RBCC

Full text data of APOA1

APOA1 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Apolipoprotein A-I; Apo-AI; ApoA-I (Apolipoprotein A1; Truncated apolipoprotein A-I; Apolipoprotein A-I(1-242); Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P02647
ID APOA1_HUMAN Reviewed; 267 AA.
AC P02647; A8K866; Q6LDN9; Q6Q785; Q9UCS8; Q9UCT8;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 188.
DE RecName: Full=Apolipoprotein A-I;
DE Short=Apo-AI;
DE Short=ApoA-I;
DE AltName: Full=Apolipoprotein A1;
DE Contains:
DE RecName: Full=Truncated apolipoprotein A-I;
DE AltName: Full=Apolipoprotein A-I(1-242);
DE Flags: Precursor;
GN Name=APOA1;
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].
RX PubMed=6406984; DOI=10.1093/nar/11.9.2827;
RA Shoulders C.C., Kornblihtt A.R., Munro B.S., Baralle F.E.;
RT "Gene structure of human apolipoprotein A1.";
RL Nucleic Acids Res. 11:2827-2837(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6304641; DOI=10.1093/nar/11.11.3703;
RA Cheung P., Chan L.;
RT "Nucleotide sequence of cloned cDNA of human apolipoprotein A-I.";
RL Nucleic Acids Res. 11:3703-3715(1983).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6413973; DOI=10.1073/pnas.80.20.6147;
RA Karathanasis S.K., Zannis V.I., Breslow J.L.;
RT "Isolation and characterization of the human apolipoprotein A-I
RT gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:6147-6151(1983).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6207999;
RA Seilhamer J.J., Protter A.A., Frossard P., Levy-Wilson B.;
RT "Isolation and DNA sequence of full-length cDNA and of the entire gene
RT for human apolipoprotein AI -- discovery of a new genetic polymorphism
RT in the apo AI gene.";
RL DNA 3:309-317(1984).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6328445; DOI=10.1093/nar/12.9.3917;
RA Sharpe C.R., Sidoli A., Shelley C.S., Lucero M.A., Shoulders C.C.,
RA Baralle F.E.;
RT "Human apolipoproteins AI, AII, CII and CIII. cDNA sequences and mRNA
RT abundance.";
RL Nucleic Acids Res. 12:3917-3932(1984).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6198645; DOI=10.1073/pnas.81.1.66;
RA Law S.W., Brewer H.B. Jr.;
RT "Nucleotide sequence and the encoded amino acids of human
RT apolipoprotein A-I mRNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:66-70(1984).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2995392;
RA Law S.W., Brewer H.B. Jr.;
RT "Tangier disease. The complete mRNA sequence encoding for preproapo-A-
RT I.";
RL J. Biol. Chem. 260:12810-12814(1985).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (VARIANT TANGIER).
RX PubMed=3129297; DOI=10.1111/j.1432-1033.1988.tb14022.x;
RA Makrides S.C., Ruiz-Opazo N., Hayden M.R., Nussbaum A.L.,
RA Breslow J.L., Zannis V.I.;
RT "Sequence and expression of Tangier apoA-I gene.";
RL Eur. J. Biochem. 173:465-471(1988).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2673706;
RA Moguilevsky N., Roobol C., Loriau R., Guillaume J.P., Jacobs P.,
RA Cravador A., Herzog A., Brouwers L., Scarso A., Gilles P.,
RA Holmquist L., Carlson L.A., Bollen A.;
RT "Production of human recombinant proapolipoprotein A-I in Escherichia
RT coli: purification and biochemical characterization.";
RL DNA 8:429-436(1989).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT THR-61.
RX PubMed=15108119; DOI=10.1007/s00439-004-1106-x;
RA Fullerton S.M., Buchanan A.V., Sonpar V.A., Taylor S.L., Smith J.D.,
RA Carlson C.S., Salomaa V., Stengaard J.H., Boerwinkle E., Clark A.G.,
RA Nickerson D.A., Weiss K.M.;
RT "The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster.";
RL Hum. Genet. 115:36-56(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Bollen A., Gobert J., Wuelfert E.;
RT "Expression of human proapolipoprotein A-1.";
RL Patent number EP0293357, 30-NOV-1988.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [15]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Skeletal muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [16]
RP PROTEIN SEQUENCE OF 19-27.
RX PubMed=6409108; DOI=10.1016/0006-291X(83)91772-2;
RA Brewer H.B. Jr., Fairwell T., Kay L., Meng M., Ronan R., Law S.,
RA Light J.A.;
RT "Human plasma proapoA-I: isolation and amino-terminal sequence.";
RL Biochem. Biophys. Res. Commun. 113:626-632(1983).
RN [17]
RP PROTEIN SEQUENCE OF 25-267.
RX PubMed=164450;
RA Baker H.N., Gotto A.M. Jr., Jackson R.L.;
RT "The primary structure of human plasma high density apolipoprotein
RT glutamine I (ApoA-I). II. The amino acid sequence and alignment of
RT cyanogen bromide fragments IV, III, and I.";
RL J. Biol. Chem. 250:2725-2738(1975).
RN [18]
RP PROTEIN SEQUENCE OF 25-267.
RX PubMed=204308; DOI=10.1016/0006-291X(78)91614-5;
RA Brewer H.B. Jr., Fairwell T., Larue A., Ronan R., Houser A.,
RA Bronzert T.J.;
RT "The amino acid sequence of human APOA-I, an apolipoprotein isolated
RT from high density lipoproteins.";
RL Biochem. Biophys. Res. Commun. 80:623-630(1978).
RN [19]
RP PROTEIN SEQUENCE OF 25-56.
RX PubMed=3047170; DOI=10.1172/JCI113682;
RA Yui Y., Aoyama T., Morishita H., Takahashi M., Takatsu Y., Kawai C.;
RT "Serum prostacyclin stabilizing factor is identical to apolipoprotein
RT A-I (Apo A-I). A novel function of Apo A-I.";
RL J. Clin. Invest. 82:803-807(1988).
RN [20]
RP PROTEIN SEQUENCE OF 25-50, FUNCTION, AND IDENTIFICATION IN THE SPAP
RP COMPLEX.
RC TISSUE=Serum;
RX PubMed=1909888; DOI=10.1021/bi00101a011;
RA Aakerloef E., Joernvall H., Slotte H., Pousette A.;
RT "Identification of apolipoprotein A1 and immunoglobulin as components
RT of a serum complex that mediates activation of human sperm motility.";
RL Biochemistry 30:8986-8990(1991).
RN [21]
RP PROTEIN SEQUENCE OF 25-48.
RX PubMed=2506184;
RA Manjunath P., Marcel Y.L., Uma J., Seidah N.G., Chretien M.,
RA Chapdelaine A.;
RT "Apolipoprotein A-I binds to a family of bovine seminal plasma
RT proteins.";
RL J. Biol. Chem. 264:16853-16857(1989).
RN [22]
RP PROTEIN SEQUENCE OF 25-43.
RX PubMed=3120314; DOI=10.1126/science.3120314;
RA Prioli R.P., Ordovas J.M., Rosenberg I., Schaeffer E.J.,
RA Pereira M.E.A.;
RT "Similarity of cruzin, an inhibitor of Trypanosoma cruzi
RT neuraminidase, to high-density lipoprotein.";
RL Science 238:1417-1419(1987).
RN [23]
RP PROTEIN SEQUENCE OF 25-42.
RC TISSUE=Heart;
RX PubMed=7895732; DOI=10.1002/elps.11501501209;
RA Corbett J.M., Wheeler C.H., Baker C.S., Yacoub M.H., Dunn M.J.;
RT "The human myocardial two-dimensional gel protein database: update
RT 1994.";
RL Electrophoresis 15:1459-1465(1994).
RN [24]
RP PROTEIN SEQUENCE OF 25-34.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [25]
RP PROTEIN SEQUENCE OF 25-33, AND INTERACTION WITH APOA1BP AND CLU.
RX PubMed=1742316; DOI=10.1016/0005-2760(91)90167-G;
RA Ehnholm C., Bozas S.E., Tenkanen H., Kirszbaum L., Metso J.,
RA Murphy B., Walker I.D.;
RT "The apolipoprotein A-I binding protein of placenta and the SP-40,40
RT protein of human blood are different proteins which both bind to
RT apolipoprotein A-I.";
RL Biochim. Biophys. Acta 1086:255-260(1991).
RN [26]
RP PROTEIN SEQUENCE OF 35-64; 70-101; 121-140; 165-173; 185-195 AND
RP 240-263, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [27]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 118-267.
RX PubMed=6294659; DOI=10.1073/pnas.79.22.6861;
RA Breslow J.L., Ross D., McPherson J., Williams H.W., Kurnit D.,
RA Nussbaum A.L., Karathanasis S.K., Zannis V.I.;
RT "Isolation and characterization of cDNA clones for human
RT apolipoprotein A-I.";
RL Proc. Natl. Acad. Sci. U.S.A. 79:6861-6865(1982).
RN [28]
RP PALMITOYLATION.
RX PubMed=3005308;
RA Hoeg J.M., Meng M.S., Ronan R., Fairwell T., Brewer H.B. Jr.;
RT "Human apolipoprotein A-I. Post-translational modification by fatty
RT acid acylation.";
RL J. Biol. Chem. 261:3911-3914(1986).
RN [29]
RP PROTEOLYTIC PROCESSING.
RX PubMed=6405383; DOI=10.1073/pnas.80.9.2574;
RA Zannis V.I., Karathanasis S.K., Keutmann H.T., Goldberger G.,
RA Breslow J.L.;
RT "Intracellular and extracellular processing of human apolipoprotein A-
RT I: secreted apolipoprotein A-I isoprotein 2 is a propeptide.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:2574-2578(1983).
RN [30]
RP GLYCATION AT LYS-263.
RX PubMed=8261628; DOI=10.1016/0009-8981(93)90165-Z;
RA Calvo C., Ulloa N., Campos M., Verdugo C., Ayrault-Jarrier M.;
RT "The preferential site of non-enzymatic glycation of human
RT apolipoprotein A-I in vivo.";
RL Clin. Chim. Acta 217:193-198(1993).
RN [31]
RP INTERACTION WITH APOA1BP.
RX PubMed=11991719; DOI=10.1006/geno.2002.6761;
RA Ritter M., Buechler C., Boettcher A., Barlage S., Schmitz-Madry A.,
RA Orso E., Bared S.M., Schmiedeknecht G., Baehr C.H., Fricker G.,
RA Schmitz G.;
RT "Cloning and characterization of a novel apolipoprotein A-I-binding
RT protein, AI-BP, secreted by cells of the kidney proximal tubules in
RT response to HDL or ApoA-I.";
RL Genomics 79:693-702(2002).
RN [32]
RP MASS SPECTROMETRY, OXIDATION AT MET-110 AND MET-136 TO METHIONINE
RP SULFOXIDES, AND TISSUE SPECIFICITY.
RX PubMed=12576517; DOI=10.1194/jlr.M200256-JLR200;
RA Pankhurst G., Wang X.L., Wilcken D.E., Baernthaler G., Panzenboeck U.,
RA Raftery M., Stocker R.;
RT "Characterization of specifically oxidized apolipoproteins in mildly
RT oxidized high density lipoprotein.";
RL J. Lipid Res. 44:349-355(2003).
RN [33]
RP MASS SPECTROMETRY.
RX PubMed=12562854; DOI=10.1194/jlr.D200034-JLR200;
RA Niederkofler E.E., Tubbs K.A., Kiernan U.A., Nedelkov D., Nelson R.W.;
RT "Novel mass spectrometric immunoassays for the rapid structural
RT characterization of plasma apolipoproteins.";
RL J. Lipid Res. 44:630-639(2003).
RN [34]
RP INTERACTION WITH NDRG1.
RX PubMed=15922294; DOI=10.1016/j.bbrc.2005.05.050;
RA Hunter M., Angelicheva D., Tournev I., Ingley E., Chan D.C.,
RA Watts G.F., Kremensky I., Kalaydjieva L.;
RT "NDRG1 interacts with APO A-I and A-II and is a functional candidate
RT for the HDL-C QTL on 8q24.";
RL Biochem. Biophys. Res. Commun. 332:982-992(2005).
RN [35]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [36]
RP STRUCTURE BY NMR OF 190-209.
RX PubMed=8664326; DOI=10.1016/0005-2760(96)00037-9;
RA Wang G., Treleaven W.D., Cushley R.J.;
RT "Conformation of human serum apolipoprotein A-I(166-185) in the
RT presence of sodium dodecyl sulfate or dodecylphosphocholine by 1H-NMR
RT and CD. Evidence for specific peptide-SDS interactions.";
RL Biochim. Biophys. Acta 1301:174-184(1996).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (4.0 ANGSTROMS) OF 67-267.
RX PubMed=9356442; DOI=10.1073/pnas.94.23.12291;
RA Borhani D.W., Rogers D.P., Engler J.A., Brouillette C.G.;
RT "Crystal structure of truncated human apolipoprotein A-I suggests a
RT lipid-bound conformation.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:12291-12296(1997).
RN [38]
RP DISEASE.
RX PubMed=8240372; DOI=10.1006/bbrc.1993.2341;
RA Nakata K., Kobayashi K., Yanagi H., Shimakura Y., Tsuchiya S.,
RA Arinami T., Hamaguchi H.;
RT "Autosomal dominant hypoalphalipoproteinemia due to a completely
RT defective apolipoprotein A-I gene.";
RL Biochem. Biophys. Res. Commun. 196:950-955(1993).
RN [39]
RP DISEASE.
RX PubMed=8282791; DOI=10.1172/JCI116949;
RA Ng D.S., Leiter L.A., Vezina C., Connelly P.W., Hegele R.A.;
RT "Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I
RT deficiency in a family with analphalipoproteinemia.";
RL J. Clin. Invest. 93:223-229(1994).
RN [40]
RP VARIANT MILANO CYS-197.
RX PubMed=6401735;
RA Weisgraber K.H., Rall S.C. Jr., Bersot T.P., Mahley R.W.,
RA Franceschini G., Sirtori C.R.;
RT "Apolipoprotein A-IMilano. Detection of normal A-I in affected
RT subjects and evidence for a cysteine for arginine substitution in the
RT variant A-I.";
RL J. Biol. Chem. 258:2508-2513(1983).
RN [41]
RP VARIANT TANGIER.
RX PubMed=6412234; DOI=10.1073/pnas.80.19.6081;
RA Schmitz G., Assmann G., Rall S.C. Jr., Mahley R.W.;
RT "Tangier disease: defective recombination of a specific Tangier
RT apolipoprotein A-I isoform (pro-apo A-I) with high density
RT lipoproteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:6081-6085(1983).
RN [42]
RP VARIANT GIESSEN ARG-167.
RX PubMed=6489332; DOI=10.1111/j.1432-1033.1984.tb08467.x;
RA Utermann G., Haas J., Steinmetz A., Paetzold R., Rall S.C. Jr.,
RA Weisgraber K.H., Mahley R.W.;
RT "Apolipoprotein A-IGiessen (Pro143-->Arg). A mutant that is defective
RT in activating lecithin:cholesterol acyltransferase.";
RL Eur. J. Biochem. 144:325-331(1984).
RN [43]
RP VARIANT NORWAY LYS-160.
RX PubMed=6432779;
RA Rall S.C. Jr., Weisgraber K.H., Mahley R.W., Ogawa Y., Fielding C.J.,
RA Utermann G., Haas J., Steinmetz A., Menzel H.J., Assmann G.;
RT "Abnormal lecithin:cholesterol acyltransferase activation by a human
RT apolipoprotein A-I variant in which a single lysine residue is
RT deleted.";
RL J. Biol. Chem. 259:10063-10070(1984).
RN [44]
RP PROTEIN SEQUENCE OF 25-107, AND VARIANT AMYL8 ARG-50.
RX PubMed=3142462; DOI=10.1016/S0006-291X(88)80909-4;
RA Nichols W.C., Dwulet F.E., Liepnieks J., Benson M.D.;
RT "Variant apolipoprotein AI as a major constituent of a human
RT hereditary amyloid.";
RL Biochem. Biophys. Res. Commun. 156:762-768(1988).
RN [45]
RP VARIANT AMYL8 ARG-50.
RX PubMed=2123470; DOI=10.1016/0888-7543(90)90288-6;
RA Nichols W.C., Gregg R.E., Brewer H.B. Jr., Benson M.D.;
RT "A mutation in apolipoprotein A-I in the Iowa type of familial
RT amyloidotic polyneuropathy.";
RL Genomics 8:318-323(1990).
RN [46]
RP PROTEIN SEQUENCE OF 25-267, AND VARIANT FUKUOKA LYS-134.
RX PubMed=2107878; DOI=10.1016/0005-2760(90)90292-6;
RA Takada Y., Sasaki J., Ogata S., Nakanishi T., Ikehara Y., Arakawa K.;
RT "Isolation and characterization of human apolipoprotein A-I Fukuoka
RT (110 Glu-->Lys). A novel apolipoprotein variant.";
RL Biochim. Biophys. Acta 1043:169-176(1990).
RN [47]
RP PROTEIN SEQUENCE OF 25-112, AND VARIANT AMYL8 ARG-84.
RX PubMed=1502149; DOI=10.1073/pnas.89.16.7389;
RA Soutar A.K., Hawkins P.N., Vigushin D.M., Tennent G.A., Booth S.E.,
RA Hutton T., Nguyen O., Totty N.F., Feest T.G., Hsuan J.J., Pepys M.B.;
RT "Apolipoprotein AI mutation Arg-60 causes autosomal dominant
RT amyloidosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:7389-7393(1992).
RN [48]
RP VARIANT BALTIMORE LEU-34.
RX PubMed=2108924; DOI=10.1007/BF00195816;
RA Ladias J.A.A., Kwiterovich P.O. Jr., Smith H.H., Karathanasis S.K.,
RA Antonarakis S.E.;
RT "Apolipoprotein A1 Baltimore (Arg-10-->Leu), a new ApoA1 variant.";
RL Hum. Genet. 84:439-445(1990).
RN [49]
RP VARIANTS ARG-27; ARG-28 AND ARG-189.
RX PubMed=2512329; DOI=10.1172/JCI114355;
RA von Eckardstein A., Funke H., Henke A., Altland K., Benninghoven A.,
RA Assmann G., Welp S., Roetrige A., Kock R.;
RT "Apolipoprotein A-I variants. Naturally occurring substitutions of
RT proline residues affect plasma concentration of apolipoprotein A-I.";
RL J. Clin. Invest. 84:1722-1730(1989).
RN [50]
RP VARIANTS GLU-113; MET-131; GLY-163; VAL-171 AND LYS-222.
RX PubMed=2111322;
RA von Eckardstein A., Funke H., Walter M., Altland K., Benninghoven A.,
RA Assmann G.;
RT "Structural analysis of human apolipoprotein A-I variants. Amino acid
RT substitutions are nonrandomly distributed throughout the
RT apolipoprotein A-I primary structure.";
RL J. Biol. Chem. 265:8610-8617(1990).
RN [51]
RP VARIANTS HITA AND TSUSHIMA.
RX PubMed=7918609;
RA Araki K., Sasaki J., Matsunaga A., Takada Y., Moriyama K., Hidaka K.,
RA Arakawa K.;
RT "Characterization of two new human apolipoprotein A-I variants:
RT apolipoprotein A-I Tsushima (Trp-108-->Arg) and A-I Hita (Ala-
RT 95-->Asp).";
RL Biochim. Biophys. Acta 1214:272-278(1994).
RN [52]
RP VARIANT AMYL8 ARG-50.
RX PubMed=8208902;
RA Vigushin D.M., Gough J., Allan D., Alguacil A., Penner B.,
