Lipoproteins: Genetic Disorders

Anne K Soutar, Medical Research Council Clinical Sciences Centre, London, UK

Published online: September 2009

DOI: 10.1002/9780470015902.a0002279.pub2

The primary function of plasma lipoproteins is to transport newly synthesised or dietary lipids in the circulation; these water-insoluble substances include triacylglycerol, cholesterol and fat-soluble vitamins. Mutations in genes for the many enzymes, receptors and structural proteins that regulate lipoprotein metabolism and transport are often detrimental to health, and may increase the amount of normal lipoproteins, result in accumulation of abnormal lipoproteins or cause lipoprotein deficiencies. Some defects increase the risk of coronary heart disease, whereas other deficiency disorders cause neurological and/or gastrointestinal symptoms. Genetic disorders of lipoprotein metabolism highlight the importance of lipid transport and metabolism in normal human physiology.

Key Concepts

  • Normal regulation of plasma lipoprotein metabolism is critical for transport of lipids and fat-soluble vitamins in the circulation.
  • Once secreted from cells in the liver or intestine, lipoproteins undergo many complex metabolic changes in the blood circulation brought about by enzymes and their cofactors, exchange factors and cell-surface receptors.
  • Variation in the genes for these proteins can alter their function and cause changes in the composition, concentration and/or function of plasma lipoproteins that are frequently deleterious to health.
  • Several defects in lipoprotein metabolism result in increased risk of premature coronary heart disease because of cholesterol deposition in the blood vessels, whereas others lead to neurological symptoms due to deficiency of fat-soluble vitamins.
  • The inheritance pattern varies: most known lipoprotein disorders are monogenic, with either autosomal dominant inheritance, where heterozygous carriers are affected or autosomal recessive inheritance, where heterozygous carriers are apparently unaffected. Some dominantly inherited disorders have a gene dosage effect, where homozygous individuals are more severely affected than heterozygous ones.
  • Some gene variants only have a marked physiological effect in a particular genetic or environmental background, so not all carriers are affected.
  • Families exist who have a clinical phenotype characteristic of a known monogenic disorder, but who have no detectable defect in the known causal genes; this suggests that novel genes still remain to be identified that influence lipoprotein metabolism.
  • One of the commonest inherited disorders, familial combined hyperlipidaemia, is not monogenic and requires several gene variants to be present for symptoms to be manifest. These variants are also unlikely to be the same for all families.

Keywords: lipid metabolism; atherosclerosis; hyperlipidaemia; coronary heart disease; mutations; fat-soluble vitamin deficiency

