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Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders

      Abstract

      Mutations in ABCA1 have been shown to be the cause of Tangier disease (TD) and some forms of familial hypoalphalipoproteinemia (HA), two genetic disorders characterized by low plasma HDL levels. Here we report six subjects with low HDL, carrying seven ABCA1 mutations, six of which are previously unreported. Two mutations (R557X and H160FsX173) were predicted to generate short truncated proteins; two mutations (E284K and Y482C) were located in the first extracellular loop and two (R1901S and Q2196H) in the C-terminal cytoplasmic domain of ABCA1. Two subjects found to be compound heterozygotes for ABCA1 mutations did not have overt clinical manifestations of TD. Three subjects, all with premature coronary artery disease (pCAD), had a combination of genetic defects. Besides being heterozygotes for ABCA1 mutations, two of them were also carriers of the R3500Q substitution in apolipoprotein B and the third was a carrier of N291S substitution in lipoprotein lipase. By extending family studies we identified 17 heterozygotes for ABCA1 mutations. Plasma HDL-C and Apo A-I values in these subjects were 38.3 and 36.9% lower than in unaffected family members and similar to the values found in heterozygotes for Apo A-I gene mutations which prevent Apo A-I synthesis. This survey underlines the allelic heterogeneity of ABCA1 mutations and suggests that: (i) TD subjects, if asymptomatic, may be overlooked and (ii) there may be a selection bias in genotyping towards carriers of ABCA1 mutations who have pCAD possibly related to a combination of genetic and environmental cardiovascular risk factors.

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      References

        • Genest J
        • McNamara J.R
        • Ordovas J.M
        • Jenner J.L
        • Silberman S.R
        • Anderson K.M
        • et al.
        Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease.
        J Am Coll Cardiol. 1992; 19: 792-802
        • Franceschini G
        Epidemiologic evidence for high-density lipoprotein cholesterol as a risk factor for coronary artery disease.
        Am J Cardiol. 2001; 88: 9N-13N
        • O’Connell B.J
        • Genest J
        High-density lipoproteins and endothelial function.
        Circulation. 2001; 104: 1978-1983
        • Nofer J.R
        • Kehrel B
        • Fobker M
        • Levkau B
        • Assmann G
        • von Eckardstein A
        HDL and atherosclerosis: beyond reverse cholesterol transport.
        Atherosclerosis. 2002; 161: 1-16
        • Sviridov D
        • Nestel P
        Dynamics of reverse cholesterol transport: protection against atherosclerosis.
        Atherosclerosis. 2002; 161: 245-254
        • von Eckardstein A
        • Nofer J.-R
        • Assmann G
        High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport.
        Arterioscler Thromb Vasc Biol. 2001; 21: 13-27
      1. Assmann G, von Eckardstein A, Brewer H. Familial analphalipoproteinemia: Tangier disease. In: Scriver CR, Beaudet AL, Sly WS, Valle I, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill: 2001. p. 2937–60.

