Tangier disease caused by compound heterozygosity for ABCA1 mutations R282X and Y1532C



      Inherited low levels of high density lipoprotein (HDL) cholesterol may be due to mutations in the genes encoding the ATP-binding cassette transporter A1 (ABCA1), apolipoprotein (apo) A-I or lecithin:cholesterol acyltransferase (LCAT).


      The ABCA1, apoA-I and LCAT genes of a 40-year-old male subject with serum HDL cholesterol of 0.06 mmol/l were subjected to DNA sequencing. The proband's family was examined for co-segregation between mutations and levels of HDL cholesterol. Cholesterol efflux in fibroblasts from the proband and a normocholesterolemic subject was compared. The effects of an ABCA1 mutation on cholesterol efflux and membrane localization of ABCA1 were studied in transfected HEK293 and HeLa cells, respectively.


      The proband was a compound heterozygote for ABCA1 mutations R282X (c.844 C>T) and Y1532C (c.4595 A>G). Relatives who were heterozygous for one of these mutations, had about half-normal HDL cholesterol levels. Cholesterol efflux was reduced in fibroblasts from the proband, as was cholesterol efflux from HEK293 cells transfected with an human (h) ABCA1 expression plasmid harboring the Y1532C mutation. Confocal microscopy of HeLa cells transfected with the Y1532C–hABCA1 plasmid revealed that the Y1532C mutation inhibits ABCA1 from reaching the cellular membrane.


      Compound heterozygosity for the nonsense mutation R282X and the missense mutation Y1532C in the ABCA1 gene causes Tangier disease. R282X has a detrimental effect on the function of ABCA1 since a premature stop codon is introduced. Mutation Y1532C disrupts the normal function of ABCA1 as determined by in vitro analyses.


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        • Tall A.R.
        • Breslow J.L.
        • Rubin E.M.
        • Brewer Jr., H.B.
        Genetic disorders affecting plasma high-density lipoproteins.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The metabolic basis of inherited disease. McGraw-Hill, New York2001: 2915-2936
        • Santamarina-Fojo S.
        • Hoeg J.M.
        • Assmann G.
        • Brewer Jr., H.B.
        Lecitin cholesterol acyltransferase deficiency and fish eye disease.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The metabolic basis of inherited disease. McGraw-Hill, New York2001: 2817-2833
        • Assmann G.
        • von Eckardstein A.
        • Brewer Jr., H.B.
        Familial analphalipoproteinemia: Tangier disease.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The metabolic basis of inherited disease. McGraw-Hill, New York2001: 2937-2960
        • Tall A.R.
        Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins.
        J Intern Med. 2008; 263: 256-273
        • Rader D.J.
        Molecular regulation of HDL metabolism and function: implications for novel therapies.
        J Clin Invest. 2006; 116: 3090-3100
        • Leren T.P.
        • Bakken K.S.
        • Ulrike Dawn U.
        • et al.
        Heterozygosity for apolipoprotein A-I(R160L)Oslo is associated with low levels of high density lipoprotein cholesterol and HDL-subclass LpA-I/A-II but normal levels of HDL-subclass LpA-I.
        J Lipid Res. 1997; 38: 121-131
        • Huang W.
        • Sasaki J.
        • Matsunaga A.
        • et al.
        A novel homozygous missense mutation in the apo A-I gene with apo A-I deficiency.
        Arterioscler Thromb Vasc Biol. 1998; 18: 389-396
        • Daum U.
        • Leren T.P.
        • Langer C.
        • et al.
        Multiple dysfunctions of two apolipoprotein A-I variants, apoA-I(R160L)Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers.
        J Lipid Res. 1999; 40: 486-494
        • Gordon D.J.
        • Probstfield J.L.
        • Garrison R.J.
        • et al.
        High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.
        Circulation. 1989; 79: 8-15
        • Franceschini G.
        • Sirtori C.R.
        • Capurso 2nd, A.
        • Weisgraber K.H.
        • Mahley R.W.
        A-Imilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family.
        J Clin Invest. 1980; 66: 892-900
        • Calabresi L.
        • Pisciotta L.
        • Costantin A.
        • et al.
        The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1972-1978
        • Hovingh G.K.
        • Hutten B.A.
        • Holleboom A.G.
        • et al.
        Compromised LCAT function is associated with increased atherosclerosis.
        Circulation. 2005; 112: 879-884
        • Fredrickson D.S.
        • Altrocchi P.H.
        • Avioli L.V.
        • Goodman D.S.
        • Goodman H.C.
        Tangier disease.
        Ann Intern Med. 1961; 55: 1016-1031
        • Bodzioch M.
        • Orso E.
        • Klucken J.
        • et al.
        The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.
        Nat Genet. 1999; 22: 347-351
        • Brooks-Wilson A.
        • Marcil M.
        • Clee S.M.
        • et al.
        Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.
        Nat Genet. 1999; 22: 336-345
        • Rust S.
        • Rosier M.
        • Funke H.
        • et al.
        Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.
        Nat Genet. 1999; 22: 352-355
        • Clee S.M.
        • Kastelein J.J.
        • van Dam M.
        • et al.
        Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes.
        J Clin Invest. 2000; 106: 1263-1270
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        • Stene M.C.
        • et al.
        Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.
        JAMA. 2008; 299: 2524-2532
        • Altilia S.
        • Pisciotta L.
        • Garuti R.
        • et al.
        Abnormal splicing of ABCA1 pre-mRNA in Tangier disease due to a IVS2 +5G>C mutation in ABCA1 gene.
        J Lipid Res. 2003; 44: 254-264
        • Tanaka A.R.
        • Abe-Dohmae S.
        • Ohnishi T.
        • et al.
        Effects of mutations of ABCA1 in the first extracellular domain on subcellular trafficking and ATP binding/hydrolysis.
        J Biol Chem. 2003; 278: 8815-8819
        • Fitzgerald M.L.
        • Morris A.L.
        • Rhee J.S.
        • et al.
        Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I.
        J Biol Chem. 2002; 277: 33178-33187
        • Singaraja R.R.
        • Visscher H.
        • James E.R.
        • et al.
        Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro.
        Circ Res. 2006; 99: 389-397
        • Albrecht C.
        • Baynes K.
        • Sardini A.
        • et al.
        Two novel missense mutations in ABCA1 result in altered trafficking and cause severe autosomal recessive HDL deficiency.
        Biochim Biophys Acta. 2004; 1689: 47-57