Advertisement

Molecular diagnosis of hypobetalipoproteinemia: An ENID review

      Abstract

      Primary hypobetalipoproteinemia (HBL) includes a group of genetic disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CRD), with a recessive transmission, and familial hypobetalipoproteinemia (FHBL) with a co-dominant transmission. ABL and CRD are rare disorders due to mutations in the MTP and SARA2 genes, respectively. Heterozygous FHBL is much more frequent. FHBL subjects often have fatty liver and, less frequently, intestinal fat malabsorption. FHBL may be linked or not to the APOB gene. Most mutations in APOB gene cause the formation of truncated forms of apoB which may or may be not secreted into the plasma. Truncated apoBs with a size below that of apoB-30 are not detectable in plasma; they are more frequent in patients with the most severe phenotype. Only a single amino acid substitution (R463W) has been reported as the cause of FHBL. Approximately 50% of FHBL subjects are carriers of pathogenic mutations in APOB gene; therefore, a large proportion of FHBL subjects have no apoB gene mutations or are carriers of rare amino acid substitutions in apoB with unknown effect. In some kindred FHBL is linked to a locus on chromosome 3 (3p21) but the candidate gene is unknown. Recently a FHBL plasma lipid phenotype was observed in carriers of mutations of the PCSK9 gene causing loss of function of the encoded protein, a proprotein convertase which regulates LDL-receptor number in the liver. Inactivation of this enzyme is associated with an increased LDL uptake and hypobetalipoproteinemia. HBL carriers of PCSK9 mutations do not develop fatty liver disease.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kane J.P.
        • Havel R.J.
        Disorders of the biogenesis and secretion of lipoproteins containing the B apolipoproteins.
        in: 8th ed. The metabolic and molecular bases of inherited disease. Vol. II. McGraw Hill, New York2001: 2717-2752
        • Linton M.F.
        • Farese R.V.
        • Young S.G.
        Familial hypobetalipoproteinemia.
        J Lipid Res. 1993; 34: 521-541
        • Schonfeld G.
        Familial hypobetalipoproteinemia: a review.
        J Lipid Res. 2003; 44: 878-883
        • Hooper A.J.
        • van Bockxmeer F.M.
        • Burnett J.R.
        Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism.
        Crit Rev Clin Lab Sci. 2005; 42: 515-545
        • Wetterau J.R.
        • Aggerbeck L.P.
        • Bouma M.E.
        • et al.
        Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.
        Science. 1992; 258: 999-1001
        • Shoulders C.C.
        • Brett D.J.
        • Bayliss J.D.
        • et al.
        Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein.
        Hum Mol Genet. 1993; 2: 2109-2116
        • Berriot-Varoqueaux N.
        • Aggerbeck L.P.
        • Samson-Bouma M.
        • Wetterau J.R.
        The role of the microsomal triglyceride transfer protein in abetalipoproteinemia.
        Annu Rev Nutr. 2000; 20: 663-697
        • Wang J.
        • Hegele R.A.
        Microsomal triglyceride transfer protein (MTP) mutations in Canadian subjects with abetalipoproteinemmia.
        Hum Mutat. 2000; 15: 294-295
        • Ohashi K.
        • Ishibashi S.
        • Osuga J.
        • et al.
        Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.
        J Lipid Res. 2000; 41: 1199-1204
        • Jones B.
        • Jones E.L.
        • Bonney S.A.
        • et al.
        Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.
        Nat Genet. 2003; 34: 29-31
        • Tarugi P.
        • Lonardo A.
        • Ballarini G.
        • et al.
        Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B.
        Gastroenterology. 1996; 111: 1125-1133
        • Tarugi P.
        • Lonardo A.
        • Ballarini G.
        • et al.
        A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (apoB-54.5).
        J Hepatol. 2000; 33: 361-370
        • Tarugi P.
        • Lonardo A.
        • Gabelli C.
        • et al.
        Phenotypic expression of familial hypobetalipoproteinemia in three kindred with mutations of apolipoprotein B gene.
        J Lipid Res. 2001; 42: 1552-1561
        • Lancellotti S.
        • Di Leo E.
        • Penacchioni J.Y.
        • et al.
        Hypobetalipoproteinemia with an apparently recessive inheritance due to a “de novo” mutation of apolipoprotein B.
        Biochim Biophys Acta. 2004; 1688: 61-67
        • Schonfeld G.
        • Lin X.