        • Santamarina-Fojo S
        • Peterson K
        • Knapper C
        • Qiu Y
        • Freeman L
        • Cheng J.-F
        • et al.
        Complete genomic sequence of the human ABCA1 gene: analysis of the human and mouse ATP-binding cassette A promoter.
        Proc Natl Acad Sci USA. 2000; 97: 7987-7992
        • Basso F
        • Freeman L
        • Knapper C.L
        • Remaley A
        • Stonik J
        • Neufeld E.B
        • et al.
        Role of hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL concentrations.
        J Lipid Res. 2003; 44: 296-302
        • Brousseau M.E
        • Schaefer E.J
        • Dupuis J
        • Eustace B
        • van Erdewegh P
        • Goldkamp A.L
        • et al.
        Novel mutations in the gene encoding ATP-binding cassette 1 in four Tangier disease kindreds.
        J Lipid Res. 2000; 41: 433-441
        • Wang J
        • Burnett J.R
        • Near S
        • Young K
        • Zinman B
        • Hanley A.J.G
        • et al.
        Common and rare ABCA1 variants affecting plasma HDL cholesterol.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1983-1989
        • Clee S.M
        • Kastelein J.J.P
        • van Dam M
        • Marcil M
        • Roomp K
        • Zwarts K.Y
        • 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
        • Lapicka-Bodzioch K
        • Bodzioch M
        • Krull M
        • Kielar D
        • Probst M
        • Kiec B
        • et al.
        Homogeneous assay based on 52 primer sets to scan for mutations of the ABCA1 gene and its application in genetic analysis of a new patient with familial high-density lipoprotein deficiency syndrome.
        Biochim Biophys Acta. 2001; 1537: 42-48
        • Huang W
        • Moriyama K
        • Koga T
        • Hua H
        • Ageta M
        • Kawabata S
        • et al.
        Novel mutations in ABCA1 gene in Japanese patients with Tangier disease and familial high density lipoprotein deficiency with coronary heart disease.
        Biochim Biophys Acta. 2001; 1537: 71-78
        • Guo Z
        • Inazu A
        • Yu W
        • Suzumura T
        • Okamoto M
        • Nohara A
        • et al.
        Double deletions and missense mutations in the first nucleotide-binding fold of the ATP-binding cassette transporter A1 (ABCA1) gene in Japanese patients with Tangier Disease.
        J Hum Genet. 2002; 47: 325-329
        • Ishii J
        • Nagano M
        • Kujiraoka T
        • Ishihara M
        • Egashira T
        • Takada D
        • et al.
        Clinical variant of Tangier disease in Japan: mutation of the ABCA1 gene in hypoalphalipoproteinemia with corneal lipidosis.
        J Hum Genet. 2002; 47: 366-369
        • Hovingh G.K
        • Van Tol A
        • Smelt A.H.M
        • Hayden M.R
        • Kastelein J.J.P
        • Kuivenhoven J.A
        Tangier disease: a case report.
        Atherosclerosis. 2002; 3: 127
        • Bertolini S
        • Pisciotta L
        • Seri M
        • Cusano R
        • Cantafora A
        • Calabresi L
        • et al.
        A point mutation in ABC1 gene in a patient with severe premature coronary heart disease and mild clinical phenotype of Tangier Disease.
        Atherosclerosis. 2001; 154: 599-605
        • Nishida Y
        • Hirano K
        • Tsukamoto K
        • Nagano M
        • Ikegami C
        • Roomp K
        • et al.
        Expression and functional analyses of novel mutations of ATP-binding cassette transporter-1 in Japanese patients with high-density lipoprotein deficiency.
        Biochim Biophys Res Commun. 2002; 290: 713-721
        • Hong S.H
        • Rhyne J
        • Zeller K
        • Miller M
        Novel ABCA1 compound variant associated with HDL cholesterol deficiency.
        Biochim Biophys Acta. 2002; 1587: 60-64
        • Altilia S
        • Pisciotta L
        • Garuti R
        • Tarugi P
        • Cantafora A
        • Calabresi L
        • 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
        • Miller M
        • Rhyne J
        • Hamlette S
        • Birnbaum J
        • Rodriguez A
        Genetics of HDL regulation in humans.
        Curr Opin Lipidol. 2003; 14: 273-279
        • Singaraja R.R
        • Brunham L.R
        • Visscher H
        • Kastelein J.J.P
        • Hayden M.R
        Efflux and atherosclerosis. The clinical and biochemical impact of variations in the ABCA1 gene.
        Arterioscler Thromb Vasc Biol. 2003; 23: 1322-1332
        • Marcil M
        • Brooks-Wilson A
        • Clee M.S
        • Roomp K
        • Zhang L.-H
        • Collins J.A
        • et al.
        Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux.
        Lancet. 1999; 354: 1341-1346
        • Mott S
        • Yu L
        • Marcil M
        • Boucher B
        • Rondeau C
        • Genest Jr., J
        Decreased cellular cholesterol efflux is a common cause of familial hypoalphalipoproteinemia: role of the ABCA1 gene mutations.
        Atherosclerosis. 2000; 152: 457-468
        • Hong S.H
        • Rhyne J
        • Zeller K
        • Miller M
        ABCA1Alabama: a novel variant associated with HDL deficiency and premature coronary artery disease.
        Atherosclerosis. 2002; 164: 245-250
        • Hong S.H
        • Riley W
        • Rhyne J
        • Friel G
        • Miller M
        Lack of association between increased carotid intima-media thickening and decreased HDL-cholesterol in a family with a novel ABCA1 variant, G2265T.
        Clin Chem. 2002; 48: 2066-2070
        • Hovingh G.K
        • van Wijland M.J.A
        • Brownlie A
        • Bisoendial R.B
        • Hayden M.R
        • Kastelein J.J.P
        • et al.
        The role of the ABCA1 transporter and cholesterol efflux in Familial Hypoalphalipoproteinemia.
        J Lipid Res. 2003; 44: 1251-1255
      2. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1989.