Figure 1. Metabolism of apolipoprotein B (ApoB)-containing lipoproteins. Triacylglycerol (TAG) and ApoB100 are synthesized in liver and assembled to form very low-density lipoproteins (VLDL) by a mechanism that requires microsomal triacylglycerol transfer protein (MTP). In the circulation the TAG is hydrolysed by lipoprotein lipase (LPL), which requires ApoCII as cofactor, with the formation of intermediate density lipoprotein (IDL). Excess surface components (phospholipid, cholesterol and non-ApoB apoproteins) are transferred to HDL (see Figure 2). TAG in IDL is further hydrolysed by LPL and hepatic lipase (HL), to finally form low-density lipoproteins (LDL), which accumulate in plasma. LDL is removed from the circulation mainly by LDL receptor (LDLR)-mediated uptake and degradation in the liver. LDL in the circulation is liable to oxidative modification, thus allowing it to be taken up by macrophage scavenger receptors. Chylomicrons (CM) are synthesized and secreted from the intestine following ingestion of fat and contain ApoB48 rather than ApoB100. Once in the circulation, they suffer a similar fate to VLDL. CM remnants (CMR) are cleared rapidly from the circulation by CM-remnant receptors (CMRR) on the liver. Genetic disorders are known that influence all these processes.
Figure 2. Metabolism of high-density lipoproteins (HDL). HDL in plasma is formed from several sources, including excess surface material generated during the hydrolysis of triacylglycerol (TAG)-rich lipoproteins (see Figure 1), as well as by direct secretion of HDL precursors, sometimes called ‘nascent HDL’, from the liver and intestine. Nascent HDL acquires free cholesterol from cells by interaction with a cell-surface cholesterol efflux protein called ATP-binding cassette transporter A1 (ABCA1). The free cholesterol on the surface of HDL is rapidly esterified by the enzyme lecithin cholesterol acyltransferase (LCAT) which requires Apo-A-I, a major HDL apolipoprotein, as cofactor. The cholesteryl ester (CE) is hydrophobic and thus forms the core of the HDL particle and HDL can then take up more free cholesterol on its surface, eventually forming CE-rich HDL. Exchange and transfer of lipids between lipoproteins is catalysed by the cholesteryl ester transfer protein (CETP), allowing exchange of HDL CE for TAG in VLDL, forming an HDL particle that is richer in TAG. TAG in HDL is removed from the particles by hepatic lipase (HL) activity in the liver, without degradation of the HDL. Similarly CE can be removed from HDL by interaction with HDL receptors (SR-B1) in liver. Thus HDL functions to transfer cholesterol from peripheral tissues to the liver, a process referred to as reverse cholesterol transport. Genetic disorders are known that influence all these processes.
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 References
    Abifadel M, Varret M, Rabes JP et al. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics 34: 154–156.
    Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M and Wetterau JR (2000) The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. Annual Review of Nutrition 20: 663–697.
    Bijvoet S, Gagne SE, Moorjani S et al. (1996) Alterations in plasma lipoproteins and apolipoproteins before the age of 40 in heterozygotes for lipoprotein lipase deficiency. Journal of Lipid Research 37: 640–650.
    Booth DR, Tan SY, Booth SE et al. (1996) Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene. Journal of Clinical Investigation 97: 2714–2721.
    Brewer HB Jr, Zech LA, Gregg RE, Schwartz D and Schaefer EJ (1983) NIH conference. Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment. Annals of Internal Medicine 98: 623–640.
    Brown MS and Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–47.
    Cohen JC, Boerwinkle E, Mosley TH Jr and Hobbs HH (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New England Journal of Medicine 354: 1264–1272.
    Cohen JC, Kiss RS, Pertsemlidis A et al. (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305: 869–872.
    Connelly PW and Hegele RA (1998) Hepatic lipase deficiency. Critical Reviews in Clinical Laboratory Sciences 35: 547–572.
    Corder EH, Saunders AM, Strittmatter WJ et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261: 921–923.
    Cunningham D, Danley DE, Geoghegan KF et al. (2007) Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nature Structural & Molecular Biology 14: 413–419.
    Dubuc G, Chamberland A, Wassef H et al. (2004) Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology 24: 1454–1459.
    Eurlings PMH, van der Kallen CJH, Geurts JMW, van Greevenbroek MMJ and de Bruin TWA (2001) Genetic dissection of familial combined hyperlipidemia. Molecular Genetics and Metabolism 74: 98–104.
    Foubert L, De Gennes JL, Lagarde JP et al. (1997) Assessment of French patients with LPL deficiency for French Canadian mutations. Journal of Medical Genetics 34: 672–675.
    Garcia CK, Wilund K, Arca M et al. (2001) Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292: 1394–1398.
    Goldstein JL, Schrott HG, Hazzard WR, Bierman EL and Motulsky AG (1973) Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. Journal of Clinical Investigation 52: 1544–1568.
    Henneman P, van der Sman-de Beer F, Moghaddam PH et al. (2009) The expression of type III hyperlipoproteinemia: involvement of lipolysis genes. European Journal of Human Genetics. 17: 620–628.
    Horton JD, Cohen JC and Hobbs HH (2007) Molecular biology of PCSK9: its role in LDL metabolism. Trends in Biochemical Sciences 32: 71–77.
    Jones B, Jones EL, Bonney SA et al. (2003) Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nature Genetics 34: 29–31.
    Karathanasis SK, Ferris E and Haddad IA (1987) DNA inversion within the apolipoproteins AI/CIII/AIV-encoding gene cluster of certain patients with premature atherosclerosis. Proceedings of the National Academy of Sciences of the USA 84: 7198–7202.
    Kuivenhoven JA, Pritchard H, Hill J et al. (1997) The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. Journal of Lipid Research 38: 191–205.
