; Lees, A. M.; Lees, R. S.; Breslow, J. L.: Abnormal
apoprotein A-I isoprotein composition in patients with Tangier disease. J.
Biol. Chem. 257: 4978-4986, 1982.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Face];
Facial diplegia due to peripheral neuropathy;
[Eyes];
Corneal opacities;
Decreased corneal sensation due to peripheral neuropathy;
Cicatricial ectropion;
Incomplete eyelid closure;
Exposure keratopathy;
Visual impairment;
[Mouth];
Enlarged, yellow-orange tonsils

CARDIOVASCULAR:
[Heart];
Heart disease, premature;
Myocardial infarction;
Left ventricular hypertrophy;
[Vascular];
Coronary artery disease, premature;
Atherosclerosis

ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly

SKIN, NAILS, HAIR:
[Skin];
Dry skin;
[Nails];
Dystrophic nails;
[Hair];
Distal loss of facial hair

MUSCLE, SOFT TISSUE:
Distal muscle atrophy due to peripheral neuropathy

NEUROLOGIC:
Syringomyelia-like syndrome;
[Peripheral nervous system];
Peripheral axonal neuropathy;
Pain and temperature sensation loss;
Hyporeflexia;
Nerve biopsy showed demyelination, remyelination, and deposition of
fat droplets in axons

LABORATORY ABNORMALITIES:
Decreased serum HDL cholesterol;
Decreased or absent apolipoprotein A-I;
Accumulation of cholesterol esters in various tissues;
Deficient efflux of intracellular cholesterol

MOLECULAR BASIS:
Caused by mutation in the ATP-binding cassette, subfamily A, member
1 gene (ABCA1, 600046.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 2/24/2009

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

*FIELD* ED
joanna: 05/14/2009
ckniffin: 2/24/2009

*FIELD* CN
Cassandra L. Kniffin - updated: 2/24/2009
Victor A. McKusick - updated: 11/19/1999
Victor A. McKusick - updated: 8/2/1999
Victor A. McKusick - updated: 8/28/1998

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
terry: 11/13/2012
carol: 3/12/2012
terry: 6/3/2009
wwang: 2/27/2009
ckniffin: 2/24/2009
terry: 2/10/2009
carol: 10/14/2005
terry: 10/7/2005
cwells: 11/6/2003
ckniffin: 6/26/2002
alopez: 6/20/2002
alopez: 6/10/2002
alopez: 5/11/2001
carol: 8/8/2000
mcapotos: 12/16/1999
alopez: 11/19/1999
alopez: 8/3/1999
carol: 8/2/1999
alopez: 9/17/1998
alopez: 9/2/1998
alopez: 8/31/1998
terry: 8/28/1998
alopez: 6/10/1997
mimadm: 11/12/1995
davew: 8/26/1994
carol: 11/18/1993
carol: 2/25/1993
carol: 3/26/1992
supermim: 3/16/1992

MIM 600046
*RECORD*
*FIELD* NO
600046
*FIELD* TI
+600046 ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 1; ABCA1
;;ATP-BINDING CASSETTE 1; ABC1;;
read moreATP-BINDING CASSETTE TRANSPORTER 1;;
ABC TRANSPORTER 1;;
CHOLESTEROL EFFLUX REGULATORY PROTEIN; CERP
CORONARY HEART DISEASE IN FAMILIAL HYPERCHOLESTEROLEMIA, PROTECTION
AGAINST, INCLUDED;;
HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS
13, INCLUDED; HDLCQ13, INCLUDED
*FIELD* TX

DESCRIPTION

ABCA1 functions as a cholesterol efflux pump in the cellular lipid
removal pathway.

CLONING

By a PCR-based approach, Luciani et al. (1994) identified 2 novel
mammalian members of the family of ATP-binding cassette (ABC)
transporters designated ABC1 and ABC2 (600047). They belong to a group
of traffic ATPases encoded as a single multifunctional protein, such as
CFTR (602421) and P-glycoproteins (see 171050). Both ABC1 and ABC2 are
large, internally symmetrical molecules that contain complete
information for a functional 'channel-like' structure, a feature typical
of the mammalian transporters at the plasma membrane. In both ABC1 and
ABC2, the 2 halves of the molecules do not share extensive sequence
similarity, apart from the nucleotide binding domains. This feature,
shared with CFTR and with MRP1 (158343), is in contrast with the high
similarity shown by the 2 halves of P-glycoproteins. The finding argues
against internal gene duplication as the event giving rise to the
symmetric structure and favors the alternative hypothesis of the fusion
of 2 independently evolved genes encoding the 2 halves.

Using PCR primers based on the mouse sequence, Langmann et al. (1999)
amplified and cloned ABCA1 from differentiated mononuclear phagocytes.
The deduced 2,201-amino acid protein has a calculated molecular mass of
220 kD and contains 2 highly conserved ATP-binding cassettes including
Walker A and B motifs. The human and mouse ABCA1 proteins share 94%
sequence identity. Dot blot analysis of 50 tissues revealed ubiquitous
expression of ABCA1 mRNA, with highest expression in placenta, liver,
lung, adrenal glands, and all fetal tissues examined, and lowest
expression in kidney, pancreas, pituitary, mammary gland, and bone
marrow.

Santamarina-Fojo et al. (2000) reported the complete genomic sequence of
the ABCA1 gene. The transcription start site was 315 bp upstream of a
newly identified initiation methionine codon and encodes an ORF of 6,783
bp. Thus, the ABCA1 protein contains 2,261 amino acids. Analysis of the
1,453 bp 5-prime upstream of the transcriptional start site revealed
multiple binding sites for transcription factors with roles in lipid
metabolism.

Zhao et al. (2000) also obtained the full-length sequence of ABCA1.

GENE STRUCTURE

Remaley et al. (1999) reported that the organization of the human ABC1
gene is similar to that of the mouse Abc1 gene and other related ABC
genes. They found that the ABC1 gene contains 49 exons, ranging in size
from 33 to 249 bp, and is over 70 kb long.

Santamarina-Fojo et al. (2000) found that the ABCA1 gene spans 149 kb
and contains 50 exons. They identified 62 repetitive Alu sequences in
the 49 introns. Comparative analysis of the mouse and human ABCA1
promoter sequences identified specific regulatory elements that are
evolutionarily conserved.

Pullinger et al. (2000) analyzed the promoter region of ABCA1. They
identified 7 putative SP1 (189906)-binding sites, 4 sterol regulatory
elements (SREs) similar to the SRE of the low density lipoprotein
receptor (LDLR; 606945) promoter region, a CpG island, a possible weak
TATA box, 2 distal CCAAT sequences, and binding sites for several other
transcription factors.

MAPPING

By isotopic in situ hybridization, Luciani et al. (1994) mapped the ABC1
gene to 9q22-q31 and ABC2 to 9q34. In the mouse, the homologs map to
chromosomes 4 and 2, respectively, in regions showing homology of
synteny to human 9q. Previous results had suggested that the ancestral
chromosome split in the mouse lineage at an evolutionary breakpoint
situated between hexabrachion (187380) and gelsolin (137350), both of
which map to human chromosome 9 and to mouse chromosomes 4 and 2,
respectively. Thus, ABC1 and ABC2 probably originated through a
duplication event that took place before speciation and predated the
splitting of the ancestral chromosome equivalent to human 9q. Their
degree of sequence similarity, less impressive than that of the
P-glycoprotein isoforms, also argues for a duplication event occurring
at an earlier evolutionary stage.

GENE FAMILY

Decottignies and Goffeau (1997) found that the complete sequence of the
yeast genome predicts the existence of 29 proteins belonging to the
ubiquitous ATP-binding cassette (ABC) superfamily. Using binary
comparison, phylogenetic classification, and detection of conserved
amino acid residues, they classified the yeast ABC proteins in a total
of 6 clusters, including 10 subclusters of distinct predicted topology
and presumed distinct function. They pointed out that study of the yeast
ABC proteins provided insight into the physiologic function and
biochemical mechanisms of their human homologs, such as those involved
in cystic fibrosis, adrenoleukodystrophy (300100), Zellweger syndrome
(see 214100), multidrug resistance, and the antiviral activity of
interferons.

See TAP1 (170260) and TAP2 (170261) for related ABC transporters encoded
by genes on 6p21.3.

NOMENCLATURE

Since the protein encoded by ABC1 is a key gatekeeper influencing
intracellular cholesterol transport, Brooks-Wilson et al. (1999) named
it 'cholesterol efflux regulatory protein' (CERP).

GENE FUNCTION

Becq et al. (1997) expressed mouse Abc1 in Xenopus oocytes and found
that it is a cAMP-dependent and sulfonylurea-sensitive anion
transporter.

Lawn et al. (1999) concluded that ABC1 has the properties of a key
protein in the cellular lipid removal pathway.

Using primary macrophage cultures, Langmann et al. (1999) induced
expression of ABCA1 protein and mRNA with acetylated low density
lipoprotein. They reversed the increased expression with cholesterol
depletion through the addition of high density lipoprotein.

Young and Fielding (1999) commented on the role of ABC1 in cholesterol
efflux.

