Monogenic Dyslipidemias: Window on Determinants of Plasma Lipoprotein Metabolism
2001; Elsevier BV; Volume: 69; Issue: 6 Linguagem: Inglês
10.1086/324647
ISSN1537-6605
Autores Tópico(s)Lipid metabolism and disorders
ResumoPlasma lipoproteins are important determinants of atherosclerosis, a disease of the large arteries that underlies most deaths in industrialized nations (Lusis Lusis, 2000Lusis AJ Atherosclerosis.Nature. 2000; 407: 233-241Crossref PubMed Scopus (2552) Google Scholar). Atherogenesis begins in response to an arterial injury, which leads to a series of inflammatory, proliferative, and apoptotic cellular events that produce complicated arterial-wall plaques (Ross Ross, 1993Ross R The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-809Crossref PubMed Scopus (7854) Google Scholar, Ross, 1999Ross R Atherosclerosis--an inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (13535) Google Scholar). Some plaques are vulnerable to rupture and thrombosis, leading to arterial occlusion, whose location specifies the clinical presentation, usually a heart attack or stroke (Ross Ross, 1993Ross R The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-809Crossref PubMed Scopus (7854) Google Scholar, Ross, 1999Ross R Atherosclerosis--an inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (13535) Google Scholar). Genetic susceptibility plays a key role in atherosclerosis, particularly when clinical end points strike early in life. Some risk factors—such as dyslipidemia, diabetes and hypertension—themselves have complex genetic determinants. Other risk factors—such as smoking, poor diet, inactivity, and stress—can modulate expression of the genetic susceptibility. Study of monogenic dyslipidemias has exposed key metabolic mechanisms. The exemplar was the autosomal dominant (AD) form of familial hypercholesterolemia (FH) (MIM 143890), whose characterization led to the discovery of receptor-mediated endocytosis (RME) via the LDL receptor (Brown and Goldstein Brown and Goldstein, 1986Brown MS Goldstein JL A receptor-mediated pathway for cholesterol homeostasis.Science. 1986; 232: 34-47Crossref PubMed Google Scholar). This in turn led to development of statin drugs, which reduce LDL cholesterol and coronary heart disease (CHD) mortality (4S Investigators 4S Investigators, 19944S Investigators Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).Lancet. 1994; 334: 1383-1389Google Scholar) and which are now used by tens of millions of people. However, LDL-cholesterol reduction does not always prevent CHD (Superko Superko, 1996Superko HR Beyond LDL cholesterol reduction.Circulation. 1996; 94: 2351-2354Crossref PubMed Google Scholar), and many patients with CHD do not have elevated LDL cholesterol as their primary dyslipidemia (Genest et al. Genest et al., 1992Genest Jr, JJ Martin-Munley SS McNamara JR Ordovas JM Jenner J Myers RH Silberman SR Wilson PWF Salem DN Schaefer EJ Familial lipoprotein disorders in patients with premature coronary artery disease.Circulation. 1992; 85: 2025-2033Crossref PubMed Google Scholar). Recent delineation of the molecular basis of other monogenic dyslipidemias therefore has the potential to reveal new pathways that could lead to additional downstream public-health benefits for CHD reduction. Nongenetic and nonhuman experiments have revealed many fascinating gene products for lipoprotein metabolism. This review will focus on monogenic lipoprotein disorders, summarized in table 1. Before 1999, most mutations for monogenic lipoprotein disorders were identified on the basis of the function of the gene product. Since 1999, positional cloning has revealed novel genes—such as those for Tangier disease, sitosterolemia, and autosomal recessive (AR) hypercholesterolemia (ARH). Rather