        • Moriyama K
        • Sasaki J
        • Takada Y
        • Matsunaga A
        • Fukui J
        • Albers J.J
        • et al.
        A cysteine-containing truncated Apo A-I variant associated with HDL deficiency.
        Arterioscler Thromb Vasc Biol. 1996; 16: 1416-1423
        • Guerin M
        • Dachet C
        • Goulinet S
        • Chevet D
        • Dolphin P.J
        • Chapman M.J
        • et al.
        Familial lecithin:cholesterol acyltransferase deficiency: molecular analysis of a compound heterozygote: LCAT (Arg147 → Trp) and LCAT (Tyr171 → Stop).
        Atherosclerosis. 1997; 131: 85-95
      3. Antonarakis SE, The Nomenclature Working Group. Recommendations for a nomenclature system for human gene mutations. Hum Mutat 1998;11:1–3.

        • Wittekoek M.E
        • Pimstone S.N
        • Reymer P.W.A
        • Feuth L
        • Botma G.-J
        • Defesche J.C
        • et al.
        A common mutation in the lipoprotein lipase gene (N291S) alters the lipoprotein phenotype and risk for cardiovascular disease in patients with familial hypercholesterolemia.
        Circulation. 1998; 97: 729-735
        • Wittekoek M.E
        • Moll E
        • Pimstone S.N
        • Trip M.D
        • Lansberg P.J
        • Defesche J.C
        • et al.
        A frequent mutation in the lipoprotein lipase gene (D9N) deteriorates the biochemical and clinical phenotype of familial hypercholesterolemia.
        Arterioscler Thromb Vasc Biol. 1999; 19: 2708-2713
        • Hixson J.E
        • Vernier D.T
        Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.
        J Lipid Res. 1990; 31: 545-548
        • Bertolini S
        • Cantafora A
        • Averna M
        • Cortese C
        • Motti C
        • Martini S
        • et al.
        Clinical expression of familial hypercolesterolemia in clusters of mutations of LDL-receptor gene causing receptor-defective or receptor-negative phenotype.
        Arterioscler Thromb Vasc Biol. 2000; 20: e41-e51
        • Tarugi P
        • Lonardo A
        • Gabelli C
        • Sala F
        • Ballarini G
        • Cortella I
        • et al.
        Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene.
        J Lipid Res. 2001; 42: 1552-1561
        • Brousseau M.E
        • Eberhart G.P
        • Dupuis J
        • Asztalos B.F
        • Goldkamp A.L
        • Schaefer E.J
        • et al.
        Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size.
        J Lipid Res. 2000; 41: 1125-1135
        • Serfaty-Lacrosniere C
        • Civeira F
        • Lanzberg A
        • Isaia P
        • Berg J
        • Janus E.D
        • et al.
        Homozygous Tangier disease and cardiovascular disease.
        Atherosclerosis. 1994; 107: 85-98
        • Fitzgerald M.L
        • Morris A.L
        • Rhee J.S
        • Andersson L.P
        • Mendez A.J
        • Freeman M.W
        Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with Apolipoprotein A-I.
        J Biol Chem. 2002; 277: 33178-33187
        • Rigot V
        • Hamon Y
        • Chambenoit O
        • Alibert M
        • Duverger N
        • Chimini G
        Distinct sites on ABCA1 control distinct steps required for cellular release of phospholipids.
        J Lipid Res. 2002; 43: 2077-2086
        • Attie A.D
        • Hamon Y
        • Brooks-Wilson A.R
        • Gray-Keller M.P
        • MacDonald M.L.E
        • Rigot V
        • et al.
        Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken.
        J Lipid Res. 2002; 43: 1610-1617
        • Wang J
        • Near S
        • Young K
        • Connelly P.W
        • Hegele R.A
        ABCC6 gene polymorphism associated with variation in plasma lipoproteins.
        J Hum Genet. 2001; 46: 699-705
        • Pocovi M
        • Cenarro A
        • Civeira F
        • Torralba M.A
        • Perez-Calvo J.I
        • Mazas P
        • et al.
        β-Glucocerebrosidase gene locus as a link for Gaucher’s disease and familial hypo-α-lipoproteinemia.
        Lancet. 1998; 351: 1919-1923
        • Lee C.Y
        • Krimbou L
        • Vincent J
        • Bernard C
        • Larramée P
        • Genest Jr., J
        • et al.
        Compound heterozygosity at the sphingomyelin phosphodiesterare-1 (SMPD1) gene is associated with low HDL cholesterol.