RA Pettigrew N.M., Quinonez G., Bernstein K., Booth S.E., Booth D.R.,
RA Soutar A.K., Hawkins P.N., Pepys M.B.;
RT "Familial nephropathic systemic amyloidosis caused by apolipoprotein
RT AI variant Arg26.";
RL Q. J. Med. 87:149-154(1994).
RN [53]
RP VARIANT AOITA GLU-180.
RX PubMed=9514407;
RA Huang W., Sasaki J., Matsunaga A., Nanimatsu H., Moriyama K., Han H.,
RA Kugi M., Koga T., Yamaguchi K., Arakawa K.;
RT "A novel homozygous missense mutation in the apo A-I gene with apo A-I
RT deficiency.";
RL Arterioscler. Thromb. Vasc. Biol. 18:389-396(1998).
RN [54]
RP VARIANT ZARAGOZA ARG-168.
RA Recalde D., Cenarro A., Civeira F., Pocovi M.;
RT "Apo A-I Zaragoza(L144R): a novel mutation in the apolipoprotein A-I
RT gene associated with familial hypoalphalipoproteinemia.";
RL Hum. Mutat. 11:416-416(1998).
RN [55]
RP VARIANT ILE-92.
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 [56]
RP VARIANT ILE-92, AND MASS SPECTROMETRY.
RX PubMed=22028381; DOI=10.1093/jmcb/mjr024;
RA Su Z.D., Sun L., Yu D.X., Li R.X., Li H.X., Yu Z.J., Sheng Q.H.,
RA Lin X., Zeng R., Wu J.R.;
RT "Quantitative detection of single amino acid polymorphisms by targeted
RT proteomics.";
RL J. Mol. Cell Biol. 3:309-315(2011).
CC -!- FUNCTION: Participates in the reverse transport of cholesterol
CC from tissues to the liver for excretion by promoting cholesterol
CC efflux from tissues and by acting as a cofactor for the lecithin
CC cholesterol acyltransferase (LCAT). As part of the SPAP complex,
CC activates spermatozoa motility.
CC -!- SUBUNIT: Interacts with APOA1BP and CLU. Component of a sperm
CC activating protein complex (SPAP), consisting of APOA1, an
CC immunoglobulin heavy chain, an immunoglobulin light chain and
CC albumin. Interacts with NDRG1.
CC -!- INTERACTION:
CC Self; NbExp=6; IntAct=EBI-701692, EBI-701692;
CC P05067:APP; NbExp=5; IntAct=EBI-701692, EBI-77613;
CC P00738:HP; NbExp=3; IntAct=EBI-701692, EBI-1220767;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Major protein of plasma HDL, also found in
CC chylomicrons. Synthesized in the liver and small intestine. The
CC oxidized form at Met-110 and Met-136 is increased in individuals
CC with increased risk for coronary artery disease, such as in
CC carrier of the eNOSa/b genotype and exposure to cigarette smoking.
CC It is also present in increased levels in aortic lesions relative
CC to native ApoA-I and increased levels are seen with increasing
CC severity of disease.
CC -!- PTM: Palmitoylated.
CC -!- PTM: Met-110 and Met-136 are oxidized to methionine sulfoxides.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- MASS SPECTROMETRY: Mass=28081; Method=Electrospray; Range=25-267;
CC Note=Without methionine sulfoxide; Source=PubMed:12576517;
CC -!- MASS SPECTROMETRY: Mass=28098; Method=Electrospray; Range=25-267;
CC Note=With 1 methionine sulfoxide, oxidation at Met-110;
CC Source=PubMed:12576517;
CC -!- MASS SPECTROMETRY: Mass=28095; Method=Electrospray; Range=25-267;
CC Note=With 1 methionine sulfoxide, oxidation at Met-136;
CC Source=PubMed:12576517;
CC -!- MASS SPECTROMETRY: Mass=28114; Method=Electrospray; Range=25-267;
CC Note=With 2 methionine sulfoxides, oxidation at Met-110 and Met-
CC 136; Source=PubMed:12576517;
CC -!- POLYMORPHISM: Genetic variations in APOA1 can result in APOA1
CC deficiency and are associated with low levels of HDL cholesterol
CC [MIM:107680].
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 -!- 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: Note=APOA1 mutations may be involved in the pathogenesis
CC of amyloid polyneuropathy-nephropathy Iowa type, also known as
CC amyloidosis van Allen type or familial amyloid polyneuropathy type
CC III (PubMed:3142462 and PubMed:2123470). The clinical picture is
CC dominated by neuropathy in the early stages of the disease and
CC nephropathy late in the course. Death is due in most cases to
CC renal amyloidosis.
CC -!- DISEASE: Amyloidosis 8 (AMYL8) [MIM:105200]: A hereditary
CC generalized amyloidosis due to deposition of apolipoprotein A1,
CC fibrinogen and lysozyme amyloids. Viscera are particularly
CC affected. There is no involvement of the nervous system. Clinical
CC features include renal amyloidosis resulting in nephrotic
CC syndrome, arterial hypertension, hepatosplenomegaly, cholestasis,
CC petechial skin rash. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the apolipoprotein A1/A4/E family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/APOA1";
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;=APOA1";
CC -----------------------------------------------------------------------
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DR EMBL; J00098; AAB59514.1; -; Genomic_DNA.
DR EMBL; X01038; CAA25519.1; -; Genomic_DNA.
DR EMBL; X02162; CAA26097.1; -; mRNA.
DR EMBL; X00566; CAA25232.1; -; mRNA.
DR EMBL; M11791; AAA35545.1; -; mRNA.
DR EMBL; X07496; CAA30377.1; -; Genomic_DNA.
DR EMBL; M27875; AAA62829.1; -; mRNA.
DR EMBL; M29068; AAA51747.1; -; mRNA.
DR EMBL; AY422952; AAQ91811.1; -; Genomic_DNA.
DR EMBL; AY555191; AAS68227.1; -; Genomic_DNA.
DR EMBL; A14829; CAA01198.1; -; mRNA.
DR EMBL; AK292231; BAF84920.1; -; mRNA.
DR EMBL; EF444948; ACA05932.1; -; Genomic_DNA.
DR EMBL; EF444948; ACA05933.1; -; Genomic_DNA.
DR EMBL; EF444948; ACA05934.1; -; Genomic_DNA.
DR EMBL; EF444948; ACA05935.1; -; Genomic_DNA.
DR EMBL; EF444948; ACA05936.1; -; Genomic_DNA.
DR EMBL; CH471065; EAW67274.1; -; Genomic_DNA.
DR EMBL; BC005380; AAH05380.1; -; mRNA.
DR EMBL; BC110286; AAI10287.1; -; mRNA.
DR PIR; A90947; LPHUA1.
DR RefSeq; NP_000030.1; NM_000039.1.
DR RefSeq; XP_005271596.1; XM_005271539.1.
DR RefSeq; XP_005271597.1; XM_005271540.1.
DR UniGene; Hs.93194; -.
DR PDB; 1AV1; X-ray; 4.00 A; A/B/C/D=68-267.
DR PDB; 1GW3; NMR; -; A=166-211.
DR PDB; 1GW4; NMR; -; A=166-211.
DR PDB; 1ODP; NMR; -; A=190-209.
DR PDB; 1ODQ; NMR; -; A=190-209.
DR PDB; 1ODR; NMR; -; A=190-209.
DR PDB; 2A01; X-ray; 2.40 A; A/B/C=25-267.
DR PDB; 3J00; EM; -; 0/1=68-267.
DR PDB; 3K2S; X-ray; -; A/B=25-267.
DR PDB; 3R2P; X-ray; 2.20 A; A=25-208.
DR PDBsum; 1AV1; -.
DR PDBsum; 1GW3; -.
DR PDBsum; 1GW4; -.
DR PDBsum; 1ODP; -.
DR PDBsum; 1ODQ; -.
DR PDBsum; 1ODR; -.
DR PDBsum; 2A01; -.
DR PDBsum; 3J00; -.
DR PDBsum; 3K2S; -.
DR PDBsum; 3R2P; -.
DR DisProt; DP00386; -.
DR ProteinModelPortal; P02647; -.
DR SMR; P02647; 26-267.
DR DIP; DIP-29619N; -.
DR IntAct; P02647; 58.
DR MINT; MINT-5000866; -.
DR STRING; 9606.ENSP00000236850; -.
DR ChEMBL; CHEMBL5984; -.
DR PhosphoSite; P02647; -.
DR DMDM; 113992; -.
DR DOSAC-COBS-2DPAGE; P02647; -.
DR OGP; P02647; -.
DR REPRODUCTION-2DPAGE; IPI00021841; -.
DR REPRODUCTION-2DPAGE; P02647; -.
DR SWISS-2DPAGE; P02647; -.
DR UCD-2DPAGE; P02647; -.
DR PaxDb; P02647; -.
DR PeptideAtlas; P02647; -.
DR PRIDE; P02647; -.
DR DNASU; 335; -.
DR Ensembl; ENST00000236850; ENSP00000236850; ENSG00000118137.
DR Ensembl; ENST00000359492; ENSP00000352471; ENSG00000118137.
DR Ensembl; ENST00000375320; ENSP00000364469; ENSG00000118137.
DR Ensembl; ENST00000375323; ENSP00000364472; ENSG00000118137.
DR GeneID; 335; -.
DR KEGG; hsa:335; -.
DR UCSC; uc001ppv.1; human.
DR CTD; 335; -.
DR GeneCards; GC11M116706; -.
DR HGNC; HGNC:600; APOA1.
DR HPA; CAB016778; -.
DR MIM; 105200; phenotype.
DR MIM; 107680; gene+phenotype.
DR MIM; 205400; phenotype.
DR MIM; 604091; phenotype.
DR neXtProt; NX_P02647; -.
DR Orphanet; 425; Apolipoprotein A-I deficiency.
DR Orphanet; 93560; Familial renal amyloidosis due to Apolipoprotein AI variant.
DR Orphanet; 314701; Primary systemic amyloidosis.
DR PharmGKB; PA49; -.
DR eggNOG; NOG39720; -.
DR HOGENOM; HOG000033998; -.
DR HOVERGEN; HBG105708; -.
DR InParanoid; P02647; -.
DR KO; K08757; -.
DR OMA; YRQKVAP; -.
DR OrthoDB; EOG7TBC3N; -.
DR PhylomeDB; P02647; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; APOA1; human.
DR EvolutionaryTrace; P02647; -.
DR GeneWiki; Apolipoprotein_A1; -.
DR GenomeRNAi; 335; -.
DR NextBio; 1387; -.
DR PMAP-CutDB; P02647; -.
DR PRO; PR:P02647; -.
DR ArrayExpress; P02647; -.
DR Bgee; P02647; -.
DR CleanEx; HS_APOA1; -.
DR Genevestigator; P02647; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005769; C:early endosome; TAS:Reactome.
DR GO; GO:0071682; C:endocytic vesicle lumen; TAS:Reactome.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0034774; C:secretory granule lumen; TAS:Reactome.
DR GO; GO:0034366; C:spherical high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0001540; F:beta-amyloid binding; IDA:BHF-UCL.
DR GO; GO:0015485; F:cholesterol binding; IDA:BHF-UCL.
DR GO; GO:0017127; F:cholesterol transporter activity; IMP:BHF-UCL.
DR GO; GO:0008035; F:high-density lipoprotein particle binding; IEA:Ensembl.
DR GO; GO:0055102; F:lipase inhibitor activity; IEA:Ensembl.
DR GO; GO:0060228; F:phosphatidylcholine-sterol O-acyltransferase activator activity; IDA:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL.
DR GO; GO:0005548; F:phospholipid transporter activity; IEA:Ensembl.
DR GO; GO:0030325; P:adrenal gland development; IEA:Ensembl.
DR GO; GO:0043534; P:blood vessel endothelial cell migration; IEA:Ensembl.
DR GO; GO:0006695; P:cholesterol biosynthetic process; 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:0070508; P:cholesterol import; IMP:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IMP:BHF-UCL.
DR GO; GO:0001935; P:endothelial cell proliferation; IEA:Ensembl.
DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0008211; P:glucocorticoid metabolic process; IEA:Ensembl.
DR GO; GO:0034380; P:high-density lipoprotein particle assembly; IDA:BHF-UCL.
DR GO; GO:0034384; P:high-density lipoprotein particle clearance; IC:BHF-UCL.
DR GO; GO:0034375; P:high-density lipoprotein particle remodeling; IC:BHF-UCL.
DR GO; GO:0019915; P:lipid storage; IEA:Ensembl.
DR GO; GO:0042158; P:lipoprotein biosynthetic process; IEA:Ensembl.
DR GO; GO:0042157; P:lipoprotein metabolic process; TAS:Reactome.
DR GO; GO:0060354; P:negative regulation of cell adhesion molecule production; IDA:BHF-UCL.
DR GO; GO:0002740; P:negative regulation of cytokine secretion involved in immune response; IDA:BHF-UCL.
DR GO; GO:0034115; P:negative regulation of heterotypic cell-cell adhesion; IDA:BHF-UCL.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IDA:BHF-UCL.
DR GO; GO:0050713; P:negative regulation of interleukin-1 beta secretion; IDA:BHF-UCL.
DR GO; GO:0060192; P:negative regulation of lipase activity; IEA:Ensembl.
DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; IDA:BHF-UCL.
DR GO; GO:0010903; P:negative regulation of very-low-density lipoprotein particle remodeling; IDA:BHF-UCL.
DR GO; GO:0031100; P:organ regeneration; IEA:Ensembl.
DR GO; GO:0018206; P:peptidyl-methionine modification; IDA:UniProtKB.
DR GO; GO:0014012; P:peripheral nervous system axon regeneration; IEA:Ensembl.
DR GO; GO:0006656; P:phosphatidylcholine biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0033700; P:phospholipid efflux; IDA:BHF-UCL.
DR GO; GO:0055091; P:phospholipid homeostasis; IDA:BHF-UCL.
DR GO; GO:0007603; P:phototransduction, visible light; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0010873; P:positive regulation of cholesterol esterification; IDA:BHF-UCL.
DR GO; GO:0051345; P:positive regulation of hydrolase activity; IDA:BHF-UCL.
DR GO; GO:0051347; P:positive regulation of transferase activity; IEA:Ensembl.
DR GO; GO:0018158; P:protein oxidation; IDA:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IDA:BHF-UCL.
DR GO; GO:0032489; P:regulation of Cdc42 protein signal transduction; IDA:BHF-UCL.
DR GO; GO:0030300; P:regulation of intestinal cholesterol absorption; IEA:Ensembl.
DR GO; GO:0001932; P:regulation of protein phosphorylation; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0043627; P:response to estrogen stimulus; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0001523; P:retinoid metabolic process; TAS:Reactome.
DR GO; GO:0043691; P:reverse cholesterol transport; IMP:BHF-UCL.
DR GO; GO:0070328; P:triglyceride homeostasis; IDA:BHF-UCL.
DR InterPro; IPR000074; ApoA1_A4_E.
DR Pfam; PF01442; Apolipoprotein; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amyloid; Amyloidosis; Atherosclerosis;
KW Cholesterol metabolism; Complete proteome; Direct protein sequencing;
KW Disease mutation; Glycation; Glycoprotein; HDL; Lipid metabolism;
KW Lipid transport; Lipoprotein; Neuropathy; Oxidation; Palmitate;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat; Secreted;
KW Signal; Steroid metabolism; Sterol metabolism; Transport.
FT SIGNAL 1 18
FT PROPEP 19 24
FT /FTId=PRO_0000001938.
FT CHAIN 25 267 Apolipoprotein A-I.
FT /FTId=PRO_0000001939.
FT CHAIN 25 266 Truncated apolipoprotein A-I.
FT /FTId=PRO_0000001940.
FT REPEAT 68 89 1.
FT REPEAT 90 111 2.
FT REPEAT 112 122 3; half-length.
FT REPEAT 123 144 4.
FT REPEAT 145 166 5.
FT REPEAT 167 188 6.
FT REPEAT 189 210 7.
FT REPEAT 211 232 8.
FT REPEAT 233 243 9; half-length.
FT REPEAT 244 267 10.
FT REGION 68 267 10 X approximate tandem repeats.
FT MOD_RES 110 110 Methionine sulfoxide.
FT MOD_RES 136 136 Methionine sulfoxide.
FT CARBOHYD 263 263 N-linked (Glc) (glycation).
FT VARIANT 27 27 P -> H (in Munster-3C;
FT dbSNP:rs121912720).
FT /FTId=VAR_000605.
FT VARIANT 27 27 P -> R (in dbSNP:rs121912720).
FT /FTId=VAR_000606.
FT VARIANT 28 28 P -> R (in Munster-3B).
FT /FTId=VAR_000607.
FT VARIANT 34 34 R -> L (in Baltimore; dbSNP:rs28929476).
FT /FTId=VAR_000608.
FT VARIANT 50 50 G -> R (in AMYL8; also found in a family
FT with amyloid polyneuropathy-nephropathy
FT Iowa; dbSNP:rs28931574).
FT /FTId=VAR_000609.
FT VARIANT 61 61 A -> T (in dbSNP:rs12718465).
FT /FTId=VAR_025445.
FT VARIANT 84 84 L -> R (in AMYL8).
FT /FTId=VAR_000610.
FT VARIANT 92 92 T -> I (polymorphism confirmed at protein
FT level).
FT /FTId=VAR_017017.
FT VARIANT 113 113 D -> E.
FT /FTId=VAR_000611.
FT VARIANT 119 119 A -> D (in Hita).
FT /FTId=VAR_000612.
FT VARIANT 126 126 D -> H (in dbSNP:rs5077).
FT /FTId=VAR_016189.
FT VARIANT 127 127 D -> N (in Munster-3A).
FT /FTId=VAR_000613.
FT VARIANT 131 131 K -> M (in dbSNP:rs4882).
FT /FTId=VAR_000615.
FT VARIANT 131 131 Missing (in Marburg/Munster-2).
FT /FTId=VAR_000614.
FT VARIANT 132 132 W -> R (in Tsushima).
FT /FTId=VAR_000616.
FT VARIANT 134 134 E -> K (in Fukuoka).
FT /FTId=VAR_000617.
FT VARIANT 160 160 E -> K (in Norway).
FT /FTId=VAR_000618.
FT VARIANT 163 163 E -> G.
FT /FTId=VAR_000619.
FT VARIANT 167 167 P -> R (in Giessen).
FT /FTId=VAR_000620.
FT VARIANT 168 168 L -> R (in Zaragoza).
FT /FTId=VAR_000621.
FT VARIANT 171 171 E -> V.
FT /FTId=VAR_000622.
FT VARIANT 180 180 V -> E (in Oita; 60% of normal apoA-I and
FT normal HDL cholesterol levels. Rapidly
FT cleared from plasma).
FT /FTId=VAR_021362.
FT VARIANT 184 184 R -> P (in dbSNP:rs5078).
FT /FTId=VAR_014609.
FT VARIANT 189 189 P -> R.
FT /FTId=VAR_000623.
FT VARIANT 197 197 R -> C (in Milano; associated with
FT decreased HDL levels and moderate
FT increases in triglycerides; no evidence
FT of association with premature vascular
FT disease; dbSNP:rs28931573).
FT /FTId=VAR_000624.
FT VARIANT 222 222 E -> K (in Munster-4).
FT /FTId=VAR_000625.
FT CONFLICT 32 32 W -> P (in Ref. 25; AA sequence).
FT HELIX 33 42
FT HELIX 45 59
FT HELIX 61 65
FT STRAND 69 73
FT HELIX 80 88
FT HELIX 93 158
FT TURN 159 164
FT HELIX 166 203
FT TURN 212 214
FT STRAND 215 217
FT HELIX 220 237
FT STRAND 238 240
FT HELIX 243 266
SQ SEQUENCE 267 AA; 30778 MW; 1A28B8366E620310 CRC64;
MKAAVLTLAV LFLTGSQARH FWQQDEPPQS PWDRVKDLAT VYVDVLKDSG RDYVSQFEGS
ALGKQLNLKL LDNWDSVTST FSKLREQLGP VTQEFWDNLE KETEGLRQEM SKDLEEVKAK
VQPYLDDFQK KWQEEMELYR QKVEPLRAEL QEGARQKLHE LQEKLSPLGE EMRDRARAHV
DALRTHLAPY SDELRQRLAA RLEALKENGG ARLAEYHAKA TEHLSTLSEK AKPALEDLRQ
GLLPVLESFK VSFLSALEEY TKKLNTQ
//