than describing in depth any particular pathway, this review will attempt to position newer genetic findings within the context of prior knowledge of plasma lipoprotein metabolism.Table 1Monogenic Disorders Affecting Plasma LipoproteinsLipoprotein Profile and GeneGene ProductDisease(s)Cholesterol: LDL: Increased: LDLR (MIM 143890)LDL receptorAD FH APOB (MIM 107730)apo BFDB ARH (MIM 603813)ARHAR FH LIPA (MIM 278000)Lysosomal lipaseWolman disease, cholesteryl-ester–storage disease Decreased: MTP (MIM 157147)MTPABL APOB (MIM 107730)apo BHypobetalipoproteinemia SLC10A2 (MIM 601295)ASBTPrimary BA malabsorption HDL: Decreased: APOA1 (MIM 107680)apo AIAnalphalipoproteinemia LCAT (MIM 245900)LCATFish-eye disease, familial LCAT deficiency ABCA1 (MIM 600046)ABCA1Tangier disease, familial hypoalphalipoproteinemia Increased: CETP (MIM 118470)Cholesteryl-ester–transfer proteinCETP deficiency LIPC (MIM 151670)HLHL deficiencyTriglycerides: APOC2 (MIM 207750)APOC2APOC2 deficiency, hyperchylomicronemia LPL (MIM 238600)LPLLPL deficiency, hyperchylomicronemiaRemnants and IDL: APOE (MIM 107741)apo EDysbetalipoproteinemia LIPC (MIM 151670)HLHL deficiencySitosterol: ABCG5 (MIM 605459)ATP-binding cassette, subfamily G, member 5Sitosterolemia ABCG8 (MIM 605460)ATP-binding cassette, subfamily G, member 8Sitosterolemia Open table in a new tab The most clinically relevant plasma lipids are cholesterol and triglyceride (TG). Cholesterol in particular has captivated generations of researchers: cholesterol-related discoveries serve as scientific milestones for the 20th century (Vance and van den Bosch Vance and van den Bosch, 2000Vance DE van den Bosch H Cholesterol in the year 2000.Biochim Biophys Acta. 2000; 1529: 1-8Crossref PubMed Scopus (47) Google Scholar). Cholesterol is a structural component of cell membranes and is the precursor of steroid hormones and vitamin D and also of oxysterols and bile acids (BA), which activate nuclear-hormone receptors involved in sterol metabolism (Russell Russell, 1999Russell DW Nuclear orphan receptors control cholesterol catabolism.Cell. 1999; 97: 539-542Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Cholesterol is also required for activation of sonic hedgehog, which is involved with forebrain patterning (Parisi and Lin Parisi and Lin, 1998Parisi MJ Lin H The role of the hedgehog/patched signaling pathway in epithelial stem cell proliferation: from fly to human.Cell Res. 1998; 8: 15-21Crossref PubMed Google Scholar). But cholesterol also has a dark side. For instance, cholesterol entrapped within arterial-wall macrophages leads to foam-cell formation and plaque growth. In men, a rise in total plasma cholesterol from 5.2 to 6.2 mmol/liter (from 200 to 240 mg/dl) is associated with a threefold-increased risk of death from CHD (Stamler et al. Stamler et al., 2000Stamler J Daviglus ML Garside DB Dyer AR Greenland P Neaton JD Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.JAMA. 2000; 284: 311-318Crossref PubMed Google Scholar). Lipoproteins are spherical macromolecules that transport cholesterol and TG—in addition to phospholipid (PL), fat-soluble antioxidants and vitamins, and cholesteryl ester (CE)—through plasma, from sites of synthesis and absorption to sites of uptake. Lipoproteins have a nonpolar lipid core with a hydrophilic surface coat containing free cholesterol (FC), PL, and apolipoprotein (apo) molecules. The main TG-carrying lipoproteins are chylomicrons (CM) and very-low-density lipoprotein (VLDL). The main cholesterol-carrying lipoproteins are LDL and HDL. Lipoproteins are distinguished from each other on the basis of size, density, electrophoretic mobility, lipid and protein content, composition, and function (table 2). Lipoprotein metabolism is a complex network of