Using human ABCA1 expressed in the membrane fraction of sf9 insect
cells, Szakacs et al. (2001) found specific, Mg(2+)-dependent ATP
binding and low basal ATPase activity. Addition of potential lipid
substrates or lipid acceptors did not modify the ATPase activity or
nucleotide occlusion by ABCA1. Szakacs et al. (2001) speculated that
ABCA1 may be a regulatory protein or may require other protein partners
for full activation.

Tanaka et al. (2001) found that the electrophoretic mobilities of ABCA1
expressed in transfected HEK293 and COS-7 cells increased when treated
with N-glycosidase F, suggesting that ABCA1 is highly glycosylated. They
confirmed that ABCA1 binds ATP in the presence of Mg(2+) and showed that
ABCA1 expression supports apolipoprotein A-I (APOA1; 107680)-mediated
release of cholesterol and choline-phospholipids. They also demonstrated
loss of the N-terminal signal peptide in the mature protein. Confocal
microscopy showed cell surface immunolocalization in nonpermeabilized
cells.

Patients with Tangier disease (205400), caused by mutations in the ABCA1
gene (see MOLECULAR GENETICS), have a defect in cellular cholesterol
removal, which results in near zero plasma levels of HDL and in massive
tissue deposition of cholesteryl esters. Blocking the expression or
activity of ABC1 reduces apolipoprotein-mediated lipid efflux from
cultured cells, and increasing expression of ABC1 enhances it (Lawn et
al., 1999). ABC1 expression is induced by cholesterol loading and cAMP
treatment, and is reduced upon subsequent cholesterol removal by
apolipoproteins. The ABC1 protein is incorporated into the plasma
membrane in proportion to its level of expression.

In an elegant series of experiments designed to understand the effect of
retinoid X receptor (RXR; see 180245) activation on cholesterol balance,
Repa et al. (2000) treated animals with the rexinoid LG268. Animals
treated with rexinoid exhibited marked changes in cholesterol balance,
including inhibition of cholesterol absorption and repressed bile acid
synthesis. Studies with receptor-selective agonists revealed that
oxysterol receptors (LXRs, see 602423 and 600380) and the bile acid
receptor, FXR (603826), are the RXR heterodimeric partners that mediate
these effects by regulating expression of the reverse-cholesterol
transporter, ABC1, and the rate-limiting enzyme of bile acid synthesis,
CYP7A1 (118455), respectively. These RXR heterodimers serve as key
regulators in cholesterol homeostasis by governing reverse cholesterol
transport from peripheral tissues, bile acid synthesis in liver, and
cholesterol absorption in intestine. Activation of RXR/LXR heterodimers
inhibits cholesterol absorption by upregulation of ABC1 expression in
the small intestine. Activation of RXR/FXR heterodimers represses CYP7A1
expression and bile acid production, leading to a failure to solubilize
and absorb cholesterol. Studies have shown that RXR/FXR-mediated
repression of CYP7A1 is dominant over RXR/LXR-mediated induction of
CYP7A1, which explains why the rexinoid represses rather than activates
CYP7A1 (Lu et al., 2000). Activation of the LXR signaling pathway
results in the upregulation of ABC1 in peripheral cells, including
macrophages, to efflux free cholesterol for transport back to the liver
through high density lipoprotein, where it is converted to bile acids by
the LXR-mediated increase in CYP7A1 expression. Secretion of biliary
cholesterol in the presence of increased bile acid pools normally
results in enhanced reabsorption of cholesterol; however, with the
increased expression of ABC1 and efflux of cholesterol back into the
lumen, there is a reduction in cholesterol absorption and net excretion
of cholesterol and bile acid. Rexinoids therefore offer a novel class of
agents for treating elevated cholesterol.

Wang et al. (2003) showed that ABCA1 protein degradation is regulated by
a PEST sequence (a sequence rich in proline, glutamic acid, serine, and
threonine) in ABCA1 and is mediated by calpain protease (see 114170). In
a novel form of positive feedback control, the interaction of ABCA1 with
apolipoprotein A-I (APOA1; 107680) leads to inhibition of calpain
protease degradation and an increase in ABCA1 protein on the cell
surface. Wang et al. (2003) suggested that ABCA1 degradation by calpain
may represent a novel therapeutic approach to increasing macrophage
cholesterol efflux and decreasing atherosclerosis.

Singaraja et al. (2001) developed transgenic mice that expressed human
ABCA1. Increased total ABCA1 expression did not alter the pattern of
ABCA1 distribution, but resulted in increased cholesterol efflux,
elevated HDL cholesterol levels, and increased apoA1 and apoA2
expression. The authors also demonstrated, both in vitro and in vivo,
that the ABCA1 gene contains an internal promoter with LXR elements
within intron 1. Activation of this functional internal promoter by
oxysterols in vivo directly contributed to an increase in human-specific
mRNA and protein levels. Singaraja et al. (2001) identified a total of 3
novel ABCA1 transcripts with different transcription initiation sites
utilizing sequences in intron 1.

Neufeld et al. (2004) found that late endocytic trafficking was
defective in Tangier disease fibroblasts. Late endocytic vesicles
accumulated both cholesterol and sphingomyelin and were immobilized in a
perinuclear localization. The excess cholesterol in Tangier disease late
endocytic vesicles retained massive amounts of NPC1 (607623), which
traffics lysosomal cholesterol to other cellular sites. Exogenous apoA1
abrogated the cholesterol-induced retention of NPC1 in wildtype but not
Tangier disease late endosomes. Adenovirus-mediated expression of
fluorescence-tagged ABCA1 (ABCA1-GFP) in Tangier disease fibroblasts
corrected the late endocytic trafficking defects and restored
apoA1-mediated cholesterol efflux. ABCA1-GFP expression in wildtype
fibroblasts also reduced late endosome-associated NPC1, induced a marked
uptake of fluorescent apoA1 into ABCA1-GFP-containing endosomes that
shuttled between late endosomes and the cell surface, and enhanced
apoA1-mediated cholesterol efflux. Neufeld et al. (2004) concluded that
ABCA1 converts pools of late endocytic lipids that retain NPC1 to pools
that can associate with endocytosed apoA1 and be released from the cell
as nascent HDL.

Nofer et al. (2004) found that ABCA1 is expressed in platelet plasma
membranes. Platelets from Tangier patients and Abca1-deficient animals
showed impaired responses to collagen and to low concentrations of
thrombin, but their responses to ADP remained intact. Tangier platelets
were characterized by defective surface exposure of dense body and
lysosomal markers, and granules showed an abnormally high pH. Nofer et
al. (2004) presented evidence that the impaired response to activation
was a consequence of defective dense body function and decreased
liberation of agonists during activation. They concluded that ABCA1
deficiency results in a defect in the biogenesis of lysosome-related
organelles.

The sterol regulatory element-binding proteins SREBP1 (184756) and
SREBP2 (600481) are key transcription regulators of genes involved in
cholesterol biosynthesis and uptake. Najafi-Shoushtari et al. (2010)
demonstrated that the microRNAs miR33A (612156) and miR33B (613486)
embedded within introns of SREBP2 and SREBP1, respectively, target ABCA1
for posttranscriptional repression. Antisense inhibition of miR33 in
mouse and human cell lines caused upregulation of ABCA1 expression and
increased cholesterol efflux, and injection of mice on a western-type
diet with locked nucleic acid-antisense oligonucleotides resulted in
elevated plasma HDL. Najafi-Shoushtari et al. (2010) concluded that
miR33 acts in concert with the SREBP host genes to control cholesterol
homeostasis.

Rayner et al. (2010) demonstrated that miR33, an intronic microRNA
located within the SREBF2 gene, a transcriptional regulator of
cholesterol synthesis, modulates the expression of genes involved in
cellular cholesterol transport. In mouse and human cells, miR33
inhibited the expression of the ATP binding cassette transporter ABCA1,
thereby attenuating cholesterol efflux to apolipoprotein A1.

MiR33A and miR33B are intronic miRNAs whose encoding regions are
embedded in the sterol response element-binding protein genes SREBF2 and
SREBF1, respectively. These miRNAs repress expression of the cholesterol
transporter ABCA1, which is a key regulator of HDL biogenesis. Studies
in mice suggested that antagonizing miR33a may be an effective strategy
for raising plasma HDL levels and providing protection against
atherosclerosis; however, extrapolating these findings to humans is
complicated by the fact that mice lack miR33b, which is present only in
the SREBF1 gene of medium and large mammals. Rayner et al. (2011) showed
in African green monkeys that systemic delivery of an anti-miRNA
oligonucleotide that targets both miR33a and miR33b increased hepatic
expression of ABCA1 and induced a sustained increase in plasma HDL
levels over 12 weeks. Notably, miR33 antagonism in this nonhuman primate
model also increased the expression of miR33 target genes involved in
fatty acid oxidation (CROT, 606090; CPT1A, 600528; HADHB, 143450; and
PRKAA1, 602739) and reduced the expression of genes involved in fatty
acid synthesis (SREBF1; FASN, 600212; ACLY, 108728; and ACACA, 200350),
resulting in a marked suppression of the plasma levels of very low
density lipoprotein (VLDL)-associated triglycerides, a finding that had
not previously been observed in mice. Rayner et al. (2011) concluded
that their results established, in a model that is highly relevant to
humans, that pharmacologic inhibition of miR33a and miR33b is a
promising therapeutic strategy to raise plasma HDL and lower VLDL
triglyceride levels for the treatment of dyslipidemias that increase
cardiovascular disease risk.