MIM 105200
*RECORD*
*FIELD* NO
105200
*FIELD* TI
#105200 AMYLOIDOSIS, FAMILIAL VISCERAL
;;AMYLOIDOSIS VIII;;
OSTERTAG TYPE AMYLOIDOSIS;;
read moreGERMAN TYPE AMYLOIDOSIS;;
AMYLOIDOSIS, FAMILIAL RENAL;;
AMYLOIDOSIS, SYSTEMIC NONNEUROPATHIC
*FIELD* TX
A number sign (#) is used with this entry because of the evidence that
systemic nonneuropathic amyloidosis is the result of mutation in the
apolipoprotein A1 gene (APOA1; 107680), the fibrinogen alpha-chain gene
(FGA; 134820), the lysozyme gene (LYZ; 153450), or the gene encoding
beta-2-microglobulin (B2M; 109700).

CLINICAL FEATURES

Ostertag (1932, 1950) reported on a family with visceral amyloidosis. A
woman, 3 of her children, and 1 of her grandchildren were affected with
chronic nephropathy, arterial hypertension, and hepatosplenomegaly.
Albuminuria, hematuria and pitting edema were early signs. The age of
onset was variable. Death occurred about 10 years after onset. The
visceral involvement by amyloid was found to be extensive.

Maxwell and Kimbell (1936) described 3 brothers who died of visceral,
especially renal, amyloidosis in their 40s. Chronic weakness, edema,
proteinuria, and hepatosplenomegaly were features. McKusick (1974)
followed up on the family reported by Maxwell and Kimbell (1936). The
father of the 3 affected brothers died at age 72 after an automobile
accident and their mother died suddenly at age 87 after being in
apparent good health. A son of one of the brothers had frequent bouts of
unexplained fever in childhood (as did his father and 2 uncles),
accompanied at times by nonspecific rash. At the age of 35, proteinuria
was discovered and renal amyloidosis was diagnosed by renal biopsy. For
2 years thereafter he displayed the nephrotic syndrome, followed in the
next 2 years by uremia from which he died at age 39. Autopsy revealed
amyloidosis, most striking in the kidneys but also involving the adrenal
glands and spleen. Although some features of the family of Maxwell and
Kimbell (1936) are similar to those of urticaria, deafness and
amyloidosis (191900), no deafness was present in their family. Weiss and
Page (1974) reported a family with 2 definite and 4 probable cases in 3
generations.

Mornaghi et al. (1981, 1982) reported rapidly progressive biopsy-proved
renal amyloidosis in 3 brothers, aged 49, 52 and 55, of Irish-American
origin. None had evidence of a plasma cell dyscrasia, a monoclonal serum
or urine protein, or any underlying chronic disease. Immunoperoxidase
staining of 1 pulmonary and 1 renal biopsy specimen was negative for
amyloid A (AA), amyloid L (AL) and prealbumin. The authors concluded
that the disorder in the 3 brothers closely resembled that described by
Ostertag (1932).

Studying the proband of a kindred with the familial amyloidosis of
Ostertag, Lanham et al. (1982) demonstrated permanganate-sensitive
congophilia of the amyloid but found no immunofluorescent staining for
amyloid A or prealbumin. They concluded that this amyloid may be
chemically distinct from previously characterized forms.

Libbey and Talbert (1987) described a case of nephropathic amyloidosis,
presumably of the Ostertag type. In their case, the amyloid showed no
staining for light chains or prealbumin. Involvement of the liver was
associated with cholestasis. In the kindred reported by Lanham et al.
(1982), 6 members in 2 generations showed the onset of renal disease
between ages 23 and 45 years. The deposition of amyloid is
characteristically interstitial rather than glomerular as seen in other
forms of amyloidosis. The proband had the sicca syndrome. The details of
their patient's family history were not given by Libbey and Talbert
(1987).