biochemical processes, including assembly, secretion, processing, and catabolism, as shown in figure 1. The liver (fig. 1A), intestine (fig. 1B), and peripheral cells (fig. 1D) are important determinants of plasma lipoproteins (fig. 1C).Table 2Features of Primary Plasma LipoproteinsCholesterol (% wt)Lipoprotein ClassSize (nm)Density (g/ml)Electrophoretic MobilityTG (% wt)PL (% wt)FreeEsterifiedProtein (% wt)Primary Apolipoprotein(s)CM75–1,200.94Origin (cathode)80–953–61–32–41–2A-I, A-IV, B-48, C-I, C-III, EVLDL30–70.94–1.006Pre-β45–6515–204–816–226–10B-100, E, C-I, C-II, C-IIILDL18–301.019–1.063β4–818–246–845–5018–22B-100HDL5–121.063–1.21α2–726–323–515–2045–55A-I, A-II, E Open table in a new tab In the liver (and also in extrahepatic tissues), FC (fig. 1A) is synthesized from acetyl coenzyme A (CoA) (fig. 1A, Ac) by a multistep synthetic pathway, with the last committed step catalyzed by 3-hydroxy-3-methylglutaryl (HMG) CoA reductase. FC can also be (re-)esterified to CE (fig. 1A) by an acyl CoA:cholesterol acyltransferase (ACAT), also called “sterol O-acyltransferase” (SOAT2) (fig. 1A), for incorporation into cytosolic lipid-storage droplets or lipoprotein assembly. Lipoprotein-derived CE can be hydrolyzed to release FC by lysosomal CE hydrolase (CEH) (fig. 1A), also called “lysosomal acid lipase,” and a distinct neutral CEH hydrolyzes cytoplasmic CE. Hepatic FC can be diverted to BA (fig. 1A) synthetic pathway by hydroxylation, for which cholesterol 7-α-hydroxylase (CYP7A1) (MIM 118445) (fig. 1A) is rate limiting. Fat or carbohydrate not required by the liver for energy or synthesis is converted to TG (fig. 1A) by several biosynthetic pathways. The microsomal TG-transfer protein (MTP) (fig. 1A) in hepatocytes directs assembly of CE and TG together with apo B-100 and apo E, to produce VLDL (fig. 1C and table 2) for secretion into plasma. In the intestine, dietary fat is processed prior to absorption; for instance, pancreatic lipase (PNLIP) (MIM 246600) (fig. 1B) hydrolyzes dietary TG to liberate free fatty acid (FFA) (fig. 1B), which is absorbed both passively and actively. BA (fig. 1A) from liver is secreted and subsequently reabsorbed through specific mediators. BA permits absorption of lumenal FC (fig. 1B). The ABCG5 and ABCG8 half-transporters (fig. 1B) may also re-excrete absorbed FC, in addition to plant sterols such as sitosterol (fig. 1B, S). Intestinal ABCA1 (fig. 1B) also mediates re-excretion of absorbed FC into the bowel lumen. There is likely to be redundancy between the ABCA1, ABCG5, and ABCG8 pathways for intestinal FC absorption. Within enterocytes, processing by SOAT2 (fig. 1B) and TG biosynthetic pathways prepare CE and TG, respectively, for MTP-mediated assembly (fig. 1B) with apo B-48 and apo E into CM (fig. 1C), which is the main lipoprotein carrying fat of exogenous origin secreted into lymph and plasma. Within the capillaries of adipose tissue and muscle, CM and VLDL core TG are hydrolyzed to FFA by endothelial-bound lipoprotein lipase (LPL) (fig. 1C), which uses apo CII (APOC2) (fig. 1C) as a cofactor. FFAs are either re-esterified and stored as TG in fat cells or oxidized to provide energy in muscle. CM and VLDL are remodeled into the short-lived, smaller, denser, more CE-rich CM remnants (CMR) (fig. 1C) and intermediate-density lipoprotein (IDL) (fig. 1C), respectively. CMR and some IDL are cleared by apo E-mediated endocytosis through hepatic-remnant receptors (fig. 1A), contributing to the hepatic CE pool (fig. 1A). IDL that is not cleared is then hydrolyzed by hepatic lipase (HL) (fig. 1C, LIPC), making smaller, CE-rich LDL particles (fig. 1C). Approximately 70% of total plasma cholesterol is partitioned into LDL (fig. 1C). LDL is actually a spectrum of particles whose main lipid