MOLECULAR GENETICS

Zwarts et al. (2002) identified several SNPs in noncoding regions of
ABCA1 that may be important for the appropriate regulation of ABCA1
expression (i.e., in the promoter, intron 1, and the 5-prime
untranslated region), and examined the phenotypic effects of these SNPs
in 804 Dutch men with proven coronary artery disease. They presented
data suggesting that common variation in noncoding regions of ABCA1 may
significantly alter the severity of atherosclerosis, without necessarily
influencing plasma lipid levels.

- Tangier Disease and Familial Hypoalphalipoproteinemia

Brooks-Wilson et al. (1999), Bodzioch et al. (1999), and Rust et al.
(1999) identified mutations in the ABC1 gene in patients with Tangier
disease (205400), a disorder that is characterized by absence of high
density lipoprotein cholesterol from plasma, hepatosplenomegaly,
peripheral neuropathy, and frequently premature coronary artery disease.
In heterozygotes, HDL cholesterol levels are about one-half those of
normal individuals. Impaired cholesterol efflux from macrophages leads
to the presence of foam cells throughout the body, which may explain the
increased risk of coronary artery disease in some Tangier disease
families.

Lawn et al. (1999) detected different mutations in the ABC1 gene in 3
unrelated patients with Tangier disease.

The recessively inherited Tangier disease is sometimes referred to as
'high density lipoprotein deficiency of Tangier type 1.' A more common
form of genetic HDL deficiency has been described (familial
hypoalphalipoproteinemia, or FHA; 604091) in patients with dominantly
inherited low plasma HDL cholesterol, usually below the 5th percentile,
but with an absence of clinical manifestations of Tangier disease
(Marcil et al., 1995). Marcil et al. (1999) demonstrated that some
patients with FHA, or type 2 familial high density lipoprotein
deficiency, have reductions in cellular cholesterol efflux that is the
same as that observed in Tangier disease. Brooks-Wilson et al. (1999)
studied 4 French-Canadian families with FHA and demonstrated mutations
in the ABC1 gene, indicating that FHA is allelic to Tangier disease.

Remaley et al. (1999) identified a mutation in the ABC1 gene in the
original Tangier disease kindred. Sequence analysis of the ABC1 gene
revealed that the proband for Tangier disease was homozygous for a
deletion of nucleotides 3283 and 3284 (TC) in exon 22 (600046.0011). The
loss of an Mnl1 restriction site, which resulted from the deletion, was
used to establish the genotype of the rest of the kindred.

Guo et al. (2002) stated that more than 60 cases of Tangier disease had
been reported worldwide. Among Japanese patients, 9 unrelated cases,
including 3 in their report, had been described.

Fitzgerald et al. (2002) found that 5 missense mutations were expressed
at the plasma membrane but produced little or no apoA1-stimulated
cholesterol efflux when transfected into HEK293 cells. All mutants
except for one showed a marked decline in interaction between the ABCA1
mutant and apoA1. Fitzgerald et al. (2002) concluded that the deficits
shown by these mutations establish their causality in Tangier disease,
and that binding of apoA1 by ABCA1 is necessary, but not sufficient, to
stimulate cholesterol efflux.

Tanaka et al. (2003) determined that 3 mutations in the first
extracellular domain of ABCA1 showed little or no apoA1-mediated HDL
assembly when expressed in HEK293 cells. Two of these mutations were
associated with impaired glycosylation, retention in the endoplasmic
reticulum or the cis-Golgi complex, and failure to localize to the
plasma membrane.

- Association with Plasma Lipids

Heritable variation underlying complex traits is generally considered to
be conferred by common DNA sequence polymorphisms. Cohen et al. (2004)
tested whether rare DNA sequence variants collectively contribute to
variation in plasma levels of high density lipoprotein cholesterol
(HDLC). They sequenced 3 candidate genes that cause mendelian forms of
low HDLC levels in individuals from a population-based study. These
genes were ABCA1, which is the site of mutations causing Tangier
disease, APOA1 (107680), and LCAT (606967), which is the site of
mutations causing Norum disease (245900). Nonsynonymous sequence
variants were significantly more frequent (16% vs 2%) in individuals
with low HDLC (less than fifth percentile) than in those with high HDLC
(greater than 95th percentile). Similar findings were obtained in an
independent population, and biochemical studies indicated that most
sequence variants in the low HDLC group were functionally important.
Thus, rare alleles with major phenotypic effects contribute
significantly to low plasma HDLC levels in the general population.

In a study of a Swedish population of 1,177 individuals with a first
myocardial infarction event and 1,526 controls, Katzov et al. (2006)
found an association between the R219K polymorphism (600046.0024) and
serum levels of apolipoprotein B (APOB; 107730) and LDL cholesterol
among smokers, but not among nonsmokers.

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 rs3890182 (600046.0025) of ABCA1, 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 (e.g., CYP7A1, 118455; NPC1L1, 608010; SCARB1, 601040)
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
rs1883025 in the ABCA1 gene as having an effect on HDL cholesterol
concentrations with an effect size of -0.94 mg per deciliter and a P
value of 2 x 10(-33).

In a 76-year-old woman carrying a missense mutation in the SCARB1 gene
known to be associated with HDL cholesterol levels in the 95th
percentile (601040.0003; see HDLCQ6, 610762), but who had an HDLC level
at the 15th percentile and a history of early cerebrovascular disease
and coronary artery disease, Brunham et al. (2011) identified
heterozygosity for a missense mutation (V2091I) in the ABCA1 gene as
well. The authors suggested that ABCA1 mutations may be dominant to
SCARB1 mutations with respect to HDLC.

- Other Phenotypic Associations

In a patient with Scott syndrome (262890), Albrecht et al. (2005)
identified a heterozygous missense mutation (arg1925 to gln) in the
ABCA1 gene, which was not found in unaffected family members or
controls. However, both mutant and wildtype alleles were reduced in mRNA
expression, and the authors found no causative mutation for this
phenomenon in the ABCA1 gene or its proximal promoter. Albrecht et al.
(2005) suggested that a putative second mutation in a trans-acting
regulatory gene might be involved in the disorder in this patient.

For a discussion of a possible association between variation in the
ABCA1 gene and Alzheimer disease, see 104300.

ANIMAL MODEL

Orso et al. (2000) demonstrated that mice with a targeted inactivation
of Abc1 display morphologic abnormalities and perturbations in their
lipoprotein metabolism concordant with Tangier disease. ABC1 is
expressed on the plasma membrane and the Golgi complex, mediates
apolipoprotein AI (APOA1; 107680)-associated export of cholesterol and
phospholipids from the cell, and is regulated by cholesterol flux.
Structural and functional abnormalities in caveolar processing and the
trans-Golgi secretory pathway of cells lacking functional ABC1 indicated
that lipid export processes involving vesicular budding between the
Golgi and the plasma membrane were severely disturbed.

To investigate the role of the ABC1 protein in vivo, McNeish et al.
(2000) used gene targeting in embryonic stem cells to produce
ABC1-deficient mice. Lipid profiles in the knockout mice revealed a
reduction of approximately 70% in cholesterol, markedly reduced plasma
phospholipids, and an almost complete lack of high density lipoproteins,
when compared with wildtype littermates. Dramatic alterations in HDL
cholesterol and near absence of apolipoprotein AI were found.
Inactivation of the Abc1 gene led to an increase in the absorption of
cholesterol in mice fed a chow or a high fat and high cholesterol diet.
Histopathologic examination of knockout mice showed a striking
accumulation of lipid-laden macrophages and type II pneumocytes in the
lungs. The findings demonstrated that the knockout mice had
pathophysiologic hallmarks of human Tangier disease and highlighted the
capacity of ABC1 transporters to participate in the regulation of
dietary cholesterol absorption.

ABCA1 is expressed in Purkinje and cortical pyramidal neurons in the
central nervous system (Wellington et al., 2002), as well as in
astrocytes and microglia. Hirsch-Reinshagen et al. (2004) found that
astrocytes and microglia from Abca1-null mice showed impaired ability to
efflux cholesterol to exogenous apolipoprotein E (ApoE; 107741),
although residual efflux was present. The mutant cells showed increased
intracellular lipid accumulation compared to wildtype cells. In
addition, Abca1-null mice showed a 65% decrease in brain levels of ApoE
as a consequence of reduced ApoE secretion from mutant glial cells, with
the hippocampus and striatum being the most severely affected.
Hirsch-Reinshagen et al. (2004) concluded that ABCA1 plays a role in
cholesterol transport and ApoE metabolism in the central nervous system.

By analyzing brain tissue, cerebrospinal fluid, plasma, and primary
astrocyte cultures from wildtype, Abca1 +/-, and Abca1 -/- mice, Wahrle
et al. (2004) determined that deletion of Abca1 markedly affects
metabolism of apoE and cholesterol in the central nervous system and in
nascent lipoprotein particles secreted by cultured astrocytes.

Brunham et al. (2006) generated intestine-specific Abca1-null mice and
found that approximately 30% of the steady-state plasma HDL pool is
contributed by intestinal Abca1 in mice. HDL derived from intestinal
Abca1 appeared to be secreted directly into the circulation. Analysis of
lymph from liver-specific Abca1-null mice with very low plasma HDL
showed that HDL in lymph was predominantly derived from the plasma
compartment. Brunham et al. (2006) concluded that intestinal ABCA1 plays
a critical role in plasma HDL biogenesis in vivo.