    Lohse P, Brewer HB 3rd, Meng MS et al. (1992) Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. Journal of Lipid Research 33: 1583–1590.
    Lusis AJ, Attie AD and Reue K (2008) Metabolic syndrome: from epidemiology to systems biology. Nature Reviews. Genetics 9: 819–830.
    Ma Y, Ooi TC, Liu MS et al. (1994) High frequency of mutations in the human lipoprotein lipase gene in pregnancy-induced chylomicronemia: possible association with apolipoprotein E2 isoform. Journal of Lipid Research 35: 1066–1075.
    Mahley RW, Huang Y and Rall SC Jr (1999) Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. Journal of Lipid Research 40: 1933–1949.
    McNutt MC, Lagace TA and Horton JD (2007) Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. Journal of Biological Chemistry 282: 20799–20803.
    Myant NB (1993) Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis 104: 1–18.
    Naoumova RP, Thompson GR and Soutar AK (2004) Current management of severe homozygous hypercholesterolaemias. Current Opinion in Lipidology 15: 413–422.
    Naoumova RP, Tosi I, Patel D et al. (2005) Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arteriosclerosis, Thrombosis, and Vascular Biology 25: 2654–2660.
    Neuman RJ, Yuan B, Gerhard DS et al. (2002) Replication of linkage of familial hypobetalipoproteinemia to chromosome 3p in six kindreds. Journal of Lipid Research 43: 407–415.
    Nissen SE, Tsunoda T, Tuzcu EM et al. (2003) Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290: 2292–2300.
    Norman D, Sun XM, Bourbon M et al. (1999) Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia. Journal of Clinical Investigation 104: 619–628.
    Oram JF (2000) Tangier disease and ABCA1. Biochimica et Biophysica Acta 1529: 321–330.
    Oram JF and Lawn RM (2001) ABCA1. The gatekeeper for eliminating excess tissue cholesterol. Journal of Lipid Research 42: 1173–1179.
    Pennacchio LA, Olivier M, Hubacek JA et al. (2001) An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science 294: 169–173.
    Priore Oliva C, Carubbi F, Schaap FG, Bertolini S and Calandra S (2008) Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A-V deficiency due to a novel mutation in the APOA5 gene. Journal of Internal Medicine 263: 450–458.
    Roy CC, Levy E, Green PH et al. (1987) Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B. Chylomicron retention disease. Gastroenterology 92: 390–399.
    Sagoo GS, Tatt I, Salanti G et al. (2008) Seven lipoprotein lipase gene polymorphisms, lipid fractions, and coronary disease: a HuGE association review and meta-analysis. American Journal of Epidemiology 168: 1233–1246.
    Santamarina-Fojo S (1998) The familial chylomicronemia syndrome. Endocrinology and Metabolism Clinics of North America 27: 551–567.
    Schmitz G, Langmann T and Heimerl S (2001) Role of ABCG1 and other ABCG family members in lipid metabolism. Journal of Lipid Research 42: 1513–1520.
    Schonfeld G (2003) Familial hypobetalipoproteinemia: a review. Journal of Lipid Research 44: 878–883.
    Sherva R, Yue P, Schonfeld G and Neuman RJ (2007) Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families. Journal of Lipid Research 48: 2632–2639.
    Shoulders CC, Jones EL and Naoumova RP (2004) Genetics of familial combined hyperlipidemia and risk of coronary heart disease. Human Molecular Genetics 13(Spec No. 1): R149–R160.
    Sirtori CR, Calabresi L, Franceschini G et al. (2001) Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. Circulation 103: 1949–1954.
    Smit M, de Knijff P, van der Kooij-Meijs E et al. (1990) Genetic heterogeneity in familial dysbetalipoproteinemia. The E2(lys146----gln) variant results in a dominant mode of inheritance. Journal of Lipid Research 31: 45–53.
    Sorci-Thomas MG and Thomas MJ (2002) The effects of altered apolipoprotein A-I structure on plasma HDL concentration. Trends in Cardiovascular Medicine 12: 121–128.
    Soutar AK, Hawkins PN, Vigushin DM et al. (1992) Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis. Proceedings of the National Academy of Sciences of the USA 89: 7389–7393.
    Soutar AK and Naoumova RP (2007) Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nature Clinical Practice. Cardiovascular Medicine 4: 214–225.
    Soutar AK, Naoumova RP and Traub LM (2003) Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology 23: 1963–1970.
    Suviolahti E, Lilja HE and Pajukanta P (2006) Unraveling the complex genetics of familial combined hyperlipidemia. Annals of Medicine 38: 337–351.
    Talmud PJ (2007) Rare APOA5 mutations – clinical consequences, metabolic and functional effects: an ENID review. Atherosclerosis 194: 287–292.
    Tarugi P, Averna M, Di Leo E et al. (2007) Molecular diagnosis of hypobetalipoproteinemia: an ENID review. Atherosclerosis 195: e19–e27.
    Utermann G (1987) Apolipoprotein E polymorphism in health and disease. American Heart Journal 113: 433–440.
    Yamashita S, Hirano K, Sakai N and Matsuzawa Y (2000) Molecular biology and pathophysiological aspects of plasma cholesteryl ester transfer protein. Biochimica et Biophysica Acta 1529: 257–275.
 Further Reading
    book Betteridge DJ, Illingworth DR and Shepherd J (eds) (1999) Lipoproteins in Health and Disease. London: Arnold.
    Breslow JL (2000) Genetics of lipoprotein abnormalities associated with coronary artery disease susceptibility. Annual Review of Genetics 34: 233–254.
    book Scriver CR, Beaud AL, Valle D et al. (eds) (2001) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill Professional.
    book Soutar AK (1993) "Investigation and diagnosis of disorders of lipoprotein metabolism". In: Rapley R and Walker MR (eds) Molecular Diagnostics. Oxford: Blackwell Scientific.

Related Sub-Topics:

Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Proteins: Structure, Function, Metabolism | Lipids: Structure, Function, Metabolism
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Article Title: Lipoproteins: Genetic Disorders
 
How to Cite close
Soutar, Anne K(Sep 2009) Lipoproteins: Genetic Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002279.pub2]