is CE and whose defining protein moiety is a single molecule of apo B-100 (table 2). LDL is principally responsible for cholesterol transport into peripheral tissues. LDL has a plasma half-life of ∼3 d and is cleared by the binding of apo B-100 to hepatocyte LDLR (fig. 1A), clustering in coated pits, internalization by RME, and degradation in lysosomes. The ARH product (fig. 1A) probably interacts with the LDLR. After RME, apo B-100–containing lipoproteins are processed through lysosomes, and freed cholesterol enters the cellular pool. As hepatic FC increases, LDLR transcription is suppressed, RME is reduced, and plasma LDL rises. Chronic excess LDL alters arterial endothelial function. LDL that does not undergo regulated RME is taken up in an unregulated manner by scavenger receptors (such as CD36 and SRA-I/II; not shown in fig. 1) on arterial-wall macrophages. Entrapped LDL lipids can become oxidized, generating toxic intermediates that induce cytokine production and chemotaxis of inflammatory cells (Ross Ross, 1999Ross R Atherosclerosis--an inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (13535) Google Scholar). Arterial-wall macrophages can become engorged with cholesterol from LDL, creating foam cells, which are a key component of atherogenic plaques (Ross Ross, 1993Ross R The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-809Crossref PubMed Scopus (7854) Google Scholar). Apolipoproteins provide plasma lipoproteins with structural stability and solubility. They also serve as ligands for receptors and/or as activators for enzymes. Apo B-100 of VLDL, IDL, and LDL (fig. 1C) is synthesized in the liver, whereas apo B-48 of CM and CMR (fig. 1C) is synthesized in the small intestine. Both apo B-100 (4,356 amino acids) and apo B-48 (2,152 amino acids) are APOB (MIM 107730) products. Apo B-48 mRNA is produced by editing of the apo B-100 mRNA (Hodges and Scott Hodges and Scott, 1992Hodges P Scott J Apolipoprotein B mRNA editing: a new tier for the control of gene expression.Trends Biochem Sci. 1992; 17: 77-81Abstract Full Text PDF PubMed Google Scholar), mediated by a 27-kD editase (APOBEC1) (MIM 600130). Other apolipoproteins represented in figure 1C are APOC2 (a cofactor for LPL), apo E (a ligand for RME), and apo AI (an activator of LCAT). RCT describes cholesterol transport from peripheral cells back to the liver, for secretion in bile (Glomset Glomset, 1980Glomset JA High-density lipoproteins in human health and disease.Adv Intern Med. 1980; 25: 91-116PubMed Google Scholar). The liver and small intestine produce nascent HDL particles (fig. 1C), which attract excess FC both from extrahepatic cells and from other circulating lipoproteins. Within peripheral cells, SOAT1 and CEH (fig. 1D) maintain the balance between FC and CE. PL (fig. 1D) and FC (fig. 1D) that accumulate in the intimal layer of the arteries are transferred to apo AI (fig. 1C) of nascent HDL, a process mediated by the ABCA1 (fig. 1D). Using apo AI as a cofactor, plasma lecithin:cholesterol acyltransferase (LCAT) (fig. 1C) converts FC to CE, providing a source of core lipid and thus supporting plasma HDL levels. Plasma CE-transfer protein (CETP) (fig. 1C) and PL-transfer protein (PLTP) (MIM 172425) (fig. 1C) modify HDL by shuttling CE and PL between HDL and TG-rich lipoproteins (fig. 1C, VLDL and CM), and these lipoproteins are rapidly cleared by the liver, as described above. HL (encoded by LIPC, as shown in fig. 1D) hydrolyzes HDL TG, thus reducing HDL size. HDL delivers cholesterol to the liver, and scavenger-receptor BI (fig. 1A, SRBI) mediates selective uptake of lipids. Macrophages ingest large amounts of lipoprotein-derived cholesterol and cannot down-regulate uptake in response to cholesterol loading (Brown and Goldstein Brown and Goldstein, 1983Brown MS Goldstein JL Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis.Annu Rev Biochem. 