Brunham et al. (2007) generated mice with specific inactivation of Abca1
in pancreatic beta cells and observed markedly impaired glucose
tolerance and defective insulin secretion but normal insulin
sensitivity. Islets isolated from these mice showed altered cholesterol
homeostasis and impaired insulin secretion in vivo. The authors found
that rosiglitazone, a thiazolidinedione, requires beta-cell Abca1 for
its beneficial effects on glucose tolerance. Brunham et al. (2007)
concluded that ABCA1 plays a role in beta-cell cholesterol homeostasis
and insulin secretion, and suggested that cholesterol accumulation may
contribute to beta-cell dysfunction in type 2 diabetes.

Yvan-Charvet et al. (2010) found that deletion of Abca1 and Abcg1
(603076) in mice led to additive defects in macrophage cholesterol
efflux and reverse cholesterol transport and accelerated atherosclerosis
in a susceptible hypercholesterolemic background. These double-knockout
mice also showed marked leukocytosis and infiltration of various organs
with macrophage foam cells. Yvan-Charvet et al. (2010) showed that mice
deficient in both Abca1 and Abcg1 displayed leukocytosis, a
transplantable myeloproliferative disorder, and a dramatic expansion of
the stem and progenitor cell population containing lineage-negative
Sca1+/Kit+ (164920) (LSK) in the bone marrow. Transplantation of
Abca1-null/Abcg1-null bone marrow into apolipoprotein A-1 (107680)
transgenic mice with elevated levels of high-density lipoprotein (HDL)
suppressed the LSK population, reduced leukocytosis, reversed the
myeloproliferative disorder, and accelerated atherosclerosis.
Yvan-Charvet et al. (2010) concluded that ABCA1, ABCG1, and HDL inhibit
the proliferation of hematopoietic stem and multipotential progenitor
cells and connect expansion of these populations with leukocytosis and
accelerated atherosclerosis.

*FIELD* AV
.0001
TANGIER DISEASE
ABCA1, CYS1417ARG

In the proband with Tangier disease (205400) in a Dutch family,
Brooks-Wilson et al. (1999) found compound heterozygosity for mutations
in the ABC1 gene. The mutation on 1 chromosome in the proband was a
T-to-C transition predicted to result in a cys1417-to-arg substitution.
The mutation was located in exon 30. The other mutation was a G-to-C
transversion in the splice donor site of exon 24, predicted to cause
alternative splicing, deleting a significant part of the transcript.

.0002
TANGIER DISEASE
ABCA1, IVS24DS, G-C

See 600046.0001 and Brooks-Wilson et al. (1999).

.0003
TANGIER DISEASE
ABCA1, GLN537ARG

In the proband of a Tangier disease (205400) family whose parents were
first cousins and in whom haplotype analysis predicted homozygosity,
Brooks-Wilson et al. (1999) indeed found homozygosity for an A-to-G
transition at nucleotide 1730 in exon 13, resulting in the substitution
of arginine for a conserved glutamine at residue 537.

.0004
HIGH DENSITY LIPOPROTEIN DEFICIENCY, TYPE 2
ABCA1, 3-BP DEL

In a French-Canadian family with familial high density lipoprotein
deficiency (604091) previously reported by Marcil et al. (1995),
Brooks-Wilson et al. (1999) found a 3-bp deletion that resulted in loss
of nucleotides 2017-2019 and deletion of a leucine at position 633,
which is conserved in mouse and C. elegans.

.0005
TANGIER DISEASE
ABCA1, 1-BP DEL, 1764G

In 1 of 5 families with Tangier disease (205400), Bodzioch et al. (1999)
found homozygosity for a 1-bp deletion, removing guanine at nucleotide
1764. This mutation, localized in codon 548, created a frameshift that
led to a premature translation stop 26 amino acids downstream of the
deletion site. The translation product was predicted to be nonfunctional
because it lacked 75% of the amino acid sequence, including all
transmembrane regions and both ATP-binding cassettes. Heterozygotes in
the family showed decreased HDL cholesterol levels. In this family and 1
other of the 5 reported by Bodzioch et al. (1999), premature coronary
artery disease was the major clinical manifestation. In the other 3
families, splenomegaly and hyperplasia of other lymphoid tissues were
prominent features.

.0006
TANGIER DISEASE
ABCA1, ASN875SER

In a family with Tangier disease (205400) reported by Bodzioch et al.
(1999), 2 affected individuals were homozygous for a 2744A-G transition
that changed asparagine to serine (N875S) in the highly conserved Walker
A motif of the amino terminal ATP-binding fold. Splenomegaly and
hyperplasia of other lymphoid tissues were prominent features.

.0007
TANGIER DISEASE
ABCA1, ALA877VAL

In a family with Tangier disease (205400), Bodzioch et al. (1999) found
compound heterozygosity for 2 missense mutations: a 2750C-T transition,
changing alanine to valine (A877V), and a 1709G-C transversion,
resulting in a trp530-to-ser (W530S) amino acid substitution.

.0008
TANGIER DISEASE
ABCA1, TRP530SER

See 600046.0007 and Bodzioch et al. (1999).

.0009
TANGIER DISEASE
ABCA1, 1-BP DEL, 1764G

In a German Tangier disease (205400) family with premature onset of
coronary artery disease, Rust et al. (1999) identified homozygosity for
a 1-bp deletion in exon 13 that caused a frameshift and introduction of
a stop codon at position 575. The mutation was predicted to result in
truncation of the encoded ABC1 protein and deletion of most of the
protein sequence, including both ATP-binding cassettes.

.0010
TANGIER DISEASE
ABCA1, 110-BP INS/14-BP DEL

In material from a family in Chile in which the clinical diagnosis of
Tangier disease (205400) was made on the basis of enlarged yellow-orange
tonsils and complete absence of HDL from plasma, Rust et al. (1999)
found an insertion of a 110-bp DNA fragment structurally related to the
Alu sequence family of repetitive sequences and deletion of 14 bp in
exon 12 of the ABC1 gene. This insertion/deletion predicted deletion of
6 amino acids and an in-frame insertion of 38 residues. Neither this
mutation nor that described in 600046.0009 allowed the synthesis of the
normal ABC1 transporter.

.0011
TANGIER DISEASE
ABCA1, 2-BP DEL, 3283TC

Remaley et al. (1999) demonstrated that in the original Tangier disease
(205400) family the disorder was caused by homozygosity for a
dinucleotide deletion in exon 22: 3283-3284TC. The deletion resulted in
a frameshift mutation and a premature stop codon starting at position
3375. The gene product was predicted to encode a nonfunctional protein
of 1,084 amino acids, which is approximately half the size of the
full-length ABC1 protein.

.0012
TANGIER DISEASE
ABCA1, 1-BP DEL, 2665C

Lapicka-Bodzioch et al. (2001) developed an assay based on 52 primer
sets to amplify all 50 ABCA1 exons and approximately 1 kb of its
promoter. The assay allowed for convenient amplification of the gene
from genomic DNA and easy mutation analysis through autonomic
sequencing. It obviated the need to use mRNA preparations, which were
difficult to handle and posed the risk of missing splice junction or
promoter mutations. They applied the test to the molecular analysis of a
new patient with Tangier disease (205400) and found compound
heterozygosity for 2 mutations: 2665delC and 4457C-T. These mutations
were derived from the father and mother, respectively. The nucleotide
substitution caused a ser1446-to-leu missense amino acid substitution
(600046.0013). The patient had come to medical attention at the age of
25 years because of splenomegaly and marked reduction of HDL cholesterol
as well as ApoA-I and ApoA-II. He had no detectable signs or symptoms of
either coronary artery disease or neuropathy.

.0013
TANGIER DISEASE
ABCA1, SER1446LEU

See 600046.0012 and Lapicka-Bodzioch et al. (2001).

.0014
TANGIER DISEASE
ABCA1, ASN935SER

In a Japanese patient with Tangier disease (205400), Guo et al. (2002)
described homozygosity for a 3199A-G transition in exon 19 of the ABCA1
gene, leading to an asn935-to-ser missense mutation. The same mutation
had been found in German and Spanish families (Bodzioch et al., 1999;
Utech et al., 2001), suggesting that it is a recurrent mutation. The
patient was a 69-year-old man who had yellow tonsils. Foamy macrophages
were found in the gastric mucosa and he had not only hepatosplenomegaly
but also chronic hepatitis and type 2 diabetes mellitus (125853). He had
no cognitive disorder and no coronary artery disease or peripheral
neuropathy. In previously reported cases of this mutation, there were no
cognitive disorders.

.0015
TANGIER DISEASE
ABCA1, ASN935HIS

Guo et al. (2002) described a Japanese patient with Tangier disease
(205400) who was homozygous for a 3198A-C transversion in exon 19 of the
ABCA1 gene, resulting in an asn935-to-his missense mutation. This and
the asn935-to-ser mutation (600046.0014) involved the Walker A motif of
the first nucleotide-binding fold. The patient was a 20-year-old man who
was diagnosed with obsessive-compulsive disorder. He had mild
splenomegaly, but no enlargement of the tonsils and no peripheral
neuropathy or coronary artery disease.