        • Yue P.
        Familial hypobetalipoproteinemia: genetics and metabolism.
        Cell Mol Life Sci. 2005; 62: 1372-1378
        • Fouchier S.W.
        • Sankatsing R.R.
        • Peter J.
        • et al.
        High frequency of APOB gene mutations causing familial hypobetalipoproteinemia in patients of Dutch and Spanish descent.
        J Med Genet. 2005; 42: e23
        • Burnett J.R.
        • Shan J.
        • Miskie B.A.
        • et al.
        A novel nontruncating APOB gene mutation, R463W, causes familial hypobetalipoproteinemia.
        J Biol Chem. 2003; 278: 13442-13452
        • Pulai J.I.
        • Neuman R.J.
        • Groenewegen A.W.
        • et al.
        Genetic heterogeneity in familial hypobetalipoproteinemia: linkage and non-linkage to the apoB gene in Caucasian families.
        Am J Med Genet. 1998; 76: 79-86
        • Yuan B.
        • Neuman R.
        • Duan S.H.
        • et al.
        Linkage of a gene for familial hypobetalipoproteinemia to chromosome 3p21. 1-22.
        Am J Hum Genet. 2000; 66: 1699-1704
        • Neuman R.J.
        • Yuan B.
        • Gerhard D.S.
        • et al.
        Replication of linkage of familial hypobetalipoproteinemia to chromosome 3p in six kindreds.
        J Lipid Res. 2002; 43: 407-415
        • Aguilar-Salinas C.A.
        • Barrett P.H.
        • Parhofer K.G.
        • et al.
        Apoprotein B-100 production is decreased in subjects heterozygous for truncations of apoprotein B.
        Arterioscler Thromb Vasc Biol. 1995; 15: 71-80
        • Elias N.
        • Patterson B.W.
        • Schonfeld G.
        Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia.
        Arterioscler Thromb Vasc Biol. 1999; 19: 2714-2721
        • Parhofer K.G.
        • Barrett P.H.
        • Bier D.M.
        • et al.
        Lipoprotein containing the truncated apo B-89 are cleared from human plasma more rapidly than apo B-100-containing lipoproteins in vivo.
        J Clin Invest. 1992; 89: 1931-1937
        • Parhofer K.G.
        • Barrett P.H.
        • Aguilar-Salinas C.A.
        • et al.
        Positive linear correlation between the length of truncated apolipoproein B and its secretion rates: in vivo studies in human apo B-89, apo B-75, apo B-54.8, and apo B-31 heterozygotes.
        J Lipid Res. 1996; 37: 844-852
        • Krul E.S.
        • Parhofer K.G.
        • Barrett P.H.
        • et al.
        ApoB-75, a truncation of apolipoprotein B associated with familial hypobetalipoproteinemia: genetic and kinetic studies.
        J Lipid Res. 1992; 33: 1037-1050
        • Zhu X.F.
        • Noto D.
        • Seip R.
        • et al.
        Organ loci of catabolism of short truncations of apoB.
        Arterioscler Thromb Vasc Biol. 1997; 17: 1032-1038
        • Chen Z.
        • Saffitz J.E.
        • Latour M.A.
        • et al.
        Truncated apo B-70.5-containing lipoproteins bind to megalin but not the LDL receptor.
        J Clin Invest. 1999; 103: 1419-1430
        • Sankatsing R.R.
        • Fouchier S.W.
        • de Haan S.
        • et al.
        Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1979-1984
        • Yue P.
        • Isley W.L.
        • Harris W.S.
        • et al.
        Genetic variants of apoE account for variability of plasma low-density lipoprotein and apolipoprotein B levels in FHBL.
        Atherosclerosis. 2005; 178: 107-113
        • Hooper A.J.
        • Robertson K.
        • Barrett H.R.
        • et al.
        Postprandial lipoprotein metabolism in familial hypobetalipoproteinemia.
        J Clin Endocrinol Metab. 2007; 92: 1474-1478
        • Welty F.
        • Lahoz C.
        • Tucker K.L.
        • et al.
        Frequency of apoB and apoE gene mutations as causes of hypobetalipoproteinemia in the Framingham offspring population.
        Arterioscler Thromb Vasc Biol. 1998; 18: 1745-1751
        • Nemeth-Slany A.
        • Talmud P.
        • Grundy S.M.
        • et al.
        Activation of a cryptic splice-site in intron 24 leads to the formation of apolipoprotein B-27.6.