1983; 52: 223-261Crossref PubMed Google Scholar). Macrophage receptors for oxidized LDL (such as CD36 and SR-AI/II; not shown in fig. 1) can be regulated, but not by cholesterol (Nicholson et al. Nicholson et al., 2000Nicholson AC Febbraio M Han J Silverstein RL Hajjar DP CD36 in atherosclerosis: the role of a class B macrophage scavenger receptor.Annu N Y Acad Sci. 2000; 902: 128-131Crossref PubMed Google Scholar; van Berkel et al. van Berkel et al., 2000van Berkel TJ Van Eck M Herijgers N Fluiter K Nion S Scavenger receptor classes A and B: their roles in atherogenesis and the metabolism of modified LDL and HDL.Ann N Y Acad Sci. 2000; 902: 113-126Crossref PubMed Google Scholar). Consequently, to prevent lipid accumulation, macrophages depend on cholesterol efflux through transfer to HDL. HDL particles can be defined on the basis of either size (table 2) or protein composition (Leroy et al. Leroy et al., 1993Leroy A Toohill KL Fruchart JC Jonas A Structural properties of high density lipoprotein subclasses homogeneous in protein composition and size.J Biol Chem. 1993; 268: 4798-4805Abstract Full Text PDF PubMed Google Scholar). In addition to RCT, HDL might (1) suppress cytokine-induced adhesion of endothelial cells, (2) protect LDL from oxidation, and/or (3) have anticoagulant effects (Lusis Lusis, 2000Lusis AJ Atherosclerosis.Nature. 2000; 407: 233-241Crossref PubMed Scopus (2552) Google Scholar; Tall and Wang Tall and Wang, 2000Tall AR Wang N Tangier disease as a test of the reverse cholesterol transport hypothesis.J Clin Invest. 2000; 106: 1205-1207Crossref PubMed Google Scholar). An enormous body of literature indicates that risk of CHD is directly related to plasma total- and LDL-cholesterol concentration (Stamler et al. Stamler et al., 2000Stamler J Daviglus ML Garside DB Dyer AR Greenland P Neaton JD Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.JAMA. 2000; 284: 311-318Crossref PubMed Google Scholar) and inversely related to plasma HDL-cholesterol concentration (Rhoads et al. Rhoads et al., 1976Rhoads GG Gulbrandsen CL Kagan A Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men.N Engl J Med. 1976; 294: 293-298Crossref PubMed Google Scholar; Stamler et al. Stamler et al., 2000Stamler J Daviglus ML Garside DB Dyer AR Greenland P Neaton JD Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.JAMA. 2000; 284: 311-318Crossref PubMed Google Scholar). HDL cholesterol <0.9 mmol/liter (<35 mg/dl) is an independent risk factor for CHD: low HDL is the most common dyslipidemia in patients with CHD who are age 600 reported LDLR mutations that reduce LDLR number and/or activity (see The Low Density Lipoprotein Receptor (LDLR) Gene in Familial Hypercholesterolemia web site). In most populations, FH heterozygotes and homozygotes have frequencies of ∼1:500 and ∼1:106, respectively, with higher frequencies in some ethnic groups, due to founder effects. Because of the gene-dosage relationship with phenotypic severity, FH can also be considered as an autosomal codominant disorder. FH homozygotes have up to eightfold-increased plasma LDL, with prominent tissue deposits of cholesterol (xanthomata), and CHD as early as childhood. FH heterozygotes have approximately threefold-increased plasma LDL, with xanthomata, and greatly increased risk of CHD in mid adulthood (Simon Broome Register Group Simon Broome Register Group, 1991Simon Broome Register Group Risk of fatal coronary heart disease in familial hypercholesterolaemia.BMJ. 1991; 303: 893-896Crossref PubMed Google Scholar). DNA analysis may complement clinical and biochemical diagnosis of FH (Williams et al. Williams et al., 1993Williams RR Hunt SC Schumacher MC Hegele RA Leppert MF Ludwig EH Hopkins PN Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics.Am J Cardiol. 