Zalin et al. (1991) described yet another family with the Ostertag type
of familial nephropathic nonneuropathic amyloidosis. Petechial skin rash
was a striking feature, and petechial hemorrhages were induced by
minimal abrasion. Extensive amyloid deposition in the lungs was
illustrated. Zalin et al. (1991) reported that the amyloid deposits
contained apolipoprotein A-I; however, it was later shown that the
disorder in this family was caused by a mutation in lysozyme (see
153450.0001).

Vella et al. (2002) reported 2 patients with glaucoma due to primary
nonneuropathic amyloidosis. Glaucoma complicating amyloidosis had been
documented previously in familial amyloidotic polyneuropathy, and in
association with primary localized orbital amyloidosis. One of their
patients developed orbital amyloidoma and secondary glaucoma. After a
sudden worsening of visual acuity, papilledema was found and
(nonarteritic) anterior ischemic optic neuropathy was diagnosed. Tumor
debulking and orbital decompression were performed. Tumor histology
showed massive deposits of amyloid containing lambda chains.
Postoperatively, glaucoma was controllable with topical therapy. The
other patient had a 2-year history of weakness, persistent abdominal
pain, paresthesias, and weight loss, and a 20-year history of open-angle
glaucoma. This patient was found to have primary systemic amyloidosis on
liver and rectal biopsies. Echocardiography showed restrictive
cardiomyopathy with a diffuse hyperrefractile 'granular sparkling
appearance.' Intraocular pressure was normal on topical therapy and
ocular fundus examination showed hard drusen-like deposits bilaterally.
The patient's course improved after 15 cycles of melphalan-prednisone
treatment over 24 months. The authors stated that the incidence of
primary amyloidosis-associated glaucoma might be underestimated because
glaucoma in Western Europe and North America is less commonly treated
surgically.

MOLECULAR GENETICS

In the family with hereditary nonneuropathic systemic amyloidosis
previously studied by Zalin et al. (1991) and in another unrelated
English family with the disease, Pepys et al. (1993) identified
heterozygosity for 2 missense mutations in the LYZ gene, respectively
(153450.0001 and 153450.0002).

In a Peruvian family in which a brother and sister and the son of the
brother died from renal amyloidosis, Benson et al. (1993) identified a
mutation in the fibrinogen A alpha polypeptide gene (FGA; 134820.0012).

In 2 large American kindreds of Irish descent with nephrotic syndrome
due to renal amyloidosis, Uemichi et al. (1993, 1994) identified a
missense mutation in the FGA gene (E526V; 134820.0013).

In an American kindred with hereditary renal amyloidosis, Uemichi et al.
(1996) identified a 1-bp deletion in the FGA gene (134820.0016), causing
a frameshift and termination sequence at codon 548.

In a French kindred with autosomal dominant hereditary renal
amyloidosis, Asl et al. (1997) identified a different 1-bp deletion in
the FGA gene, also resulting in termination at codon 548 (134820.0018).

Systemic amyloidosis is the diagnosis in 2.5% of all renal biopsies,
according to Davison (1985), and is the cause of death in more than 1 in
1,500 persons in the United Kingdom annually. Acquired monoclonal
immunoglobulin light-chain amyloidosis (AL; see 254500), formerly known
as primary amyloidosis, is the most common form of systemic amyloidosis
and can respond to chemotherapy directed at the underlying plasma cell
dyscrasia. Lachmann et al. (2002) studied 350 patients with systemic
amyloidosis in whom a diagnosis of the AL type of the disorder had been
suggested by clinical and laboratory data and by the apparent absence of
a family history. They identified amyloidogenic mutations in 34 (9.7%)
of the patients, all of whom had the diagnosis of hereditary amyloidosis
confirmed by additional investigations. In 18 (5.1%) of the 350
patients, the E526V mutation in the FGA gene was identified; 13 of the
patients had missense mutations in the transthyretin gene (176330); 2
patients had missense mutations in the APOA1 gene (107680); and 1
patient had the D67H mutation in the lysozyme gene (153450.0002). All 18
patients with the FGA E526V mutation were of northern European ancestry,
and although none was aware of any relevant family history, genealogic
studies revealed that 2 were cousins and that ancestors of 2 other
patients lived in adjacent villages. A fifth patient retrospectively
ascertained that her dizygotic twin had died of renal failure at the age
of 76 years. The median age of the 18 patients at the time of
presentation was 59 years; the youngest was in her thirties and the
oldest was 78 years old. All presented with isolated renal dysfunction
and proteinuria, and most had moderate hypertension; all had renal
amyloid deposits, and splenic amyloid was present in all but 1 of the
patients. Spontaneous splenic rupture occurred in 2 patients.

Granel et al. (2005) described a patient diagnosed with systemic
digestive and 'medullar' amyloidosis. (Grateau (2006) stated that the
term 'medullar' referred to the involvement of bone marrow.) Primary
(AL) amyloidosis was initially suspected, but results of
immunohistochemical staining were negative for immunoglobulin
kappa/lambda light chains. The results of a complementary search for
lysozyme amyloidosis were positive in colonic mucosa. A missense
mutation, a T-to-A transversion at the first nucleotide of codon 64
(W64R; 153450.0005), was found in the LYZ gene. Granel et al. (2005)
pointed out that an incorrect diagnosis could have been made if complete
analysis of the amyloid deposits had not been performed, and that
amyloidoses of different types, i.e., AA, AL, transthyretin, lysozyme,
or fibrinogen, can produce similar visceral involvement, but prognosis
and treatment are completely different.

In 4 affected members of a family with autosomal dominant visceral
amyloidosis, Valleix et al. (2012) identified a heterozygous mutation in
the B2M gene (D76N; 109700.0002). Studies on the recombinant D76N
protein showed reduced stability of the fully folded mutant protein and
significantly increased conversion of the mutant protein into fibrils
with amyloid-like properties under physiologic conditions, whereas the
wildtype protein did not aggregate at all. In mid-adult life, the
patients developed slowly progressive chronic diarrhea with weight loss
and sicca syndrome. One had sensorimotor axonal polyneuropathy and
orthostatic hypotension and 2 had severe autonomic neuropathy.
Postmortem examination of 1 patient, who died at age 70 years, showed
extensive B2M-containing amyloid deposits in the spleen, liver, heart,
salivary glands, and nerves. Colonic biopsy from another affected
individual also contained B2M-containing amyloid deposits. Amyloid
scinotography of 2 patients showed a heavy visceral amyloid burden in
the spleen and adrenal glands, but not in heart. Valleix et al. (2012)
noted that the amyloid deposition in this family was different from that
observed in dialysis-related amyloidosis, in which B2M-amyloid
accumulates around bones and joints. In addition, serum B2M was not
increased in the patients with familial disease, whereas it is increased
in those with dialysis-related amyloidosis.

CLINICAL MANAGEMENT

Bodin et al. (2010) demonstrated that administration of anti-human serum
amyloid P component (SAP; 104770) antibodies to mice with amyloid
deposits containing human SAP triggers a potent, complement-dependent,
macrophage-derived giant cell reaction that swiftly removes massive
visceral amyloid deposits without adverse effects. Anti-SAP antibody
treatment is clinically feasible because circulating human SAP can be
depleted in patients by the bis-D-proline compound CPHPC, thereby
enabling injected anti-SAP antibodies to reach residual SAP in the
amyloid deposits.

*FIELD* SA
Alexander and Atkins (1975); Weiss and Page (1973)
*FIELD* RF
1. Alexander, F.; Atkins, E. L.: Familial renal amyloidosis: case
reports, literature review and classification. Am. J. Med. 59: 121-128,
1975.

2. Asl, L. H.; Liepnieks, J. J.; Uemichi, T.; Rebibou, J.-M.; Justrabo,
E.; Droz, D.; Mousson, C.; Chalopin, J.-M.; Benson, M. D.; Delpech,
M.; Grateau, G.: Renal amyloidosis with a frame shift mutation in
fibrinogen A(alpha)-chain gene producing a novel amyloid protein. Blood 90:
4799-4805, 1997.

3. Benson, M. D.; Liepnieks, J.; Uemichi, T.; Wheeler, G.; Correa,
R.: Hereditary renal amyloidosis associated with a mutant fibrinogen
alpha-chain. Nature Genet. 3: 252-255, 1993.

4. Bodin, K.; Ellmerich, S.; Kahan, M. C.; Tennent, G. A.; Loesch,
A.; Gilbertson, J. A.; Hutchinson, W. L.; Mangione, P. P.; Gallimore,
J. R.; Millar, D. J.; Minogue, S.; Dhillon, A. P.; Taylor, G. W.;
Bradwell, A. R.; Petrie, A.; Gillmore, J. D.; Bellotti, V.; Botto,
M.; Hawkins, P. N.; Pepys, M. B.: Antibodies to human serum amyloid
P component eliminate visceral amyloid deposits. Nature 468: 93-97,
2010.

5. Davison, A. M.: The United Kingdom Medical Research Council's
glomerulonephritis registry. Contrib. Nephrol. 48: 24-35, 1985.

6. Granel, B.; Serratrice, J.; Disdier, P.; Weiller, P.-J.; Valleix,
S.; Grateau, G.; Droz, D.: Underdiagnosed amyloidosis: amyloidosis
of lysozyme variant. Am. J. Med. 118: 321-323, 2005.

7. Grateau, G.: Personal Communication. Paris, France 1/16/2006.

8. Lachmann, H. J.; Chir, B.; Booth, D. R.; Booth, S. E.; Bybee, A.;
Gilbertson, J. A.; Gillmore, J. D.; Pepys, M. B.; Hawkins, P. N.:
Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. New
Eng. J. Med. 346: 1786-1791, 2002.

9. Lanham, J. G.; Meltzer, M. L.; de Beer, F. C.; Hughes, G. R. V.;
Pepys, M. B.: Familial amyloidosis of Ostertag. Quart. J. Med. 51:
25-32, 1982.

10. Libbey, C. A.; Talbert, M. L.: A 43-year-old woman with hepatic
failure after renal transplantation because of amyloidosis. New Eng.
J. Med. 317: 1520-1531, 1987.

11. Maxwell, E. S.; Kimbell, I.: Familial amyloidosis with case reports. Med.
Bull. Vet. Admin. 12: 365-369, 1936.

12. McKusick, V. A.: Personal Communication. Baltimore, Md. 1974.

13. Mornaghi, R.; Rubinstein, P.; Franklin, E. C.: Studies of the
pathogenesis of a familial form of renal amyloidosis. Trans. Assoc.
Am. Phys. 94: 211-216, 1981.

14. Mornaghi, R.; Rubinstein, P.; Franklin, E. C.: Familial renal
amyloidosis: case reports and genetic studies. Am. J. Med. 73: 609-614,
1982.

15. Ostertag, B.: Demonstration einer eigenartigen familiaeren Paramyloidose. Zbl.
Path. 56: 253-254, 1932.

16. Ostertag, B.: Familiaere Amyloid-erkrankung. Z. Menschl. Vererb.
Konstitutionsl. 30: 105-115, 1950.

17. Pepys, M. B.; Hawkins, P. N.; Booth, D. R.; Vigushin, D. M.; Tennent,
G. A.; Soutar, A. K.; Totty, N.; Nguyen, O.; Blake, C. C. F.; Terry,
C. J.; Feest, T. G.; Zalin, A. M.; Hsuan, J. J.: Human lysozyme gene
mutations cause hereditary systemic amyloidosis. Nature 362: 553-557,
1993.

18. Uemichi, T.; Liepnieks, J. J.; Benson, M. D.: Fibrinogen Indianapolis:
a fibrinogen A-alpha chain associated with hereditary amyloidosis.
(Abstract) Clin. Res. 41: 133 only, 1993.

19. Uemichi, T.; Liepnieks, J. J.; Benson, M. D.: Hereditary renal
amyloidosis with a novel variant fibrinogen. J. Clin. Invest. 93:
731-736, 1994.

20. Uemichi, T.; Liepnieks, J. J.; Yamada, T.; Gertz, M. A.; Bang,
N.; Benson, M. D.: A frame shift mutation in the fibrinogen A-alpha
chain gene in a kindred with renal amyloidosis. Blood 87: 4197-4203,
1996.

21. Valleix, S.; Gillmore, J. D.; Bridoux, F.; Mangione, P. P.; Dogan,
A.; Nedelec, B.; Boimard, M.; Touchard, G.; Goujon, J.-M.; Lacombe,
C.; Lozeron, P.; Adams, D.; and 14 others: Hereditary systemic
amyloidosis due to asp76asn variant beta-2-microglobulin. New Eng.
J. Med. 366: 2276-2283, 2012.

22. Vella, F. S.; Simone, B.; Giannelli, G.; Sisto, D.; Sborgio, C.;
Antonaci, S.: Glaucoma in primary amyloidosis: a fortuitous or causative
association? (Letter) Am. J. Med. 113: 252-254, 2002.

23. Weiss, S. W.; Page, D. L.: Amyloid nephropathy of Ostertag with
special reference to renal glomerular giant cells. Am. J. Path. 72:
447-460, 1973.

24. Weiss, S. W.; Page, D. L.: Amyloid nephropathy of Ostertag: report
of a kindred. Birth Defects Orig. Art. Ser. X(4): 67-68, 1974.

25. Zalin, A. M.; Jones, S.; Fitch, N. J. S.; Ramsden, D. B.: Familial
nephropathic non-neuropathic amyloidosis: clinical features, immunohistochemistry
and chemistry. Quart. J. Med. 81: 945-956, 1991.

*FIELD* CS

GI:
Hepatomegaly;
Cholestasis;
Splenomegaly

GU:
Nephropathy with hematuria;
Nephrotic syndrome;
Uremia

Endocrine:
Hypertension

Skin:
Pitting edema;
Petechial skin rash

Neuro:
Nonneuropathic

Misc:
Chronic weakness

Lab:
Generalized amyloid deposition;
Proteinuria;
Hematuria

Inheritance:
Autosomal dominant

*FIELD* CN
Cassandra L. Kniffin - updated: 6/14/2012
Ada Hamosh - updated: 1/4/2011
Marla J. F. O'Neill - updated: 1/8/2009
Victor A. McKusick - updated: 2/1/2006
Jane Kelly - updated: 3/20/2003
Victor A. McKusick - updated: 1/12/2001

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

*FIELD* ED
alopez: 06/14/2012
ckniffin: 6/14/2012
alopez: 1/4/2011
terry: 1/4/2011
carol: 1/8/2009
carol: 2/1/2006
terry: 2/1/2006
wwang: 3/23/2005
wwang: 3/16/2005
cwells: 3/20/2003
carol: 9/11/2002
cwells: 1/18/2001
terry: 1/12/2001
carol: 4/6/1994
mimadm: 3/11/1994
carol: 5/17/1993
carol: 5/12/1993
carol: 5/6/1993
carol: 3/22/1993

MIM 107680
*RECORD*
*FIELD* NO
107680
*FIELD* TI
+107680 APOLIPOPROTEIN A-I; APOA1
;;APOLIPOPROTEIN OF HIGH DENSITY LIPOPROTEIN
APOA1 DEFICIENCY, INCLUDED;;
read moreAPOA1/APOC3 FUSION GENE, INCLUDED
*FIELD* TX

CLONING

Breslow et al. (1982) isolated and characterized cDNA clones for human
apoA-I. Apolipoprotein A-I is the major apoprotein of high density
lipoprotein (HDL) and is a relatively abundant plasma protein with a
concentration of 1.0-1.5 mg/ml. It is a single polypeptide chain with
243 amino acid residues of known primary amino acid sequence (Brewer et
al., 1978).