.0016
TANGIER DISEASE
ABCA1, INT12-14 DEL, INT16-31 DEL

Guo et al. (2002) identified a double deletion in the ABCA1 gene in a
57-year-old Japanese male with Tangier disease (205400). He had angina
pectoris with 90% stenosis of the left anterior descending artery,
accompanied by heart failure, yellow tonsils, and hepatosplenomegaly.
Foamy macrophages were observed in the tonsils and bone marrow, and
stomatocytosis was also noted. The patient's 49-year-old sister had a
history of splenectomy and low HDL cholesterol. Guo et al. (2002) used
PCR to examine each of the 50 exons of the ABCA1 gene. No PCR products
were amplified in exon 12, 13, or 17-31 in this patient. Using
long-range PCR, they confirmed double deletions: 1.2 kb from intron
12-14 and 19.9 kb from intron 16-31, which encodes the sixth
transmembrane region (a linker region) and the seventh transmembrane
region of the putative secondary structure. It was suggested that the
double deletion resulted from a single event, as suggested by sequence
analysis of the breakpoints. The 3-prime deletion junction had an
insertion of 21 bp. The 16 bp within the 21-bp insertion was not found
in the original sequence, but was complementary to the proximal sequence
of the 5-prime deletion junction. Indeed, the same oriented Alu sequence
was found in both intron 14 and intron 31, facilitating the
stabilization of the folding of the ABCA1 gene to promote nonhomologous
intragenic recombination.

Double deletions in the same gene had previously been reported for
dystrophin (300377) by Hoop et al. (1994); in the beta-globin gene (HBB;
141900); in the growth hormone gene (GH1; 139250) by Goossens et al.
(1986); and in the GALNS gene (612222), which is mutant in
mucopolysaccharidosis type IVA (253000). A simultaneous event of double
deletions was proposed for the case of thalassemia patients with changes
in the HBB gene because of inversion between the deletions (Jennings et
al., 1985; Kulozik et al., 1992).

.0017
TANGIER DISEASE, VARIANT
ABCA1, ARG1680TRP

In a 48-year-old Japanese male, the product of a first-cousin marriage,
Ishii et al. (2002) found a clinical variant of Tangier disease (see
205400) manifested by corneal lipidosis and premature coronary artery
disease as well as an almost complete absence of HDL cholesterol.
Although the patient had no pathognomonic lesions of Tangier disease
such as hepatosplenomegaly or peripheral neuropathy, the ABCA1 gene was
found to carry homozygosity for an arg1680-to-trp (R1680W) missense
mutation.

.0018
HIGH DENSITY LIPOPROTEIN DEFICIENCY
ABCA1, ASP1099TYR

Hong et al. (2002) identified a patient in whom isolated low high
density lipoprotein cholesterol deficiency (HDLD; 604091) was observed
at least 5 years before he was diagnosed with cerebral amyloid
angiopathy (see 105150). The patient died of complications related to
cerebral amyloid angiopathy at the age of 68 years. The patient had a
compound heterozygous mutation in the ABCA1 gene. One mutation was a
3295G-T transversion, predicted to result in an asp1099-to-tyr (D1099Y)
mutation. The other mutation was a 5966T-C transition, predicted to
result in a phe2009-to-ser (F2009S; 600046.0019) mutation. The proband
manifested neither cardiovascular disease nor Tangier disease (205400).
In the kindred, family members heterozygous for the ABCA1 variant
exhibited low levels of HDL cholesterol.

.0019
HIGH DENSITY LIPOPROTEIN DEFICIENCY
ABCA1, PHE2009SER

See Hong et al. (2002) and 600046.0018.

.0020
TANGIER DISEASE
ABCA1, ASP1229ASN

In 2 Japanese sisters with Tangier disease (205400), Huang et al. (2001)
found homozygosity for a 3805G-A transition in exon 27 of the ABCA1
gene, resulting in an asp1229-to-asn (D1229N) change, and a 6181C-T
transition in exon 47, resulting in an arg2021-to-trp (R2021W;
600046.0021) substitution.

.0021
TANGIER DISEASE
ABCA1, ARG2021TRP

See Huang et al. (2001) and 600046.0020.

.0022
HIGH DENSITY LIPOPROTEIN DEFICIENCY
ABCA1, 4-BP DEL, 3787CGCC

In a Japanese patient with familial high density lipoprotein deficiency
(HDLD; 604091), Huang et al. (2001) found homozygosity for a 4-bp
deletion (CGCC) at nucleotide 3787, resulting in premature termination
by frameshift at codon 1224. The proband, whose mother and all 4 of his
children were heterozygous for the mutation, was a 62-year-old man who,
at the age of 45 years, presented with bronchial asthma. There was no
tonsillar abnormality, lymphadenopathy, hepatosplenomegaly, or
xanthomas, and no evidence of neuropathy. Coronary angiography revealed
99% stenosis of the left coronary artery, which required percutaneous
transcutaneous coronary angioplasty.

.0023
TANGIER DISEASE
ABCA1, TYR573TER

Kolovou et al. (2003) reported a 32-year-old woman with Tangier disease
(205400), a child of second-cousin parents, who had no clinical signs of
the disorder except hepatosplenomegaly and no coronary artery disease
manifestations. She was found to be homozygous for a 2033C-A
transversion in exon 12 of the ABCA1 gene, resulting in conversion of
codon 573 from TAC (tyr) to TAA (ter) (Y573X).

.0024
CORONARY HEART DISEASE IN FAMILIAL HYPERCHOLESTEROLEMIA, PROTECTION
AGAINST
ABCA1, ARG219LYS

In heterozygous familial hypercholesterolemia (FH; 143890) patients, the
clinical expression of FH is highly variable in terms of the severity of
hypercholesterolemia and the age at onset and severity of coronary heart
disease (CHD). Cenarro et al. (2003) hypothesized that ABCA1 may play a
key role in the onset of premature CHD in FH. They studied the presence
of the arg219-to-lys (R219K) variant in the ABCA1 gene in 374 FH
patients with or without premature CHD. The K allele of the R219K
variant was significantly more frequent in FH patients without premature
CHD than in those with premature CHD, suggesting that the genetic
variant may influence the development and progression of atherosclerosis
in FH patients. The K allele of the R219K polymorphism seemed to modify
CHD risk without important modification of plasma HDL cholesterol
levels, and it appeared to be more protective for smokers than
nonsmokers.

In a large Swedish population-based study of 1,177 individuals with a
first myocardial infarction event and 1,526 healthy controls, Katzov et
al. (2006) found an association between the R219K polymorphism and
increased serum levels of apolipoprotein B (APOB; 107730) and LDL
cholesterol among smokers, but not among nonsmokers.

.0025
HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS
13
ABCA1, 74A-G

Kathiresan et al. (2008) replicated the association of dbSNP rs3890182
(74A-G) in the ABCA1 gene with high density lipoprotein cholesterol
levels in a study of 5,414 subjects from the cardiovascular cohort of
the Malmo Diet and Cancer Study (p = 3.3 x 10(-5)).

*FIELD* RF
1. Albrecht, C.; McVey, J. H.; Elliott, J. I.; Sardini, A.; Kasza,
I.; Mumford, A. D.; Naoumova, R. P.; Tuddenham, E. G. D.; Szabo, K.;
Higgins, C. F.: A novel missense mutation in ABCA1 results in altered
protein trafficking and reduced phosphatidylserine translocation in
a patient with Scott syndrome. Blood 106: 542-549, 2005.

2. Becq, F.; Hamon, Y.; Bajetto, A.; Gola, M.; Verrier, B.; Chimini,
G.: ABC1, an ATP binding cassette transporter required for phagocytosis
of apoptotic cells, generates a regulated anion flux after expression
in Xenopus laevis oocytes. J. Biol. Chem. 272: 2695-2699, 1997.

3. Bodzioch, M.; Orso, E.; Klucken, J.; Langmann, T.; Bottcher, A.;
Diederich, W.; Drobnik, W.; Barlage, S.; Buchler, C.; Porsch-Ozcurumez,
M.; Kaminski, W. E.; Hahmann, H. W.; Oette, K.; Rothe, G.; Aslanidis,
C.; Lackner, K. J.; Schmitz, G.: The gene encoding ATP-binding cassette
transporter 1 is mutated in Tangier disease. Nature Genet. 22: 347-351,
1999.

4. Brooks-Wilson, A.; Marcil, M.; Clee, S. M.; Zhang, L.-H.; Roomp,
K.; van Dam, M.; Yu, L.; Brewer, C.; Collins, J. A.; Molhuizen, H.
O. F.; Loubser, O.; Ouelette, B. F. F.; and 14 others: Mutations
in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nature
Genet. 22: 336-345, 1999.

5. Brunham, L. R.; Kruit, J. K.; Iqbal, J.; Fievet, C.; Timmins, J.
M.; Pape, T. D.; Coburn, B. A.; Bissada, N.; Staels, B.; Groen, A.
K.; Hussain, M. M.; Parks, J. S.; Kuipers, F.; Hayden, M. R.: Intestinal
ABCA1 directly contributes to HDL biogenesis in vivo. J. Clin. Invest. 116:
1052-1062, 2006.