1993; 72: 171-176Abstract Full Text PDF PubMed Google Scholar). Environment (Williams et al. Williams et al., 1986Williams RR Hasstedt SJ Wilson DE Ash KO Yanowitz FF Reiber GE Kuida H Evidence that men with familial hypercholesterolemia can avoid early coronary death: an analysis of 77 gene carriers in four Utah pedigrees.JAMA. 1986; 255: 219-224Crossref PubMed Google Scholar; Sijbrands et al. Sijbrands et al., 2001Sijbrands EJ Westendorp RG Defesche JC de Meier PH Smelt AH Kastelein JJ Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study.BMJ. 2001; 322: 1019-1023Crossref PubMed Google Scholar) and other genes (Emi et al. Emi et al., 1991Emi M Hegele RA Hopkins PN Wu LL Plaetke R Williams RR Lalouel JM Effects of three genetic loci in a pedigree with multiple lipoprotein phenotypes.Arterioscler Thromb. 1991; 11: 1349-1355Crossref PubMed Google Scholar) can modulate the clinical severity of FH. A second monogenic AD disorder causing elevated LDL cholesterol, called “familial defective apo B-100” (FDB), results from missense mutations in APOB that affect binding to LDLR (Myant Myant, 1993Myant NB Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia.Atherosclerosis. 1993; 104: 1-18Abstract Full Text PDF PubMed Google Scholar). In Europeans, heterozygous FDB has a prevalence of ∼1:1,000 and is clinically milder than heterozygous FH (Myant Myant, 1993Myant NB Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia.Atherosclerosis. 1993; 104: 1-18Abstract Full Text PDF PubMed Google Scholar). A third monogenic disorder causing elevated LDL cholesterol, ARH, has been characterized recently (Garcia et al. Garcia et al., 2001Garcia CK Wilund K Arca M Zuliani G Fellin R Maioli M Calandra S Bertolini S Cossu F Grishin N Barnes R Cohen JC Hobbs HH Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.Science. 2001; 292: 1394-1398Crossref PubMed Scopus (268) Google Scholar). ARH is distinct from homozygous FH, because parents have normal plasma LDL cholesterol, unlike the parents of FH homozygotes, who have elevated LDL. Children and adolescents with ARH have severe hypercholesterolemia, with skin findings and early CHD. ARH was initially mapped to chromosome 1p35 (Zuliani et al. Zuliani et al., 1995Zuliani G Vigna GB Corsini A Maioli M Romagnoni F Fellin R Severe hypercholesterolaemia: unusual inheritance in an Italian pedigree.Eur J Clin Invest. 1995; 25: 322-331Crossref PubMed Google Scholar, Zuliani et al., 1999Zuliani G Arca M Signore A Bader G Fazio S Chianelli M Bellosta S Campagna F Montali A Maioli M Pacifico A Ricci G Fellin R Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.Arterioscler Thromb Vasc Biol. 1999; 19: 802-809Crossref PubMed Google Scholar). Mutant ARH (MIM 605747) encodes a putative adapter protein, which might facilitate LDLR movement into coated pits (fig. 1A) (Goldstein and Brown Goldstein and Brown, 2001Goldstein JL Brown MS The cholesterol quartet.Science. 2001; 292: 1310-1312Crossref PubMed Scopus (140) Google Scholar). Interestingly, mutant ARH was found in one family in which a locus on 15q25-q26 previously had been demonstrated (Ciccarese et al. Ciccarese et al., 2000Ciccarese M Pacifico A Tonolo G Pintus P Nikoshkov A Zuliani G Fellin R Luthman H Maioli M A new locus for autosomal recessive hypercholesterolemia maps to human chromosome 15q25-q26.Am J Hum Genet. 