ApoA-I is a cofactor for LCAT (606967), which is responsible for the
formation of most cholesteryl esters in plasma. ApoA-I also promotes
efflux of cholesterol from cells. The liver and small intestine are the
sites of synthesis of apoA-I. The primary translation product of the
APOA1 gene contains both a pre and a pro segment, and posttranslational
processing of apoA-I may be involved in the formation of the functional
plasma apoA-I isoproteins. The primary gene transcript encodes a
preproapoA-I containing 24 amino acids on the amino terminus of the
mature plasma apoA-I (Law et al., 1983). Dayhoff (1976) pointed to
sequence homologies of A-I, A-II (107670), C-I (107710), and C-III
(107720).

BIOCHEMICAL FEATURES

Ajees et al. (2006) reported the crystal structure of lipid-free human
APOA1 to 2.4-angstrom resolution. They showed APOA1 was composed of an
N-terminal 4-helix bundle with a hydrophobic core and 2 C-terminal
helices. The N-terminal domain appeared to play a prominent role in
maintaining a lipid-free conformation. The C-terminal domain was
predicted to show high lipid affinity and function as a lipid-sensitive
trigger for the lipid-mediated unraveling of the N-terminal domain. The
N-terminal domain contains 4 leucines that form hydrophobic batches that
could initiate unraveling of the N-terminal domain to a lipid-bound open
configuration. APOA1 had 2 negative patches that may be a potential
ABCA1 (600046)-recognition motif and several potential positively
charged regions for binding SRB1 (SCARB1; 601040), which initiates
offloading of cholesteryl esters to the liver. Myeloperoxidase (MPO;
606989)-mediated oxidative chlorination and nitration of tyrosine in
APOA1 results in impairment of ABCA1-dependent cholesterol efflux, and
is an atherogenic risk factor. Ajees et al. (2006) found that APOA1
tyrosine-192 is the only tyrosine that was completely solvent
accessible, making it the likely target of chlorination and nitration.

GENE FUNCTION

Yui et al. (1988) found that apoA-I is identical to serum PGI(2)
stabilizing factor (PSF). They noted that PGI(2), or prostacyclin, is
synthesized by the vascular endothelium and smooth muscle, and functions
as a potent vasodilator and inhibitor of platelet aggregation. They
suggested that the stabilization of PGI(2) by HDL and apoA-I may be an
important protective action against the accumulation of platelet thrombi
at sites of vascular damage. The beneficial effects of HDL in the
prevention of coronary artery disease may be partly explained by this
effect.

Martinez et al. (2003) identified a high affinity HDL receptor for
apolipoprotein A1 as the beta chain of ATP synthase (ATP5B; 102910), a
principal protein complex of the mitochondrial inner membrane. They used
a variety of experimental approaches to confirm this ectopic
localization of components of the ATP synthase complex and the presence
of ATP hydrolase activity at the hepatocyte cell surface. Receptor
stimulation by apoA-I triggers the endocytosis of holo-HDL particles
(protein plus lipid) by a mechanism that depends strictly on the
generation of ADP. Martinez et al. (2003) confirmed this effect on
endocytosis in perfused rat liver ex vivo by using a specific inhibitor
of ATP synthase. Thus, Martinez et al. (2003) concluded that
membrane-bound ATP synthase has a previously unsuspected role in
modulating the concentrations of extracellular ADP and is regulated by a
principal plasma apolipoprotein.

Zhang et al. (2003) injected (3)H-cholesterol-labeled macrophage foam
cells intraperitoneally into mice overexpressing Apoa1 and control mice
and detected (3)H-cholesterol in plasma, lung, spleen, liver, and feces.
Mice overexpressing Apoa1 had significantly higher plasma
(3)H-cholesterol and higher (3)H-tracer in the liver and excreted 63%
more (3)H-tracer into feces over 48 hours than did control mice (p less
than 0.05). Zhang et al. (2003) concluded that APOA1 overexpression
promotes macrophage-specific reverse cholesterol transport.

MAPPING

Law et al. (1984) assigned the APOA1 gene to 11p11-q13 by filter
hybridization analysis of human-mouse cell hybrid DNAs. The genes for
apoA-I and apoC-III are on chromosome 9 in the mouse. Mouse homologs of
other genes on human 11p (insulin, beta-globin, LDHA, HRAS) are situated
on mouse chromosome 7. Using a cDNA probe to detect apoA-I structural
gene sequences in human-Chinese hamster cell hybrids, Cheung et al.
(1984) assigned the gene to the region 11q13-qter. Since other
information had suggested 11p11-q13 as the location, the SRO becomes
11q13. It is noteworthy that in the mouse and in man, APOA1 and PGBD
(called Ups in the mouse) are syntenic. Both are on chromosome 11 in man
and chromosome 9 in the mouse. Bruns et al. (1984) localized the genes
for apoA-I and apoC-III (previously shown to be in a 3-kb segment of the
genome; Breslow et al., 1982; Shoulders et al., 1983) to chromosome 11
by Southern blot analysis of DNA from human-rodent cell hybrids. Because
in the mouse apoA-I is on chromosome 9 and apoA-II is on chromosome 1
(Lusis et al., 1983), the gene for human apoA-II is probably not on
chromosome 11. Indeed, APOA2 (107670) is on human chromosome 1. On the
basis of data provided by Pearson (1987), the APOA1 locus was assigned
to 11q23-qter by HGM9. This would place APOC3 and APOA4 in the same
region. Because the XmnI genotype at the APOA1 locus was heterozygous in
a boy with partial deletion of the long arm of chromosome 11,
del(11)(q23.3-qter), Arinami et al. (1990) localized the gene to 11q23
by excluding the region 11q24-qter.

Haddad et al. (1986) found that in the rat, as in man, the APOA1, APOC3
and APOA4 genes are closely linked. Indeed, their direction of
transcription, size, relative location and intron-exon organization were
found to be remarkably similar to those of the corresponding human
genes.

The APOA1 and APOC3 genes are oriented 'foot-to-foot,' i.e., the 3-prime
end of APOA1 is followed after an interval of about 2.5 kb by the
3-prime end of APOC3 (Karathanasis et al., 1983).

MOLECULAR GENETICS

Utermann et al. (1982) described methods for rapid screening and
characterization of variant group A apolipoproteins.

Rees et al. (1983) studied the cloned APOA1 gene and a DNA polymorphism
3-prime to it. In a healthy control population, the frequency of
heterozygotes was about 5%. Among hypertriglyceridemic subjects, 34%
were heterozygotes and about 6% were homozygotes for the variant.

In 4 generations of a Norwegian kindred, Schamaun et al. (1983) found,
by 2-D electrophoresis, a variant of apolipoprotein A-I. Codominant
inheritance was displayed. One homozygote was identified. There was no
obvious cardiovascular disease, even in the homozygote.

Karathanasis et al. (1983) found that a group of severely
hypertriglyceridemic patients with types IV and V hyperlipoproteinemia
had an increased frequency of a RFLP associated with the apoA-I gene.
Rees et al. (1985) found a strong correlation between
hypertriglyceridemia and a DNA sequence polymorphism located in or near
the 3-prime noncoding region of APOC3 and revealed by digestion of human
DNA with the restriction enzyme Sst-1 and hybridization with an APOA1
cDNA probe. In 74 hypertriglyceridemic Caucasians, 3 were homozygous and
23 were heterozygous for the polymorphism, giving a gene frequency of
0.19; none of 52 normotriglyceridemics had the polymorphism, although it
was frequent in Africans, Chinese, Japanese, and Asian Indians. No
differences in high density lipoprotein or in apolipoproteins A-I and
C-III phenotypes were found in persons with or without the polymorphism.

Ferns et al. (1985) found an uncommon allelic variant (called S2) of the
apoA-I/C-III gene cluster in 10 of 48 postmyocardial infarction patients
(21%). In 47 control subjects it was present in only 2 and in none of
those who were normotriglyceridemic. (The S2 allele, a DNA polymorphism,
is characterized by SstI restriction fragments of 5.7 and 3.2 kb,
whereas the common S1 allele produces fragments of 5.7 and 4.2 kb.)
Ferns et al. (1985) found no difference in the distribution of alleles
in the highly polymorphic region of 11p near the insulin gene.

Kessling et al. (1985) failed to find an association between any allele
of several RFLPs studied and hypertriglyceridemia.

Buraczynska et al. (1985) found association between an EcoRI
polymorphism of the APOA1 gene and noninsulin-dependent diabetes
mellitus.

Familial hypoalphalipoproteinemia, by far the most common of the forms
of primary depression of HDL cholesterol, has been thought to be an
autosomal dominant. It is associated with premature coronary artery
disease and stroke (Vergani and Bettale, 1981; Third et al., 1984;
Daniels et al., 1982). Using a PstI polymorphism at the 3-prime end of
the APOA1 gene, Ordovas et al. (1986) found the rarer allele ('3.3-kb
band') in 4.1% of 123 randomly selected control subjects and 3.3% of 30
subjects with no angiographic evidence of coronary artery disease. In
contrast, among 88 patients who had severe coronary artery disease
before age 60, as documented by angiography, the frequency was 32%. It
was also found in 8 of 12 index cases of kindreds with familial
hypoalphalipoproteinemia. Among all patients with coronary artery
disease, 58% had HDL cholesterol levels below the 10th percentile;
however, this frequency increased to 73% when patients with the 3.3-kb
band were considered.

Borecki et al. (1986) studied 16 kindreds ascertained through probands
clinically determined to have primary hypoalphalipoproteinemia
characterized by low HDL cholesterol but otherwise normal blood lipids.
They concluded that 'these families provided clear evidence for a major
gene.'

Moll et al. (1986) measured apoA-I levels in families ascertained
through cases of hypertension or early coronary artery disease. They
concluded that the findings supported 'a major effect of a single
genetic locus on the quantitative variation of plasma apoA-I in a sample
of pedigrees enriched for individuals at risk for coronary artery
disease.'

Using a radioimmunoassay, Moll et al. (1989) measured plasma apoA-I
levels in 1,880 individuals from 283 pedigrees. Complex segregation
analysis suggested heterogeneous etiologies for the individual
differences in adjusted apoA-I levels observed. The authors concluded
that environmental factors and polygenic loci account for 32% and 65%,
respectively, of the adjusted variation in a subset of 126 families. In
the other 157 pedigrees, segregation analysis strongly supported the
presence of a single locus accounting for 27% of the adjusted variation.

In Japanese, Rees et al. (1986) found association of triglyceridemia
with a different haplotype of the A-I/C-III region than that found in
Caucasians.

Ferns et al. (1986) found a common allele of the APOA2 locus which
showed a weak association with hypertriglyceridemia; in contrast, an
uncommon allele of the APOA1-APOC3-APOA4 gene cluster demonstrated a
stronger relationship with hypertriglyceridemia. Ferns et al. (1986)
found higher levels of serum triglycerides with possession of both
disease-related alleles than with either singly.

Fager et al. (1981) found an inverse relationship between serum apoA-II
and a risk of myocardial infarction.

In certain patients with premature atherosclerosis, Karathanasis et al.
(1987) demonstrated a DNA inversion containing portions of the 3-prime
ends of the APOA1 and APOC3 genes, including the DNA region between
these genes. The breakpoints of this DNA inversion were found to be
located between the fourth exon of the APOA1 gene and the first intron
of the APOC3 gene; thus, the inversion results in reciprocal fusion of
the 2 gene transcriptional units. The absence of transcripts with
correct mRNA sequences causes deficiency of both apolipoproteins in the
plasma of these patients, leading to atherosclerosis.

Bojanovski et al. (1987) found that both proapolipoprotein A-I and the
mature protein are metabolized abnormally rapidly in Tangier disease.

Thompson et al. (1988) investigated the seeming paradox that 2 RFLPs at
the A-I/C-III cluster were in strong linkage disequilibrium while a
third variant, located between the 2 other markers, appeared to be in
linkage equilibrium with these 2 'outside' markers. Thompson et al.
(1988) showed that, for the gene frequencies encountered, very large
sample sizes would be required to demonstrate negative (i.e.,
repulsion-phase) linkage disequilibrium. Such numbers are usually
difficult to attain in human studies. Therefore, failure to demonstrate
linkage disequilibrium by conventional methods does not necessarily
imply its absence.

Kessling et al. (1988) studied the high density lipoprotein-cholesterol
concentrations along with restriction fragment length polymorphisms in
the APOA2 and APOA1-APOC3-APOA4 gene cluster in 109 men selected from a
random sample of 1,910 men aged 45 to 59 years. They found no
significant difference in allelic frequencies at either locus between
the groups of individuals with high and low HDL cholesterol levels. They
did find an association between a PstI RFLP associated with apoA-I and
genetic variation determining the plasma concentration of apoA-I. No
significant association was found between alleles for the apoA-II MspI
RFLP and apoA-II or HDL concentrations.

Antonarakis et al. (1988) studied DNA polymorphism of a 61-kb segment of
11q that contains the APOA1, APOC3, and APOA4 genes within a 15-kb
stretch. Eleven RFLPs located within the 61-kb segment were used by
haplotype analysis. Considerable linkage disequilibrium was found.
Several haplotypes had arisen by recombination and the rate of
recombination within the gene cluster was estimated to be at least 4
times greater than that expected based on uniform recombination. Taken
individually, the polymorphism information content (PIC) of each of the
11 polymorphisms ranged from 0.053 to 0.375, while that of their
haplotypes ranged between 0.858 and 0.862. (The PIC value, which was
introduced by Botstein et al. (1980) in their classic paper on the use
of RFLPs as linkage markers, represents the sum of the frequency of each
possible mating multiplied by the probability that an offspring will be
informative.)

By genetic linkage analysis using RFLPs in the APOA1/C3/C4 gene cluster,
Kastelein et al. (1990) showed that the mutation causing familial
hypoalphalipoproteinemia (familial HDL deficiency) in a family of
Spanish descent was not located in this cluster.