6. Brunham, L. R.; Kruit, J. K.; Pape, T. D.; Timmins, J. M.; Reuwer,
A. Q.; Vasanji, Z.; Marsh, B. J.; Rodrigues, B.; Johnson, J. D.; Parks,
J. S.; Verchere, C. B.; Hayden, M. R.: Beta-cell ABCA1 influences
insulin secretion, glucose homeostasis and response to thiazolidinedione
treatment. Nature Med. 13: 340-347, 2007.

7. Brunham, L. R.; Tietjen, I.; Bochem, A. E.; Singaraja, R. R.; Franchini,
P. L.; Radomski, C.; Mattice, M.; Legendre, A.; Hovingh, G. K.; Kastelein,
J. J. P.; Hayden, M. R.: Novel mutations in scavenger receptor BI
associated with high HDL cholesterol in humans. Clin. Genet. 79:
575-581, 2011. Note: Erratum: Clin. Genet. 80: 406 only, 2011.

8. Cenarro, A.; Artieda, M.; Castillo, S.; Mozas, P.; Reyes, G.; Tejedor,
D.; Alonso, R.; Mata, P.; Pocovi, M.; Civeira, F.: A common variant
in the ABCA1 gene is associated with a lower risk for premature coronary
heart disease in familial hypercholesterolaemia. J. Med. Genet. 40:
163-168, 2003.

9. Cohen, J. C.; Kiss, R. S.; Pertsemlidis, A.; Marcel, Y. L.; McPherson,
R.; Hobbs, H. H.: Multiple rare alleles contribute to low plasma
levels of HDL cholesterol. Science 305: 869-872, 2004.

10. Decottignies, A.; Goffeau, A.: Complete inventory of the yeast
ABC proteins. Nature Genet. 15: 137-145, 1997.

11. Fitzgerald, M. L.; Morris, A. L.; Rhee, J. S.; Andersson, L. P.;
Mendez, A. J.; Freeman, M. W.: Naturally occurring mutations in the
largest extracellular loops of ABCA1 can disrupt its direct interaction
with apolipoprotein A-I. J. Biol. Chem. 277: 33178-33187, 2002.

12. Goossens, M.; Brauner, R.; Czernichow, P.; Duquesnoy, P.; Rappaport,
R.: Isolated growth hormone (GH) deficiency type 1A associated with
a double deletion in the human GH gene cluster. J. Clin. Endocr.
Metab. 62: 712-716, 1986.

13. Guo, Z.; Inazu, A.; Yu, W.; Suzumura, T.; Okamoto, M.; Nohara,
A.; Higashikata, T.; Sano, R.; Wakasugi, K.; Hayakawa, T.; Yoshida,
K.; Suehiro, T.; Schmitz, G.; Mabuchi, H.: Double deletions and missense
mutations in the first nucleotide-binding fold of the ATP-binding
cassette transporter A1 (ABCA1) gene in Japanese patients with Tangier
disease. J. Hum. Genet. 47: 325-329, 2002.

14. Hirsch-Reinshagen, V.; Zhou, S.; Burgess, B. L.; Bernier, L.;
McIsaac, S. A.; Chan, J. Y.; Tansley, G. H.; Cohn, J. S.; Hayden,
M. R.; Wellington, C. L.: Deficiency of ABCA1 impairs apolipoprotein
E metabolism in brain. J. Biol. Chem. 279: 41197-41207, 2004.

15. Hong, S. H.; Rhyne, J.; Zeller, K.; Miller, M.: Novel ABCA1 compound
variant associated with HDL cholesterol deficiency. Biochim. Biophys.
Acta 1587: 60-64, 2002.

16. Hoop, R. C.; Russo, L. S.; Riconda, D. L.; Schwartz, L. S.; Hoffman,
E. P.: Restoration of half the normal dystrophin sequence in a double-deletion
Duchenne muscular dystrophy family. Am. J. Med. Genet. 49: 323-327,
1994.

17. Huang, W.; Moriyama, K.; Koga, T.; Hua, H.; Ageta, M.; Kawabata,
S.; Mawatari, K.; Imamura, T.; Eto, T.; Kawamura, M.; Teramoto, T.;
Sasaki, J.: Novel mutations in ABCA1 gene in Japanese patients with
Tangier disease and familial high density lipoprotein deficiency with
coronary heart disease. Biochim. Biophys. Acta 1537: 71-78, 2001.

18. Ishii, J.; Nagano, M.; Kujiraoka, T.; Ishihara, M.; Egashira,
T.; Takada, D.; Tsuji, M.; Hattori, H.; Emi, M.: Clinical variant
of Tangier disease in Japan: mutation of the ABCA1 gene in hypoalphalipoproteinemia
with corneal lipidosis. J. Hum. Genet. 47: 366-369, 2002.

19. Jennings, M. W.; Jones, R. W.; Wood, W. G.; Weatherall, D. J.
: Analysis of an inversion within the human beta globin gene cluster. Nucleic
Acids Res. 13: 2897-2906, 1985.

20. 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.

21. Katzov, H.; Bennet, A. M.; Hoglund, K.; Wiman, B.; Lutjohann,
D.; Brookes, A. J.; Andreasen, N.; Blennow, K.; De Faire, U.; Prince,
J. A.: Quantitative trait loci in ABCA1 modify cerebrospinal fluid
amyloid-beta(1-42) and plasma apolipoprotein levels. J. Hum. Genet. 51:
171-179, 2006.

22. Kolovou, G. D.; Wade, D. P.; Sengupta, R.; Cokkinos, D. V.: Tangier
disease with unusual clinical manifestations. (Letter) Clin. Genet. 63:
323-324, 2003.

23. Kulozik, A. E.; Bellan-Koch, A.; Kohne, E.; Kleihauer, E.: A
deletion/inversion rearrangement of the beta-globin gene cluster in
a Turkish family with delta-beta(0)-thalassemia intermedia. Blood 79:
2455-2459, 1992.

24. Langmann, T.; Klucken, J.; Reil, M.; Liebisch, G.; Luciani, M.-F.;
Chimini, G.; Kaminski, W. E.; Schmitz, G.: Molecular cloning of the
human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent
regulation in macrophages. Biochem. Biophys. Res. Commun. 257: 29-33,
1999.

25. Lapicka-Bodzioch, K.; Bodzioch, M.; Krull, M.; Kielar, D.; Probst,
M.; Kiec, B.; Andrikovics, H.; Bottcher, A.; Hubacek, J.; Aslanidis,
C.; Suttorp, N.; Schmitz, G.: Homogeneous assay based on 52 primer
sets to scan for mutations of the ABCA1 gene and its application in
genetic analysis of a new patient with familial high-density lipoprotein
deficiency syndrome. Biochim. Biophys. Acta 1537: 42-48, 2001.

26. Lawn, R. M.; Wade, D. P.; Garvin, M. R.; Wang, X.; Schwartz, K.;
Porter, J. G.; Seilhamer, J. J.; Vaughan, A. M.; Oram, J. F.: The
Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated
lipid removal pathway. J. Clin. Invest. 104: R25-R31, 1999.

27. Lu, T. T.; Makishima, M.; Repa, J. J.; Schoonjans, K.; Kerr, T.
A.; Auwerx, J.; Mangelsdorf, D. J.: Molecular basis for feedback
regulation of bile acid synthesis by nuclear receptors. Molec. Cell 6:
507-515, 2000.

28. Luciani, M. F.; Denizot, F.; Savary, S.; Mattei, M. G.; Chimini,
G.: Cloning of two novel ABC transporters mapping on human chromosome
9. Genomics 21: 150-159, 1994.

29. Marcil, M.; Boucher, B.; Krimbou, L.; Solymoss, B. C.; Davignon,
J.; Frohlich, J.; Genest, J., Jr.: Severe familial HDL deficiency
in French-Canadian kindreds: clinical, biochemical, and molecular
characterization. Arterioscler. Thromb. Vasc. Biol. 15: 1015-1024,
1995.

30. Marcil, M.; Yu, L.; Krimbou, L.; Boucher, B.; Oram, J. F.; Cohn,
J. S.; Genest, J., Jr.: Cellular cholesterol transport and efflux
in fibroblasts are abnormal in subjects with familial HDL deficiency. Arterioscler.
Thromb. Vasc. Biol. 19: 159-169, 1999.

31. McNeish, J.; Aiello, R. J.; Guyot, D.; Turi, T.; Gabel, C.; Aldinger,
C.; Hoppe, K. L.; Roach, M. L.; Royer, L. J.; de Wet, J.; Broccardo,
C.; Chimini, G.; Francone, O. L.: High density lipoprotein deficiency
and foam cell accumulation in mice with targeted disruption of ATP-binding
cassette transporter-1. Proc. Nat. Acad. Sci. 97: 4245-4250, 2000.

32. Najafi-Shoushtari, S. H.; Kristo, F.; Li, Y.; Shioda, T.; Cohen,
D. E.; Gerszten, R. E.; Naar, A. M.: MicroRNA-33 and the SREBP host
genes cooperate to control cholesterol homeostasis. Science 328:
1566-1569, 2010.

33. Neufeld, E. B.; Stonik, J. A.; Demosky, S. J., Jr.; Knapper, C.
L.; Combs, C. A.; Cooney, A.; Comly, M.; Dwyer, N.; Blanchette-Mackie,
J.; Remaley, A. T.; Santamarina-Fojo, S.; Brewer, H. B., Jr.: The
ABCA1 transporter modulates late endocytic trafficking: insights from
the correction of the genetic defect in Tangier disease. J. Biol.
Chem. 279: 15571-15578, 2004.