        Atherosclerosis. 1997; 133: 163-170
        • Di Leo E.
        • Magnolo L.
        • Lancellotti S.
        • et al.
        Abnormal apolipoprotein B pre-mRNA splicing in patients with familial hypobetalipoproteinaemia.
        J Med Genet. 2007; 44: 219-224
        • Holbrook J.A.
        • Neu-Yilik G.
        • Hentze M.W.
        • et al.
        Nonsense-mediated decay approaches the clinic.
        Nat Genet. 2004; 36: 801-808
        • Young S.G.
        • Bertics S.J.
        • Curtiss L.K.
        • Witztum J.L.
        Characterization of an abnormal species of apolipoprotein B, apolipoprotein B-37, associated with familial hypobetalipoproteinemia.
        J Clin Invest. 1987; 79: 1831-1841
        • Young S.G.
        • Hubl S.T.
        • Chappell D.A.
        • et al.
        Familial hypobetalipoproteinemia associated with a mutant species of apolipoprotein B (B-46).
        N Engl J Med. 1989; 320: 1604-1610
        • Gabelli C.
        • Bilato C.
        • Martini S.
        • et al.
        Homozygous familial hypobetalipoproteinemia. Increased LDL catabolism in hypobetalipoproteinemia due to a truncated apolipoprotein B species, apo B-87Padova.
        Arterioscler Thromb Vasc Biol. 1996; 16: 1189-1196
        • Di Leo E.
        • Lancellotti S.
        • Penacchioni J.
        • et al.
        Mutations in MTP gene in abeta- and hypobeta-lipoproteinemia.
        Atherosclerosis. 2005; 180: 311-318
        • Yang X.P.
        • Inazu A.
        • Yagi K.
        • et al.
        Abetalipoproteinemia caused by maternal isodisomy of chromosome 4q containing an intron 9 splice acceptor mutation in the microsomal triglyceride transfer protein gene.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1950-1955
        • Maxwell K.N.
        • Breslow J.L.
        Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia.
        Curr Opin Lipidol. 2005; 16: 167-172
        • Rashid S.
        • Curtis D.E.
        • Garuti R.
        • et al.
        Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.
        Proc Natl Acad Sci USA. 2005; 102: 5374-5379
        • Cohen J.
        • Pertsemlidis A.
        • Kotowski I.K.
        • et al.
        Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.
        Nat Genet. 2005; 37: 161-165
        • Kotowski I.
        • Pertsemlidis A.
        • Luke A.
        • et al.
        A spectrum of PCSK9 alleles contributes to plasma levels of low density lipoprotein cholesterol.
        Am J Hum Genet. 2006; 78: 410-422
        • Yue P.
        • Averna M.
        • Lin X.
        • Schonfeld G.
        The c.43_44insCTG variation in PCSK9 is associated with low plasma LDL-Cholesterol in a Caucasian population.
        Hum Mutat. 2006; 27: 460-466
        • Berge K.E.
        • Ose L.
        • Leren T.P.
        Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy.
        Arterioscler Thromb Vasc Biol. 2006; 26: 1094-1100
        • Fasano T.
        • Cefalu A.B.
        • Di Leo E.
        • et al.
        A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol.
        Arterioscler Thromb Vasc Biol. 2007; 27: 677-681
        • Tanoli T.
        • Yue P.
        • Yablonskiy D.A.
        • et al.
        Fatty liver in familial hypobetalipoproteinemia: Roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity.
        J Lipid Res. 2004; 45: 941-947
        • Lin X.
        • Chen Z.
        • Yue P.
        • et al.
        A targeted apoB38.9 mutation in mice is associated with reduced hepatic cholesterol synthesis and enhanced lipid peroxidation.
        Am J Physiol Gastrointest Liver Physiol. 2006; 290: G1170-G1176
        • Yue P.
        • Tanoli T.
        • Wilhelm O.
        • et al.
        Absence of fatty liver in familial hypobetalipoproteinemia linked to chromosome 3p21.
        Metabolism. 2005; 54: 682-688
        • Glueck C.J.
        • Gartside P.
        • Fallat R.W.
        • et al.
        Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia.
        J Lab Clin Med. 1976; 88: 941-957
        • Cohen J.C.
        • Boerwinkle E.
        • Mosley T.H.
        • Hobbs H.H.
        Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
        N Eng J Med. 2006; 354: 1264-1272

      Linked Article