Smith et al. (1992) investigated the common G/A polymorphism in the
APOA1 gene promoter at a position 76 bp upstream of the transcriptional
start site (-76). Of 54 subjects whose apoA-I production rates had been
determined by turnover studies, 35 were homozygous for a guanosine at
this locus and 19 were heterozygous for a guanosine and adenosine (G/A).
The apoA-I production rates were significantly lower (by 11%) in the G/A
heterozygotes than in the G homozygotes (P = 0.025). However, no effect
on HDL cholesterol or apoA-I levels were noted. Differential gene
expression of the 2 alleles was tested by linking each of the alleles to
the reporter gene chloramphenicol acetyltransferase and determining
relative promoter efficiencies after transfection into the human HepG2
hepatoma cell line. The A allele, as well as the G allele, expressed
only 68%.

In addition to its ability to remove cholesterol from cells, HDL also
delivers cholesterol to cells through a poorly defined process in which
cholesteryl esters are selectively transferred from HDL particles into
the cell without the uptake and degradation of the lipoprotein particle.
In steroidogenic cells of rodents, the selective uptake pathway accounts
for 90% or more of the cholesterol destined for steroid production or
cholesteryl ester accumulation. To test the importance of the 3 major
HDL proteins in determining cholesteryl ester accumulation in
steroidogenic cells of the adrenal gland, ovary, and testis, Plump et
al. (1996) used mice which had been rendered deficient in apoA-I,
apoA-II, or apoE by gene targeting in embryonic stem cells. ApoE and
apoA-II deficiencies were found to have only modest effects on
cholesteryl ester accumulation. In contrast, apoA-I deficiency caused an
almost complete failure to accumulate cholesteryl ester in steroidogenic
cells. Plump et al. (1996) interpreted these results as indicating that
apoA-I is essential for the selective uptake of HDL cholesteryl esters.
They stated that the lack of apoA-I has a major impact on adrenal gland
physiology, causing diminished basal corticosteroid production, a
blunted steroidogenic response to stress, and increased expression of
compensatory pathways to provide cholesterol substrate for steroid
production.

Hayden et al. (1987) found an association between certain RFLPs and
familial combined hyperlipidemia (FCHL; 144250). In studies of 3
restriction enzyme polymorphisms in the AI-CIII-AIV gene cluster,
Dallinga-Thie et al. (1997) analyzed haplotypes and showed an
association with severe hyperlipidemia in subjects with FCHL.
Furthermore, nonparametric sib pair linkage analysis revealed
significant linkage between these markers in the gene cluster and the
FCHL phenotype. The findings confirmed that the AI-CIII-AIV gene cluster
contributes to the FCHL phenotype, but this contribution is genetically
complex. An epistatic interaction between different haplotypes of the
gene cluster was demonstrated. They concluded that 2 different
susceptibility loci exist in the gene cluster.

Naganawa et al. (1997) reported 2 haplotypes due to 5 polymorphisms in
the intestinal enhancer region of the APOA1 gene in endoscopic biopsy
samples from healthy volunteers. The mutant haplotype had a population
frequency of 0.44; frequency of wildtype was 0.53. APOA1 mRNA levels
were 49% lower in mutant haplotype homozygotes than in wildtype
homozygotes, while APOA1 synthesis was 37% lower than wildtype in
individuals homozygous for the mutant allele. Heterozygotes had 28% and
41% reductions of mRNA levels and APOA1 synthesis, respectively, as
compared to wildtype homozygotes. Expression studies in Caco-2 cells
showed a 46% decrease in transcriptional activity in cells containing
the mutant constructs, and binding of Caco-2 nuclear proteins in mutant,
but not wildtype, sequences. Naganawa et al. (1997) concluded that
intestinal APOA1 transcription and protein synthesis were reduced in the
presence of common mutations which induced nuclear protein binding.

Genschel et al. (1998) counted 4 naturally occurring mutant forms of
apoA-I that were known at that time to result in amyloidosis. The most
important feature of all variants was the very similar formation of
N-terminal fragments found in the amyloid deposits. They summarized the
specific features of all known amyloidogenic variants of APOA1 and
speculated about the metabolic pathway involved.

To determine the frequency of de novo hypoalphalipoproteinemia in the
general population due to mutation of the APOA1 gene, Yamakawa-Kobayashi
et al. (1999) analyzed sequence variations in the APOA1 gene in 67
children with a low high-density lipoprotein cholesterol level. These
children were selected from 1,254 school children through a school
survey. Four different mutations with deleterious potential, 3
frameshifts and 1 splice site mutation, were identified in 4 subjects.
The plasma apoA-I levels of the 4 children with these mutations were
reduced to approximately half of the normal levels and were below the
first percentile of the general population distribution (80 mg/dl). The
frequency of hypoalphalipoproteinemia due to a mutant APOA1 gene was
estimated at 6% in subjects with low HDL cholesterol levels and 0.3% in
the Japanese population generally.

Sadaf et al. (2002) found an association between a variant of the APOA1
promoter (the G-to-A difference at position -75) and blood pressure in a
study in the United Arab Emirates. Both systolic and diastolic blood
pressure varied in a gene-dosage-related manner in individuals of the
AA, AG, and GG genotypes, with lowest pressures associated with the GG
genotype.

*FIELD* AV
.0001
APOLIPOPROTEIN A-I (MILANO)
APOA1, ARG173CYS

Franceschini et al. (1980) found hypertriglyceridemia with marked
decrease of high density lipoprotein (HDL) levels in father, son, and
daughter of an Italian family. The affected persons showed no clinical
signs of atherosclerosis and the family had no unusual occurrence of
atherosclerotic disease. Analytical isoelectric focusing of HDL
apoproteins and 2-dimensional immunoelectrophoresis against apoA
antiserum showed quantitative and qualitative changes in apolipoprotein
A-I. In the anomalous protein, Weisgraber et al. (1980) found a cysteine
residue which is not present in the normal apoprotein. The anomalous
protein was designated A-I (Milano) and denoted A-I (cys) by them. This
was the first discovered example of variation in the amino acid sequence
of a plasma lipoprotein. Serum cholesterol was normal. Weisgraber et al.
(1983) showed that cysteine is substituted for arginine at position 173.
This change in the protein probably reflects a change of CGC to TGC,
since this is the only possibility requiring change of a single
nucleotide.

Gualandri et al. (1985) traced the origin of the gene for A-I (Milano)
to Limone sul Garda, a small community of about 1,000 persons in
Northern Italy. In a study of the entire population, 33 living carriers
were found, ranging in age from 2 to 81 years. The genealogy showed
origin of all cases from a single couple living in the 18th century.
Despite low HDL cholesterol levels and increased (though not
significantly so) mean level of triglycerides, no evidence of increased
atherosclerosis was found.

Shah et al. (2001) formulated recombinant A-I (Milano) in a complex with
a naturally occurring phospholipid. Studies in mice and rabbits with
experimental atherosclerosis demonstrated that such complexes rapidly
mobilized cholesterol and thereby reduced atherosclerotic plaque burden.
The antiatherosclerotic effects occurred in animals as rapidly as 48
hours after a single infusion. In humans, Nissen et al. (2003) found
that this complex, administered intravenously for 5 doses at weekly
intervals, produced significant regression of coronary atherosclerosis
as measured by intravascular ultrasound.

.0002
APOLIPOPROTEIN A-I (MARBURG)
APOA1, LYS107TER

Utermann et al. (1982) described a variant apolipoprotein they named
apoA-I(Marburg). Utermann et al. (1982) found a frequency of about 1 per
750 persons for apoA-I(Marburg) in West Germany (3 heterozygotes in
2,282 unrelated persons). All 3 heterozygotes had hypertriglyceridemia
and subnormal HDL cholesterol. Family data from 2 kindreds were
consistent with autosomal codominant inheritance.

Rall et al. (1984) demonstrated reduced activation of LCAT (606967) but
no reduction in HDL cholesterol or clinical consequences in association
with deletion of lysine-107.

Breslow (1988) noted that apoA-I(Marburg) described by Utermann et al.
(1982) and the lys107-to-ter mutation (apoA-I(Munster2A)) described by
Rall et al. (1984) are likely identical.

.0003
APOLIPOPROTEIN A-I (MUNSTER4)
APOA1, GLU198LYS

Strobl et al. (1988) described the third case of mutation of glutamic
acid 198 to lysine and the first instance in which a family study was
performed, with identification of 5 other persons with the variant in
heterozygous form. The mutation appeared to bear no relationship to
premature atherosclerosis. Despite the fact that the mutation occurred
in a part of the molecule thought to be involved in lipid binding, it
bound almost exclusively to HDL as does normal apoA-I.

Breslow (1988) noted that this mutation is designated apoA-I(Munster4).

.0004
APOLIPOPROTEIN A-I (NORWAY)
APOA1, GLU136LYS

An apoA-I mutant with electrophoretic mobility similar to that of
glu198-to-lys was found to have a glu136-to-lys substitution (Schamaun
et al., 1983; Rall et al., 1986).

Breslow (1988) noted that this mutation is designated apoA-I(Norway).

.0005
MOVED TO 107680.0002
.0006
APOLIPOPROTEIN A-I (GIESSEN)
APOA1, PRO143ARG

Utermann et al. (1982) described the apoA-I variant they designated
apo-A-I-Giessen. Utermann et al. (1984) observed defective activation of
LCAT by the Giessen variant of apoA-I.

.0007
APOLIPOPROTEIN A-I (MUNSTER3C)
APOA1, PRO3ARG

Using a simple and rapid method for the structural analysis of mutant
apolipoproteins, von Eckardstein et al. (1989) demonstrated 3 variants
in the mature apolipoprotein A-I polypeptide of 243 amino acids:
pro3-to-arg (P3R), pro4-to-arg (107680.0008), and pro165-to-arg
(107680.0009). All the variant carriers were heterozygous for the
mutant. In the case of the pro3-to-arg mutant, the variant proapoA-I was
present in increased concentrations as compared to the normal proapoA-I,
suggesting that the interspecies-conserved proline residue in position 3
of mature apoA-I is functionally important for the enzymatic conversion
of the proprotein to the mature protein. The pro165-to-arg variant was
associated with lower levels of apoA-I and HDL cholesterol. The variant
protein accounted for only 30% of the total apoA-I in plasma instead of
the expected 50%.

Breslow (1988) noted that the P3R mutation is designated
apoA-I(Munster3C).

.0008
APOLIPOPROTEIN A-I (MUNSTER3B)
APOA1, PRO4ARG

See 107680.0007 and von Eckardstein et al. (1989).

Breslow (1988) noted that the P4R mutation is designated
apoA-I(Munster3B).

.0009
APOLIPOPROTEIN A-I DEFICIENCY
APOA1, PRO165ARG

See 107680.0007 and von Eckardstein et al. (1989).

.0010
AMYLOID POLYNEUROPATHY-NEPHROPATHY, IOWA TYPE
AMYLOIDOSIS, VAN ALLEN TYPE;;
AMYLOIDOSIS IV, FORMERLY
APOA1, GLY26ARG

In a family of English-Scottish-Irish extraction, Van Allen et al.
(1968) studied a form of amyloidosis in which neuropathy dominated the
clinical picture early in the course and nephropathy late in the course.
The average age of onset was about 35 years and the average survival
after onset was about 12 years, with death ascribable in most cases to
renal amyloidosis. Severe peptic ulcer disease occurred in some and
hearing loss was frequent. Cataracts were present in several, but
vitreous opacities were not observed. The pedigree was typical of
autosomal dominant inheritance. In the Iowa or Van Allen type of
amyloidosis, Nichols et al. (1987, 1988) found that apolipoprotein A-I
is a major constituent of the amyloid. In this condition, the
apolipoprotein A-I protein was found to contain a substitution of
glycine by arginine at position 26. The mutation of arg for gly26
predicted a guanine-to-cytosine substitution as the nucleotide
corresponding to the first base of codon 26 (GGC-to-CGC) of the APOA1
gene. Using PCR and direct sequencing, Nichols et al. (1989, 1990)
confirmed the prediction on DNA extracted from paraffin-embedded tissues
from 3 members of the kindred who died in the 1960s with amyloid
neuropathy. Since the mutation does not alter the restriction pattern of
the APOA1 gene, they used PCR with an arg26 allele-specific primer for
detection of asymptomatic gene carriers. They demonstrated inheritance
of the APOA1 variant through 3 generations of the Iowa kindred and
confirmed its association with the development of systemic amyloidosis.

.0011
APOLIPOPROTEINS A-I AND C-III, COMBINED DEFICIENCY OF
HIGH DENSITY LIPOPROTEIN DEFICIENCY, DETROIT TYPE;;
HDL DEFICIENCY, DETROIT TYPE
APOA1, APOA1/APOC3 FUSION

Norum et al. (1980, 1982) studied 2 sisters, aged 30 and 25, with very
low HDL and heart failure from coronary artery disease. Both had arcus
cornealis, xanthelasmata and extensive infiltrative xanthoma of the neck
and antecubital fossa, resembling somewhat the changes of pseudoxanthoma
elasticum. The skin histology showed collections of lipid-laden
histiocytes. Plasma cholesterol was 177 and 135 mg/dl; HDL cholesterol
was 4 and 7 mg/dl. Only traces of apoprotein A-I were detected in whole
plasma; in addition, apoprotein C-III was not detectable. The parents
and children of the 2 women had low HDL cholesterol and apoA-I levels
consistent with heterozygosity. Low levels of HDL cholesterol
concentration have been associated with an increased frequency of
coronary artery disease even when HDL is no less than 50% of normal
(Miller and Miller, 1975). Heart failure without myocardial infarction
is unusual in coronary atherosclerosis, especially in young women,
suggesting small vessel disease. The patient of Gustafson et al. (1979),
although clinically similar, differed by having high apoC-III rather
than absent apoC-III.