        Hum Genet. 2003; 112: 552-562
        • Levy E
        • Rizwan Y
        • Thibault L
        • Lepage G
        • Brunet S
        • Bouthillier L
        • et al.
        Altered lipid profile, lipoprotein composition, and axidant and antioxidant status in pediatric Crohn disease.
        Am J Clin Nutr. 2000; 71: 807-815
        • Koutroubakis I.E
        • Malliaraki N
        • Vardas E
        • Ganotakis E
        • Margioris A.N
        • Manousos O.N
        • et al.
        Increased levels of lipoprotein (a) in Crohn’s disease: a relation to thrombosis?.
        Eur J Gastroeterol Hepatol. 2002; 13: 1415-1419
        • Khovidhunkit W
        • Memon R.A
        • Feingold K.R
        • Grunfeld C
        Infection and inflammation-indiced proatherogenic changes of lipoproteins.
        J Infect Dis. 2000; 181: S462-S472
        • Kervinen H
        • Palosuo T
        • Manninen V
        • Tenkanen L
        • Vaarala O
        • Mänttäri M
        Joint effects of C-reactive protein and other risk factors on acute coronary events.
        Am Heart J. 2001; 141: 580-585
        • Miserez A
        • Keller U
        Differences in the phenotypic characteristics of subjects with familial defective apolipoprotein B-100 and familial hypercholesterolemia.
        Arterioscler Thromb Vasc Biol. 1995; 15: 1719-1729
        • Hansen P.S
        • Defesche J.C
        • Kastelein J.J.P
        • Gerdes L.U
        • Fraza L
        • Gerdes C
        • et al.
        Phenotypic variation in patients heterozygous for familial defective apolipoprotein B (FDB) in three European Countries.
        Arterioscler Thromb Vasc Biol. 1997; 17: 741-747
        • Hausmann D
        • Johnson J.A
        • Sudhir K
        • Mullen W.L
        • Friedrich G
        • Fitzgerald P.J
        • et al.
        Angiographically silent atherosclerosis detected by intravascular ultrasound in patients with familial hypercholesterolemia and familial combined hyperlipidemia: correlation with high density lipoproteins.
        J Am Coll Cardiol. 1996; 27: 1562-1570
        • Gaudet D
        • Vohl M.C
        • Julien P
        • Tremblay G
        • Perron C
        • Gagné C
        • et al.
        Relative contribution of low-density lipoprotein receptor and lipoprotein lipase gene mutations to angiographically assessed coronary artery disease among French Canadians.
        Am J Cardiol. 1998; 82: 299-305
        • Wiegman A
        • Rodenburg J
        • de Jongh S
        • Defesche J.C
        • Bakker H.D
        • Kastelein J.J.P
        • et al.
        Family history and cardiovascular risk in familial hypercholesterolemia. Data in more than 1000 children.
        Circulation. 2003; 107: 1473-1478
        • Zhang H
        • Henderson H
        • Gagne S.E
        • Clee S.M
        • Miao L
        • Liu G
        • et al.
        Common sequence variants of lipoprotein lipase: standardized studies of in vitro expression and catalytic function.
        Biochim. Biophys Acta. 1996; 1302: 159-166
        • Wittrup H.H
        • Tybjaerg-Hansen A
        • Nordsterdgaard B.G
        Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.
        Circulation. 1999; 99: 2901-2907
        • Hokanson J.E
        Functional variants in the lipoprotein lipase gene and risk of cardiovascular disease.
        Curr Opin Lipidol. 1999; 10: 393-399
        • Wittrup H.H
        • Tyabjaerg-Hansen A
        • Abildgaard S
        • Steffensen R
        • Schnohr P
        • Nordestgaard B.G
        A common substitution (Asn291Ser) in lipoprotein lipase is associated with increased risk of ischemic heart disease.
        J Clin Invest. 1997; 99: 1606-1613
        • Hopkins P.C.R
        • Huang Y
        • McGuire J.G
        • Pitas R.E
        Evidence for differential effects of apoE3 and apo E4 on HDL metabolism.
        J Lipid Res. 2002; 43: 1881-1889
        • Pisciotta L
        • Miccoli R
        • Cantafora A
        • Calabresi L
        • Tarugi P
        • Alessandrini P
        • et al.
        Recurrent mutations of the apolipoprotein A-I gene in three kindreds with severe HDL deficiency.
        Atherosclerosis. 2003; 167: 335-345