34. Nofer, J.-R.; Herminghaus, G.; Brodde, M.; Morgenstern, E.; Rust,
S.; Engel, T.; Seedorf, U.; Assmann, G.; Bluethmann, H.; Kehrel, B.
E.: Impaired platelet activation in familial high density lipoprotein
deficiency (Tangier disease). J. Biol. Chem. 279: 34032-34037, 2004.

35. Orso, E.; Broccardo, C.; Kaminski, W. E.; Bottcher, A.; Liebisch,
G.; Drobnik, W.; Gotz, A.; Chambenoit, O.; Diederich, W.; Langmann,
T.; Spruss, T.; Luciani, M.-F.; Rothe, G.; Lackner, K. J.; Chimini,
G.; Schmitz, G.: Transport of lipids from Golgi to plasma membrane
is defective in Tangier disease patients and Abc1-deficient mice. Nature
Genet. 24: 192-196, 2000.

36. Pullinger, C. R.; Hakamata, H.; Duchateau, P. N.; Eng, C.; Aouizerat,
B. E.; Cho, M. H.; Fielding, C. J.; Kane, J. P.: Analysis of hABC1
gene 5-prime end: additional peptide sequence, promoter region, and
four polymorphisms. Biochem. Biophys. Res. Commun. 271: 451-455,
2000.

37. Rayner, K. J.; Esau, C. C.; Hussain, F. N.; McDaniel, A. L.; Marshall,
S. M.; van Gils, J. M.; Ray, T. D.; Sheedy, F. J.; Goedeke, L.; Liu,
X.; Khatsenko, O. G.; Kaimal, V.; Lees, C. J.; Fernandez-Hernando,
C.; Fisher, E. A.; Temel, R. E.; Moore, K. J.: Inhibition of miR-33a/b
in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478:
404-407, 2011.

38. Rayner, K. J.; Suarez, Y.; Davalos, A.; Parathath, S.; Fitzgerald,
M. L.; Tamehiro, N.; Fisher, E. A.; Moore, K. J.; Fernandez-Hernando,
C.: MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328:
1570-1573, 2010.

39. Remaley, A. T.; Rust, S.; Rosier, M.; Knapper, C.; Naudin, L.;
Broccardo, C.; Peterson, K. M.; Koch, C.; Arnould, I.; Prades, C.;
Duverger, N.; Funke, H.; Assman, G.; Dinger, M.; Dean, M.; Chimini,
G.; Santamarina-Fojo, S.; Fredrickson, D. S.; Denefle, P.; Brewer,
H. B., Jr.: Human ATP-binding cassette transporter 1 (ABC1): genomic
organization and identification of the genetic defect in the original
Tangier disease kindred. Proc. Nat. Acad. Sci. 96: 12685-12690,
1999.

40. Repa, J. J.; Turley, S. D.; Lobaccaro, J.-M. A.; Medina, J.; Li,
L.; Lustig, K.; Shan, B.; Heyman, R. A.; Dletschy, J. M.; Mangelsdorf,
D. J.: Regulation of absorption and ABC1-mediated efflux of cholesterol
by RXR heterodimers. Science 289: 1524-1529, 2000.

41. Rust, S.; Rosier, M.; Funke, H.; Real, J.; Amoura, Z.; Piette,
J.-C.; Deleuze, J.-F.; Brewer, H. B.; Duverger, N.; Denefle, P.; Assmann,
G.: Tangier disease is caused by mutations in the gene encoding ATP-binding
cassette transporter 1. Nature Genet. 22: 352-355, 1999.

42. Santamarina-Fojo, S.; Peterson, K.; Knapper, C.; Qiu, Y.; Freeman,
L.; Cheng, J.-F.; Osorio, J.; Remaley, A.; Yang, X.-P.; Haudenschild,
C.; Prades, C.; Chimini, G.; Blackmon, E.; Francois, T.; Duverger,
N.; Rubin, E. M.; Rosier, M.; Denefle, P.; Fredrickson, D. S.; Brewer,
H. B., Jr.: Complete genomic sequence of the human ABCA1 gene: analysis
of the human and mouse ATP-binding cassette A promoter. Proc. Nat.
Acad. Sci. 97: 7987-7992, 2000. Note: Erratum: Proc. Nat. Acad. Sci.
99: 1098 only, 2002.

43. Singaraja, R. R.; Bocher, V.; James, E. R.; Clee, S. M.; Zhang,
L.-H.; Leavitt, B. R.; Tan, B.; Brooks-Wilson, A.; Kwok, A.; Bissada,
N.; Yang, Y.; Liu, G.; Tafuri, S. R.; Fievet, C.; Wellington, C. L.;
Staels, B.; Hayden, M. R.: Human ABCA1 BAC transgenic mice show increased
high density lipoprotein cholesterol and ApoAI-dependent efflux stimulated
by an internal promoter containing liver X receptor response elements
in intron 1. J. Biol. Chem. 276: 33969-33979, 2001.

44. Szakacs, G.; Langmann, T.; Ozvegy, C.; Orso, E.; Schmitz, G.;
Varadi, A.; Sarkadi, B.: Characterization of the ATPase cycle of
human ABCA1: implications for its function as a regulator rather than
an active transporter. Biochem. Biophys. Res. Commun. 288: 1258-1264,
2001.

45. Tanaka, A. R.; Abe-Dohmae, S.; Ohnishi, T.; Aoki, R.; Morinaga,
G.; Okuhira, K.; Ikeda, Y.; Kano, F.; Matsuo, M.; Kioka, N.; Amachi,
T.; Murata, M.; Yokoyama, S.; Ueda, K.: Effects of mutations of ABCA1
in the first extracellular domain on subcellular trafficking and ATP
binding/hydrolysis. J. Biol. Chem. 278: 8815-8819, 2003. Note: Erratum:
J. Biol. Chem. 278: 14586 only, 2003.

46. Tanaka, A. R.; Ikeda, Y.; Abe-Dohmae, S.; Arakawa, R.; Sadanami,
K.; Kidera, A.; Nakagawa, S.; Nagase, T.; Aoki, R.; Kioka, N.; Amachi,
T.; Yokoyama, S.; Ueda, K.: Human ABCA1 contains a large amino terminal
extracellular domain homologous to an epitope of Sjogren's syndrome. Biochem.
Biophys. Res. Commun. 283: 1019-1025, 2001.

47. 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.

48. Utech, M.; Hobbel, G.; Rust, S.; Reinecke, H.; Assmann, G.; Walter,
M.: Accumulation of RhoA, RhoB, RhoG, and Rac1 in fibroblasts from
Tangier disease subjects suggests a regulatory role of Rho family
proteins in cholesterol efflux. Biochem. Biophys. Res. Commun. 280:
229-236, 2001.

49. Wahrle, S. E.; Jiang, H.; Parsadanian, M.; Legleiter, J.; Han,
X.; Fryer, J. D.; Kowalewski, T.; Holtzman, D. M.: ABCA1 is required
for normal central nervous system ApoE levels and for lipidation of
astrocyte-secreted apoE. J. Biol. Chem. 279: 40987-40993, 2004.

50. Wang, N.; Chen, W.; Linsel-Nitschke, P.; Martinez, L. O.; Agerholm-Larsen,
B.; Silver, D. L.; Tall, A. R.: A PEST sequence in ABCA1 regulates
degradation by calpain protease and stabilization of ABCA1 by apoA-I. J.
Clin. Invest. 111: 99-107, 2003.

51. Wellington, C. L.; Walker, E. K. Y.; Suarez, A.; Kwok, A.; Bissada,
N.; Singaraja, R.; Yang, Y.-Z.; Zhang, L.-H.; James, E.; Wilson, J.
E.; Francone, O.; McManus, B. M.; Hayden, M. R.: ABCA1 mRNA and protein
distribution patterns predict multiple different roles and levels
of regulation. Lab. Invest. 82: 273-283, 2002.

52. Young, S. G.; Fielding, C. J.: The ABCs of cholesterol efflux. Nature
Genet. 22: 316-318, 1999.

53. Yvan-Charvet, L.; Pagler, T.; Gautier, E. L.; Avagyan, S.; Siry,
R. L.; Han, S.; Welch, C. L.; Wang, N.; Randolph, G. J.; Snoeck, H.
W.; Tall, A. R.: ATP-binding cassette transporters and HDL suppress
hematopoietic stem cell proliferation. Science 328: 1689-1693, 2010.

54. Zhao, L.-X.; Zhou, C.-J.; Tanaka, A.; Nakata, M.; Hirabayashi,
T.; Amachi, T.; Shioda, S.; Ueda, K.; Inagaki, N.: Cloning, characterization
and tissue distribution of the rat ATP-binding cassette (ABC) transporter
ABC2/ABCA2. Biochem J. 350: 865-872, 2000.

55. Zwarts, K. Y.; Clee, S. M.; Zwinderman, A. H.; Engert, J. C.;
Singaraja, R.; Loubser, O.; James, E.; Roomp, K.; Hudson, T. J.; Jukema,
J. W.; Kastelein, J. J. P.; Hayden, M. R.: ABCA1 regulatory variants
influence coronary artery disease independent of effects on plasma
lipid levels. Clin. Genet. 61: 115-125, 2002.