Karathanasis et al. (1983) showed that the probands in the family of
Norum et al. (1982) were both homozygous for a defect in the apoA-I
locus, namely, an insertion in an intron. They could identify
heterozygotes unequivocally. The parents had the same gene defect; they
were not known to be related but both had ancestors of Scottish
extraction who lived in the Appalachian mountain region of southeastern
Kentucky. When I saw the 2 sisters in 1983, I was impressed that the
xanthomatosis of the neck and antecubital fossae simulated the changes
of PXE (177850, 264800). The obligatory heterozygotes may be at
increased risk of atherosclerosis. Norum and Alaupovic (1984) pointed
out that although the only lesion demonstrated is the insertion in the
apoA-I gene, the finding of reduced concentrations of both A-I and C-III
in heterozygotes suggests that the apoC-III deficiency in the
homozygotes is not secondary but due either to mutation also in the
apoC-III gene or to an effect of the apoA-I gene on the cis apoC-III
gene. Either hypothesis suggests linkage of the 2 loci. Norum (1983)
suggested that the gene for apolipoprotein C-II may be in the same
cluster on chromosome 11 because it, like C-III, was severely deficient
in the 2 sisters. Karathanasis et al. (1983) studied the genomic
sequences flanking the APOA1 gene and found that the APOC3 gene (see
107720) lies about 2.6 kb downstream of the 3-prime end of the APOA1
gene. They also showed that the 2 genes are 'convergently transcribed'
and that the polymorphism reported by Rees et al. (1983) to be
associated with hypertriglyceridemia may be due to a single basepair
substitution in the 3-prime-noncoding region of apoC-III mRNA. Forte et
al. (1984) cited evidence that the 6.5-kb insert in the APOA1 gene is
deleted from its normal position in the promoter region for the closely
linked APOC3 gene. Protter et al. (1984) isolated and characterized the
APOC3 gene. The coding sequence was found to be interrupted by 3
introns. The authors compared it with the APOA1 gene and sequenced the
DNA lying between the 2 genes. Karathanasis et al. (1986) studied the
restriction pattern of the APOA4 gene in the sisters with combined
apoA-I and apoC-III deficiency. Although apoA-IV had not been
demonstrated in the plasma of these patients, the relatively high levels
of plasma LCAT activity (40% of normal) and the possible involvement of
apoA-IV in LCAT activation suggested that the APOA4 gene of these
patients is functionally normal. Karathanasis et al. (1987) demonstrated
that these patients had a rearrangement in the form of an inversion
containing portions of the 3-prime ends of the APOA1 and APOC3 genes,
including the DNA between these genes. The breakpoints were located
within the fourth exon of the APOA1 gene and the first intron of the
APOC3 gene. The fusion gene was expressed as a fusion mRNA.

.0012
APOLIPOPROTEIN A-I, ABSENCE OF, DUE TO DELETION OF APOA1/APOC3/APOA4
GENE COMPLEX
APOA1, DEL

Schaefer et al. (1982) studied the plasma lipids of a middle-aged woman
who died following coronary artery bypass grafting for atherosclerotic
narrowing of multiple arteries. She had markedly reduced high density
lipoprotein, no detectable apolipoprotein A-I, normal A-II, and
moderately reduced apolipoproteins B and C. Both of her children, all 6
of her living sibs, and both parents had reduced apolipoprotein A-I and
HDL levels and normal apolipoprotein A-II. Three of the sibs and their
mother had coronary disease. The proband had corneal clouding due to
diffuse lipid deposits in the epithelial cells; none of the
heterozygotes had this finding. The condition in this family differs
from Tangier disease (205400; analphalipoproteinemia) in the complete
absence of apolipoprotein A-I and normal levels of A-II in the
homozygote. Heterozygotes in this condition have reduced A-I only,
whereas Tangier heterozygotes have reduced A-I and A-II. Consanguinity
in this family, while likely on the basis of geographic isolation, was
not proved. In the family reported by Schaefer et al. (1982), Ordovas et
al. (1989) demonstrated that all of the APOA1/APOC3/APOA4 gene complex
was deleted from a point about 3.1 kb 5-prime to the APOA1 gene to a
point 3-prime to the APOA4 gene.

.0013
APOLIPOPROTEIN A-I (BALTIMORE)
APOA1, ARG10LEU

Ladias et al. (1990) detected this variant in a man with
hypoalphalipoproteinemia who was under study for coronary artery
disease. A G-to-T substitution in codon 34 of the third exon of the
APOA1 gene resulted in an arg-to-leu amino acid substitution at the
tenth residue of mature apoA-I. (ApoA-I is synthesized in the liver and
small intestine as a 267-residue preproapolipoprotein. The presegment,
18 amino acid residues long, is cleaved at the time of translation by a
signal peptidase. The resulting proapoA-I contains a hexapeptide
prosegment covalently linked to the NH(2) terminus of mature apoA-I; it
is secreted into plasma and lymph and undergoes extracellular
posttranslational cleavage to the mature 243-residue apoA-I.) The
mutation changed a CG dinucleotide to CT and therefore was an exception
to the CG-to-TG mutation rule, in which methylation/deamination of the C
in the CpG dinucleotide results in a C-to-T substitution. Ladias et al.
(1990) were unable to demonstrate linkage between apoA-I Baltimore and
hypoalphalipoproteinemia.

.0014
CORNEAL CLOUDING DUE TO APOLIPOPROTEIN A-I DEFICIENCY
APOA1, 1-BP DEL, CODON 202

Funke et al. (1991) studied an otherwise healthy 42-year-old man for
massive corneal clouding that resembled that described in patients with
fish-eye disease. There was no history in the patient or in his family
of precocious coronary artery disease and no evidence of inbreeding; the
parents came from different parts of Germany. Funke et al. (1991)
identified a homozygous base deletion in the fourth exon of the APOA1
gene as the basic defect responsible for complete absence of HDL from
the plasma and corneal opacities. Heterozygous carriers of the base
deletion showed approximately half-normal HDL cholesterol
concentrations. A guanine residue from codon 202 was deleted, leading to
frameshift and premature termination at amino acid 229. The proband's
mother and all 3 of his children were heterozygous.

.0015
APOLIPOPROTEIN A-I DEFICIENCY
APOA1, GLN84TER

In a Japanese female patient with deficiency of APOA1 and premature
atherosclerosis, Matsunaga et al. (1991) demonstrated homozygosity for a
nonsense mutation of codon 84 in exon 4: CAG-to-TAG, gln-to-stop. The
patient was also homozygous for another mutation, ala37-to-thr
(GCC-to-ACC) in exon 3; this mutation represented a polymorphism because
it was found in other persons with normal levels of APOA1 and high
density lipoprotein cholesterol. The patient's parents were first
cousins.

.0016
AMYLOIDOSIS, SYSTEMIC NONNEUROPATHIC
APOA1, LEU60ARG

In an English family with autosomal dominant nonneuropathic systemic
amyloidosis (105200), Soutar et al. (1992) identified a CTG (leu)-to-CGG
(arg) transversion at codon 60. The affected individuals were
heterozygotes. The Iowa variant of amyloidosis is another form due to
mutation in the APOA1 gene (107680.0010). They suggested that the
systemic nonneuropathic form is the same as the Iowa form, which in turn
is the same as the Ostertag type. Indeed, the phenotype appears to be
different from that originally described by Van Allen et al. (1968); in
the Iowan family, neuropathy dominated the clinical picture early in the
course and nephropathy late in the course.

.0017
ANALPHALIPOPROTEINEMIA
APOA1, GLN-2TER

Ng et al. (1994) discovered a novel mutation causing
analphalipoproteinemia (604091) in a Canadian kindred. The 34-year-old
Caucasian proposita, the product of a consanguineous marriage, initially
presented at the age of 30 years because of xanthelasmata. In the same
year, the patient was diagnosed to have bilateral cataracts requiring
cataract extraction in the right eye. She also had bilateral subretinal
lipid deposition with exudative proliferative retinopathy complicated by
bilateral retinal detachments, which were treated surgically. She had a
longstanding history of mild imbalance, i.e., unsteadiness. Examination
showed mildly thickened Achilles tendons and mild midline cerebellar
ataxia. One sister had had a mild myocardial infarction at age 34.
Another sister with angina had cerebellar ataxia. High density
lipoprotein cholesterol was very low and apo-I was undetectable. Genomic
DNA sequencing of the APOA1 gene identified homozygosity for a nonsense
mutation at codon -2, which Ng et al. (1994) designated as Q(-2)X. The
mutation was a C-to-T transition in exon 3, which transformed a codon at
position -2 relative to the first amino acid of circulating mature
apoA-I. The normal sequence at this position encodes glutamine, but the
mutated codon encoded premature termination.

.0018
HYPOALPHALIPOPROTEINEMIA, PRIMARY
APOA1, 1-BP INS

In a Japanese family with primary hypoalphalipoproteinemia (604091) and
an anomalous apolipoprotein A-I, designated APOA1-Tsukuba, Nakata et al.
(1993) found insertion of a single C in the run of 7 cytosines in codons
325 of the mature sequence. This resulted in a frameshift, with change
of codon 5 from gln to pro and the creation of a stop at codon 34. The
proband and her mother and aunt showed low high-density lipoprotein
cholesterol and low apoA-I levels.

.0019
XANTHELASMAS, PERIORBITAL
APOA1, GLN32TER

Romling et al. (1994) found homozygosity for a gln32-to-ter (Q32X)
mutation in the APOA1 gene in a 31-year-old woman who presented with no
signs of coronary artery or other atherosclerosis. She came from a large
Sicilian family with no apparent increased prevalence of myocardial
infarction. Among 8 sibs of the proband's heterozygous parents, 7
persons, aged 57 to 73, were alive and had no symptoms of
atherosclerotic disease. The parents were first cousins. During her
first pregnancy at age 22, the homozygous proband developed bilateral
periorbital xanthelasmas, which did not progress after delivery. She had
smoked 10 to 12 cigarettes per day since the age of 18 years.
Heterozygotes showed half-normal plasma concentrations of HDL
cholesterol and apoA-I.

.0020
AMYLOIDOSIS, HEPATIC AND SYSTEMIC
APOA1, 12-BP DEL AND 2-BP INS

Booth et al. (1996) described a Spanish family with autosomal dominant
nonneuropathic hereditary amyloidosis (105200) with a unique hepatic
presentation and death from liver failure, usually by the sixth decade.
The disorder was caused by a previously unreported deletion/insertion
mutation in exon 4 of the APOA1 gene encoding loss of residues 60-71 of
the normal mature APOA1 and insertion at that position of 2 new
residues, valine and threonine. Affected individuals were heterozygous
for the mutation and had both normal APOA1 and variant molecules bearing
1 extra positive charge, as predicted from the DNA sequence. The amyloid
fibrils were composed exclusively of N-terminal fragments of the
variant, ending mainly at positions corresponding to residues 83 and 92
in the mature wildtype sequence. Amyloid fibrils derived from the other
3 known amyloidogenic APOA1 variants (107680.0010, 107680.0016, and
107680.0021) are composed of similar N-terminal fragments. All known
amyloidogenic APOA1 variants carry 1 extra positive charge in this
region, suggesting that it may be responsible for their enhanced
amyloidogenicity. In addition to causing a new phenotype, this was the
first deletion mutation to be described in association with hereditary
amyloidosis.

.0021
AMYLOIDOSIS, SYSTEMIC NONNEUROPATHIC
APOA1, TRP50ARG

Booth et al. (1996) described a trp50-to-arg variant of APOA1 causing
hereditary amyloidosis (105200).

.0022
APOLIPOPROTEIN A-I DEFICIENCY
APOA1, VAL156GLU

In a 67-year-old Japanese male with corneal opacities, coronary artery
disease, and less than 10% of normal APOA1 and HDL cholesterol levels,
Huang et al. (1998) found a homozygous mutation in the APOA1 gene. A
T-to-A substitution at nucleotide 1762 in exon 4 resulted in a
val-to-glu substitution at codon 156. Lecithin:cholesterol
acyltransferase activity and cholesterol esterification were less than
40% of normal control values. The proband's elder brother, also
homozygous for the mutation, had reduced APOA1 and HDL levels but no
clinical evidence of coronary artery disease. The heterozygous son of
the proband showed nearly 60% of normal APOA1 and normal HDL cholesterol
levels. The position of this and other mutations led the authors to
conclude that residues 143-164 are important in APOA1 function,
particularly LCAT activation.

This mutation has been designated apolipoprotein A-I (Oita).

.0023
HYPOALPHALIPOPROTEINEMIA, PRIMARY
APOA1, IVS2, G-C, +1

One of 4 mutations in the APOA1 gene found by Yamakawa-Kobayashi et al.
(1999) as the cause of primary hypoalphalipoproteinemia (604091) was a
donor splice site mutation in intron 2, changing the canonical +1 from G
to C.

.0024
AMYLOIDOSIS, CARDIAC AND CUTANEOUS
APOA1, LEU90PRO

Hamidi Asl et al. (1999) found that autosomal dominant hereditary
amyloidosis with a unique cutaneous and cardiac presentation and death
from heart failure by the sixth or seventh decade was associated with a
1389T-C transition in exon 4 of the APOA1 gene. The predicted
substitution of leu90-to-pro (L90P) substitution was confirmed by
structural analysis of amyloid protein isolated from cardiac deposits of
amyloid. The subunit protein was composed exclusively of NH2-terminal
fragments of the variant APOA1 with the longest ending at residue 94 in
the wildtype sequence. Amyloid fibrils derived from 4 previously
described APOA1 variants were composed of similar fragments with
carboxy-terminal heterogeneity, but contrary to those variants, which
all carry one extra positive charge, the leu90-to-pro substitution did
not result in any charge modification. The authors considered it
unlikely, therefore, that amyloid fibril formation is related to change
of charge for a specific residue of the precursor protein. This is in
agreement with studies on transthyretin amyloidosis in which no unifying
factor, such as change of charge for amino acid residues, has been
noted.

The family with the L90P mutation reported by Hamidi Asl et al. (1999)
was brought to attention by the case of a 54-year-old woman who
presented with recent onset of exertional dyspnea and cutaneous lesions
for many years. The skin lesions, which were yellow and maculopapular,
first appeared on the forehead and extended rapidly to the face, neck,
shoulders, and axillary and antecubital areas. The patient had
cardiomegaly, right bundle branch block, concentric thickening of the
wall of the left ventricle with a small left ventricular cavity, a
typical restrictive hemodynamic pattern on cardiac catheterization, and
amyloid deposits on endomyocardial biopsy. A 57-year-old second cousin
presented with a 3-year history of extensive cutaneous maculopapular
amyloidosis. Petechial purpura was observed on the skin, ocular
conjunctiva, tonsil pillars, buccal mucosa, and lips.