2000; 66: 453-460Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). Additional genetic heterogeneity for elevated LDL cholesterol has been suggested by reports of a new locus for AD FH (Haddad et al. Haddad et al., 1999Haddad L Day INM Hunt S Williams RR Humphries SE Hopkins PN Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred.J Lipid Res. 1999; 40: 1113-1122PubMed Google Scholar; Hunt et al. Hunt et al., 2000Hunt SC Hopkins PN Bulka K McDermott MT Thorne TL Wardell BB Bowen BR Ballinger DG Skolnick MH Samuels ME Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.Arterioscler Thromb Vasc Biol. 2000; 20: 1089-1093Crossref PubMed Google Scholar). Also, sequencing of LDLR in 60 subjects with clinical AD FH has indicated that ∼40% had neither an LDLR mutation nor an FDB mutation (Wang et al. Wang et al., 2001Wang J Huff E Janecka L Hegele RA Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent.Hum Mutat. 2001; 18: 359Crossref PubMed Google Scholar), a finding consistent with genetic heterogeneity. Finally, mutant LIPA encoding lysosomal cholesterol hydrolase (lysosomal acid lipase) underlies both Wolman disease (MIM 278000) and the milder CE-storage disease (CESD) (Anderson et al. Anderson et al., 1994Anderson RA Byrum RS Coates PM Sando GN Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease.Proc Natl Acad Sci USA. 1994; 91: 2718-2722Crossref PubMed Google Scholar), both of which have elevated plasma LDL, which is also consistent with genetic heterogeneity for the elevated-LDL-cholesterol phenotype. The archetypal disorder of LDL deficiency is abetalipoproteinemia (ABL) (MIM 200100), a very rare (frequency ∼1:106) AR disease defined by the absence of apo B-100–containing lipoproteins, giving very low plasma cholesterol and TG (Rader and Brewer Rader and Brewer, 1993Rader DJ Brewer Jr, HB Abetalipoproteinemia.JAMA. 1993; 270: 865-869Crossref PubMed Google Scholar). ABL was described in patients with acanthocytosis, spinocerebellar degeneration, and atypical retinitis pigmentosa (Bassen and Kornzweig Bassen and Kornzweig, 1950Bassen FA Kornzweig AL Malformation of the erythrocytes in a case of atypical retinitis pigmentosa.Blood. 1950; 5: 381-387Crossref PubMed Google Scholar). Mutations in MTP (MIM 157147) cause ABL (Wetterau et al. Wetterau et al., 1992Wetterau JR Aggerbeck LP Bouma ME Eisenberg C Munck A Hermier M Schmitz J Gay G Rader DJ Gregg RE Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.Science. 1992; 258: 999-1001Crossref PubMed Google Scholar; Narcis et al. Narcis et al., 1995Narcis TME Shoulders CC Chester SA Read J Brett DJ Harrison GB Grantham TT Fox MF Povey S de Bruin TWA Erkelens DW Muller DPR Lloyd JK Scott J Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia.Am J Hum Genet. 1995; 57: 1298-1310PubMed Google Scholar). MTP in the liver (fig. 1A) and intestine (fig. 1B) is required for assembly and secretion of apo B–containing lipoproteins (Wetterau et al. Wetterau et al., 1991Wetterau JR Aggerbeck LP Laplaud PM McLean LR Structural properties of the microsomal triglyceride-transfer-protein complex.Biochemistry. 1991; 30: 4406-4412Crossref PubMed Google Scholar). MTP is a heterodimer composed of the multifunctional enzyme protein disulfide isomerase (PDI) and a 97-kD subunit. PDI appears necessary to maintain the structural integrity of MTP; however, no mutations in PDI have been reported. Homozygous familial hypobetalipoproteinemia (FHBL1) (MIM 107730) is another AR disorder of LDL deficiency, and it is caused by APOB mutations affecting the integrity of the LDL particle (Schonfeld Schonfeld, 1995Schonfeld G Genetic variation of apolipoprotein B can produce both low and high levels of apo B-containing lipoproteins in plasma.Can J Cardiol. 1995; 11: 86G-92GPubMed Google Scholar). FHBL1 is distinct from ABL because parents have half-normal plasma apo B-100 and LDL cholesterol, unlike the parents of ABL homozygotes, who have no lipoprotein abnormalities. In both ABL and FHBL1, subjects develop fa
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