*FIELD* CN
Marla J. F. O'Neill - updated: 10/25/2012
Ada Hamosh - updated: 11/29/2011
Ada Hamosh - updated: 9/27/2010
Ada Hamosh - updated: 7/30/2010
Ada Hamosh - updated: 7/12/2010
Ada Hamosh - updated: 4/1/2008
Marla J. F. O'Neill - updated: 4/27/2007
Marla J. F. O'Neill - updated: 6/14/2006
Cassandra L. Kniffin - updated: 4/28/2006
Marla J. F. O'Neill - updated: 10/14/2005
Patricia A. Hartz - updated: 1/6/2005
Cassandra L. Kniffin - updated: 12/8/2004
Victor A. McKusick - updated: 10/11/2004
Victor A. McKusick - updated: 5/5/2004
Victor A. McKusick - updated: 3/1/2004
Victor A. McKusick - updated: 5/12/2003
Patricia A. Hartz - updated: 4/28/2003
Denise L. M. Goh - updated: 4/17/2003
Victor A. McKusick - updated: 10/14/2002
Victor A. McKusick - updated: 8/28/2002
Victor A. McKusick - updated: 8/5/2002
Patricia A. Hartz - updated: 7/11/2002
Patricia A. Hartz - updated: 7/3/2002
Victor A. McKusick - updated: 6/19/2002
Victor A. McKusick - updated: 5/10/2002
Victor A. McKusick - updated: 1/30/2002
Paul J. Converse - updated: 2/1/2001
Victor A. McKusick - updated: 8/31/2000
Ada Hamosh - updated: 8/31/2000
Victor A. McKusick - updated: 1/31/2000
Victor A. McKusick - updated: 11/22/1999
Victor A. McKusick - updated: 11/10/1999
Victor A. McKusick - updated: 8/2/1999
Rebekah S. Rasooly - updated: 4/9/1998
Victor A. McKusick - updated: 2/3/1997

*FIELD* CD
Victor A. McKusick: 7/20/1994

*FIELD* ED
carol: 10/01/2013
carol: 11/1/2012
terry: 10/25/2012
terry: 5/10/2012
alopez: 12/1/2011
terry: 11/29/2011
alopez: 9/27/2010
alopez: 7/30/2010
terry: 7/30/2010
alopez: 7/16/2010
terry: 7/12/2010
ckniffin: 10/13/2009
terry: 2/12/2009
carol: 8/27/2008
carol: 4/14/2008
carol: 4/2/2008
carol: 4/1/2008
wwang: 4/27/2007
alopez: 8/1/2006
terry: 7/31/2006
wwang: 6/19/2006
terry: 6/14/2006
wwang: 5/5/2006
wwang: 5/4/2006
ckniffin: 4/28/2006
wwang: 1/23/2006
carol: 12/5/2005
carol: 10/14/2005
terry: 2/9/2005
mgross: 1/10/2005
terry: 1/6/2005
tkritzer: 12/13/2004
ckniffin: 12/8/2004
alopez: 10/12/2004
terry: 10/11/2004
tkritzer: 5/7/2004
terry: 5/5/2004
joanna: 3/17/2004
tkritzer: 3/2/2004
terry: 3/1/2004
cwells: 11/6/2003
tkritzer: 5/14/2003
terry: 5/12/2003
cwells: 5/2/2003
terry: 4/28/2003
carol: 4/17/2003
terry: 2/26/2003
tkritzer: 10/28/2002
tkritzer: 10/18/2002
terry: 10/14/2002
tkritzer: 9/6/2002
tkritzer: 9/5/2002
tkritzer: 8/30/2002
terry: 8/28/2002
tkritzer: 8/8/2002
tkritzer: 8/7/2002
tkritzer: 8/6/2002
terry: 8/5/2002
carol: 7/11/2002
carol: 7/3/2002
cwells: 6/26/2002
terry: 6/19/2002
alopez: 5/28/2002
terry: 5/10/2002
carol: 2/21/2002
alopez: 2/6/2002
terry: 1/30/2002
joanna: 5/4/2001
cwells: 2/7/2001
cwells: 2/1/2001
cwells: 1/31/2001
mgross: 10/10/2000
mcapotos: 9/5/2000
mcapotos: 9/1/2000
mcapotos: 8/31/2000
mgross: 8/31/2000
alopez: 7/18/2000
carol: 2/14/2000
yemi: 2/11/2000
alopez: 1/31/2000
terry: 1/31/2000
mcapotos: 12/16/1999
carol: 11/23/1999
terry: 11/22/1999
alopez: 11/19/1999
terry: 11/10/1999
alopez: 8/3/1999
carol: 8/2/1999
psherman: 6/24/1998
psherman: 4/9/1998
carol: 3/28/1998
mark: 2/3/1997
terry: 1/30/1997
mark: 6/20/1996
mark: 3/7/1996
mimadm: 7/30/1994
jason: 7/20/1994

MIM 604091
*RECORD*
*FIELD* NO
604091
*FIELD* TI
#604091 HYPOALPHALIPOPROTEINEMIA, PRIMARY
;;HYPOALPHALIPOPROTEINEMIA, FAMILIAL; FHA;;
read moreHIGH DENSITY LIPOPROTEIN DEFICIENCY; HDLD;;
FAMILIAL HDL DEFICIENCY; FHD;;
HDL CHOLESTEROL, LOW SERUM; HDLC
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
hypoalphalipoproteinemia is caused in some families by mutation in the
ABC1 gene (ABCA1; 600046) on chromosome 9, which is also the site of
mutations causing Tangier disease (205400).

Hypoalphalipoproteinemia is also observed with mutations in the
apolipoprotein A1 gene (APOA1; 107680), which maps to 11q23.3.

Several quantitative trait loci (QTLs) for HDL cholesterol level have
been identified: see HDLCQ1 (606613).

DESCRIPTION

Twenty to 30% of early familial coronary heart disease (CHD) is ascribed
to hypoalphalipoproteinemia, or high density lipoprotein deficiency.
Although not initially recognized as a predisposing dyslipidemia,
extensive epidemiologic work has implicated low high-density lipoprotein
cholesterol (HDLC) levels in increased risk of cardiovascular disease,
and low HDLC is considered to be a true dyslipidemic syndrome (Warnick
and Wood, 1995).

CLINICAL FEATURES

As in Tangier disease, an autosomal recessive disorder, the dominantly
inherited disorder familial hypoalphalipoproteinemia shows a reduction
in cellular cholesterol efflux (Marcil et al., 1999).

MAPPING

After demonstrating mutations in the ABC1 gene in patients with Tangier
disease, Brooks-Wilson et al. (1999) studied 4 French Canadian families
with familial hypoalphalipoproteinemia. Linkage analysis revealed a
maximum lod score of 9.67 at a recombination fraction of 0.0 at D9S277,
the region to which Tangier disease had been mapped. These 2 diseases
had hitherto been considered distinct, with different clinical and
biochemical characteristics.

MOLECULAR GENETICS

In affected members of French Canadian families with
hypoalphalipoproteinemia, Brooks-Wilson et al. (1999) identified
heterozygous mutations in the ABC1 gene (600046.0001-600046.0004). One
of the families had previously been studied by Marcil et al. (1995).

*FIELD* RF
1. Brooks-Wilson, A.; Marcil, M.; Clee, S. M.; Zhang, L.-H.; Roomp,
K.; van Dam, M.; Yu, L.; Brewer, C.; Collins, J. A.; Molhuizen, H.
O. F.; Loubser, O.; Ouelette, B. F. F.; and 14 others: Mutations
in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nature
Genet. 22: 336-345, 1999.

2. Marcil, M.; Boucher, B.; Krimbou, L.; Solymoss, B. C.; Davignon,
J.; Frohlich, J.; Genest, J., Jr.: Severe familial HDL deficiency
in French-Canadian kindreds: clinical, biochemical, and molecular
characterization. Arterioscler. Thromb. Vasc. Biol. 15: 1015-1024,
1995.

3. Marcil, M.; Yu, L.; Krimbou, L.; Boucher, B.; Oram, J. F.; Cohn,
J. S.; Genest, J., Jr.: Cellular cholesterol transport and efflux
in fibroblasts are abnormal in subjects with familial HDL deficiency. Arterioscler.
Thromb. Vasc. Biol. 19: 159-169, 1999.

4. Warnick, G. R.; Wood, P. D.: National cholesterol education program
recommendations for measurement of high-density lipoprotein cholesterol:
executive summary. Clin. Chem. 41: 1427-1433, 1995.

*FIELD* CN
Victor A. McKusick - updated: 4/10/2003
Victor A. McKusick - updated: 5/20/2002

*FIELD* CD
Victor A. McKusick: 8/2/1999

*FIELD* ED
alopez: 06/27/2012
carol: 3/12/2012
wwang: 11/5/2008
carol: 7/21/2006
carol: 4/11/2003
terry: 4/10/2003
alopez: 6/20/2002
terry: 5/20/2002
carol: 8/8/2000
alopez: 4/6/2000
mcapotos: 12/16/1999
alopez: 8/3/1999
carol: 8/2/1999