.0025
AMYLOIDOSIS, CARDIAC AND CUTANEOUS
APOA1, ARG173PRO

Hamidi Asl et al. (1999) described an American kindred in which
hereditary amyloidosis showed expression mainly in the skin and heart.
The proband was a 33-year-old Caucasian woman who was referred to a
dermatologist to evaluate diffuse rash with the appearance of acanthosis
nigricans in the axillae. A skin biopsy stained with Congo red revealed
the presence of amyloid deposits. The proband's father had a history of
cerebral aneurysms at the age of 37 and subsequently was diagnosed as
having systemic amyloidosis with multiorgan involvement. He died at the
age of 63 with cardiomyopathy and liver and renal failure. The proband
had 3 sisters. One, 40 years old, developed brown skin rash in the
axillary regions at age 20. The rash progressed to involve the skin of
the neck and was associated with petechial hemorrhages and thickening of
the skin on the hands. Another sister, age 37, had also been shown to
have dermal amyloidosis by a positive skin biopsy. A 42-year-old sister,
who had not been medically evaluated, had a raspy voice, a symptom
shared by other affected individuals in this family. A sister of the
proband's father was a 71-year-old woman with a several-year history of
voice changes due to amyloid deposition in the vocal cords proven by
biopsy. She also had cutaneous amyloid and had been shown by
echocardiography to have hypertrophic cardiomyopathy. The proband's
paternal grandmother had the diagnosis of cardiac and vocal cord
amyloidosis, and a nephew of the grandmother died of cardiomyopathy at
age 52. Subsequently, a daughter of this nephew had the diagnosis of
amyloid cardiomyopathy made by endomyocardial biopsy. Characterization
of fibrils isolated from skin of the proband identified the amyloid
protein as the N-terminal 90 to 100 residues of apolipoprotein A-1.
Sequence of the APOA1 gene was normal except for a G-to-C transversion
at position 1638, which predicted an arg173-to-pro substitution. This
mutation, unlike previously described amyloidogenic mutations, was not
in the N-terminal fragment which is incorporated into the fibril. The
mutation was at the same residue as in APOA1-Milano (107680.0001), which
has an arg173-to-cys substitution but does not result in amyloid
formation. Decreased plasma HDL cholesterol levels in carriers of the
arg173-to-pro mutation suggested an increased rate of catabolism, as has
been shown for the amyloidogenic gly26-to-arg mutation (107680.0010).
This suggests that altered metabolism caused by the mutation may be a
significant factor in apolipoprotein A-1 fibrillogenesis.

.0026
AMYLOIDOSIS, SYSTEMIC NONNEUROPATHIC
APOA1, LEU174SER

In a patient with systemic nonneuropathic amyloidosis (105200), Obici et
al. (1999) identified a T-to-C transition at nucleotide 2069 of the
APOA1 gene, resulting in a leu174-to-ser substitution. The proband was
affected by amyloid deposits mainly in the heart, requiring
transplantation for end-stage congestive heart failure. The amyloid
fibrils immunoreacted exclusively with anti-APOA1 antibodies. Obici et
al. (1999) identified the same mutation in an affected uncle. The plasma
levels of high-density lipoprotein and of apoA-I were significantly
lower in the patient than in unaffected individuals. The authors stated
that this represents the first case of familial apoA-I amyloidosis in
which the mutation occurred outside the polypeptide fragment deposited
as fibrils. In the 3-dimensional structure of lipid-free apoA-I,
composed of 4 identical polypeptide chains, position 174 of one chain
was located near position 93 of an adjacent chain, suggesting that the
amino acid replacement at position 174 was permissive for a proteolytic
split at the C-terminal of val93.

.0027
AMYLOIDOSIS, SYSTEMIC NONNEUROPATHIC
APOA1, ALA175PRO

In the course of studying patients thought to have systemic amyloidosis
of the acquired monoclonal immunoglobulin light-chain (AL) type (see
254500) because of the absence of family history, Lachmann et al. (2002)
found a new mutation in the APOA1 gene causing renal amyloidosis
(105200), ala175 to pro (A175P). The age at presentation with renal
failure was 35 years in this English patient. In addition to renal
failure, he had hoarseness due to laryngeal amyloid deposits, a feature
that commonly occurs in localized AL amyloidosis and that had also been
reported in patients with mutations disrupting this particular region of
the apolipoprotein A-1 molecule (e.g., Hamidi Asl et al., 1999).
Seemingly, sterility was also a problem.

*FIELD* SA
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al. (1984); Law et al. (1983); O'Donnell and Lusis (1983); Schroeder
and Saunders (1987); Stocks et al. (1987)
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(Letter) Clin. Genet. 61: 314-316, 2002.

83. Schaefer, E. J.; Heaton, W. H.; Wetzel, M. G.; Brewer, H. B.,
Jr.: Plasma apolipoprotein A-I, absence associated with a marked
reduction of high density lipoproteins and premature coronary artery
disease. Arteriosclerosis 2: 16-26, 1982.

84. Schamaun, O.; Olaisen, B.; Gedde-Dahl, T., Jr.; Teisberg, P.:
Genetic studies of an apoA-I lipoprotein variant. Hum. Genet. 64:
380-383, 1983.

85. Schroeder, W. T.; Saunders, G. F.: Localization of the human
catalase and apolipoprotein A-I genes to chromosome 11. Cytogenet.
Cell Genet. 44: 231-233, 1987.

86. Shah, P. K.; Yano, J.; Reyes, O.; Chyu, K.-Y.; Kaul, S.; Bisgaier,
C. L.; Drake, S.; Cercek, B.: High-dose recombinant apolipoprotein
A-I(Milano) mobilizes tissue cholesterol and rapidly reduces plaque
lipid and macrophage content in apolipoprotein E-deficient mice: potential
implications for acute plaque stabilization. Circulation 103: 3047-3050,
2001.

87. Shoulders, C. C.; Kornblihtt, A. R.; Munro, B. S.; Baralle, F.
E.: Gene structure of human apolipoprotein A-I. Nucleic Acids Res. 11:
2827-2837, 1983.

88. Smith, J. D.; Brinton, E. A.; Breslow, J. L.: Polymorphism in
the human apolipoprotein A-I gene promoter region: association of
the minor allele with decreased production rate in vivo and promoter
activity in vitro. J. Clin. Invest. 89: 1796-1800, 1992.

89. Soutar, A. K.; Hawkins, P. N.; Vigushin, D. M.; Tennent, G. A.;
Booth, S. E.; Hutton, T.; Nguyen, O.; Totty, N. F.; Feest, T. G.;
Hsuan, J. J.; Pepys, M. B.: Apolipoprotein AI mutation arg-60 causes
autosomal dominant amyloidosis. Proc. Nat. Acad. Sci. 89: 7389-7393,
1992.

90. Stocks, J.; Paul, H.; Galton, D.: Haplotypes identified by DNA
restriction-fragment-length polymorphisms in the A-I C-III A-IV gene
region and hypertriglyceridemia. Am. J. Hum. Genet. 41: 106-118,
1987.

91. Strobl, W.; Jabs, H.-U.; Hayde, M.; Holzinger, T.; Assmann, G.;
Widhalm, K.: Apolipoprotein A-I (glu198-to-lys): a mutant of the
major apolipoprotein of high-density lipoproteins occurring in a family
with dyslipoproteinemia. Pediat. Res. 24: 222-228, 1988.

92. Third, J. L. H. C.; Montag, J.; Flynn, M.; Freidel, J.; Laskarzewski,
P.; Glueck, C. J.: Primary and familial hypoalphalipoproteinemia. Metabolism 33:
136-146, 1984.

93. Thompson, E. A.; Deeb, S.; Walker, D.; Motulsky, A. G.: The detection
of linkage disequilibrium between closely linked markers: RFLPs at
the AI-CIII apolipoprotein genes. Am. J. Hum. Genet. 42: 113-124,
1988.

94. Utermann, G.; Feussner, G.; Franceschini, G.; Haas, J.; Steinmetz,
A.: Genetic variants of group A apolipoproteins: rapid methods for
screening and characterization without ultracentrifugation. J. Biol.
Chem. 257: 501-507, 1982.

95. Utermann, G.; Haas, J.; Steinmetz, A.; Paetzold, R.; Rall, S.
C., Jr.; Weisgraber, K. H.; Mahley, R. W.: Apolipoprotein A-I(Giessen)
(pro143-to-arg): a mutant that is defective in activating lecithin:cholesterol
acyltransferase. Europ. J. Biochem. 144: 325-331, 1984.

96. Utermann, G.; Steinmetz, A.; Paetzold, R.; Wilk, J.; Feussner,
G.; Kaffarnik, H.; Mueller-Eckhardt, C.; Seidel, D.; Vogelberg, K.-H.;
Zimmer, F.: Apolipoprotein AI(Marburg): studies of two kindreds with
a mutant of human apolipoprotein AI. Hum. Genet. 61: 329-337, 1982.

97. Van Allen, M. W.; Frohlich, J. A.; Davis, J. R.: Inherited predisposition
to generalized amyloidosis: clinical and pathological studies of a
family with neuropathy, nephropathy and peptic ulcer. Neurology 19:
10-25, 1968.

98. Vergani, C.; Bettale, G.: Familial hypo-alpha-lipoproteinemia. Clin.
Chim. Acta 114: 45-52, 1981.

99. von Eckardstein, A.; Funke, H.; Henke, A.; Altland, K.; Benninghoven,
A.; Assmann, G.; Welp, S.; Roetrige, A.; Kock, R.: Apolipoprotein
A-I variants: naturally occurring substitutions of proline residues
affect plasma concentration of apolipoprotein A-I. J. Clin. Invest. 84:
1722-1730, 1989.

100. Weisgraber, K. H.; Bersot, T. P.; Mahley, R. W.; Franceschini,
G.; Sirtori, C. R.: A-I (Milano) apoprotein: isolation and characterization
of a cysteine-containing variant of the A-I apoprotein from human
high density lipoproteins. J. Clin. Invest. 66: 901-907, 1980.

101. Weisgraber, K. H.; Rall, S. C., Jr.; Bersot, T. P.; Mahley, R.
W.; Franceschini, G.; Sirtori, C. R.: Apolipoprotein A-I (Milano):
detection of normal A-I in affected subjects and evidence for a cysteine
for arginine substitution in the variant A-I. J. Biol. Chem. 258:
2508-2513, 1983.

102. Yamakawa-Kobayashi, K.; Yanagi, H.; Fukayama, H.; Hirano, C.;
Shimakura, Y.; Yamamoto, N.; Arinami, T.; Tsuchiya, S.; Hamaguchi,
H.: Frequent occurrence of hypoalphalipoproteinemia due to mutant
apolipoprotein A-I gene in the population: a population-based survey. Hum.
Molec. Genet. 8: 331-336, 1999.

103. Yui, Y.; Aoyama, T.; Morishita, H.; Takahashi, M.; Takatsu, Y.;
Kawai, C.: Serum prostacyclin stabilizing factor is identical to
apolipoprotein A-I (Apo A-I): a novel function of Apo A-I. J. Clin.
Invest. 82: 803-807, 1988.

104. Zhang, Y.; Zanotti, I.; Reilly, M. P.; Glick, J. M.; Rothblat,
G. H.; Rader, D. J.: Overexpression of apolipoprotein A-I promotes
reverse transport of cholesterol from macrophages to feces in vivo. Circulation 108:
661-663, 2003.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Corneal clouding (Detroit type 107680.0011, APOA1 deficiency 107680.0014)

CARDIOVASCULAR:
[Heart];
Coronary artherosclerosis (Detroit type 107680.0011);
Congestive heart failure (Detroit type 107680.0011)

ABDOMEN:
[Liver];
Hepatic amyloidosis (systemic nonneuronopathic 107680.0016);
[Spleen];
Splenic amyloidosis (systemic nonneuronopathic 107680.0016);
[Gastrointestinal];
Peptic ulcer (Iowa type 107680.0010)

GENITOURINARY:
[Kidneys];
Renal amyloidosis (Iowa type 107680.0010, systemic nonneuronopathic
107680.0016);
Renal failure (most common cause of death) (Iowa type 107680.0010)

SKIN, NAILS, HAIR:
[Skin];
Planar xanthomas (Detroit type 107680.0011)

NEUROLOGIC:
[Peripheral nervous system];
Sensorimotor polyneuropathy affecting legs more than arms (Iowa type
107680.0010)

LABORATORY ABNORMALITIES:
Amyloidosis, (Iowa type 107680.0010, nonneuropathic 107680.0016);
Low to absent high density lipoprotein (HDL) (Detroit 107680.0011);
Low to absent APO A-I (Detroit 107680.0011)

MOLECULAR BASIS:
Caused by mutation in the apolipoprotein A-I gene (APOA1, 107680.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 3/10/2000

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

*FIELD* ED
joanna: 07/23/2013
joanna: 5/17/2011
joanna: 10/27/2000
kayiaros: 3/13/2000
kayiaros: 3/10/2000

*FIELD* CN
Patricia A. Hartz - updated: 3/24/2006
Marla J. F. O'Neill - updated: 10/22/2004
Victor A. McKusick - updated: 1/23/2004
Ada Hamosh - updated: 2/3/2003
Victor A. McKusick - updated: 8/12/2002
Victor A. McKusick - updated: 6/10/2002
Victor A. McKusick - updated: 1/6/2000
Victor A. McKusick - updated: 8/2/1999
Victor A. McKusick - updated: 7/2/1999
Victor A. McKusick - updated: 3/22/1999
Victor A. McKusick - updated: 3/9/1999
Victor A. McKusick - updated: 11/3/1998
Ada Hamosh - updated: 6/16/1998
Michael J. Wright - updated: 9/25/1997
Victor A. McKusick - updated: 5/9/1997
Mark H. Paalman - updated: 10/1/1996

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

*FIELD* ED
joanna: 08/03/2012
carol: 3/7/2012
carol: 11/9/2011
carol: 5/23/2011
terry: 6/3/2009
carol: 1/16/2009
carol: 1/12/2009
terry: 1/8/2009
terry: 1/7/2009
carol: 11/25/2008
wwang: 4/24/2006
wwang: 3/29/2006
terry: 3/24/2006
carol: 10/22/2004
terry: 6/18/2004
tkritzer: 1/29/2004
terry: 1/23/2004
alopez: 2/4/2003
terry: 2/3/2003
tkritzer: 8/15/2002
tkritzer: 8/14/2002
terry: 8/12/2002
cwells: 7/2/2002
terry: 6/10/2002
ckniffin: 5/29/2002
alopez: 10/9/2001
carol: 11/20/2000
carol: 4/21/2000
terry: 1/31/2000
mgross: 1/12/2000
terry: 1/6/2000
carol: 10/5/1999
alopez: 8/11/1999
alopez: 8/3/1999
carol: 8/2/1999
jlewis: 7/15/1999
terry: 7/2/1999
carol: 3/25/1999
terry: 3/22/1999
terry: 3/9/1999
carol: 11/9/1998
terry: 11/3/1998
alopez: 9/17/1998
alopez: 6/16/1998
terry: 11/11/1997
alopez: 11/11/1997
alopez: 11/10/1997
mark: 9/1/1997
mark: 5/28/1997
alopez: 5/9/1997
mark: 5/9/1997
alopez: 5/7/1997
joanna: 2/13/1997
mark: 10/1/1996
mark: 9/5/1996
terry: 8/27/1996
marlene: 8/15/1996
terry: 7/16/1996
terry: 7/15/1996
mark: 1/27/1996
terry: 1/19/1996
carol: 2/13/1995
terry: 11/18/1994
jason: 7/5/1994
warfield: 4/7/1994
pfoster: 3/31/1994
mimadm: 2/21/1994

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 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

RBCC Red Blood Cell Collection

Full text data of APOA1