LDL Receptor and Its Role in Inherited Disease

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

Published online: September 2010

DOI: 10.1002/9780470015902.a0022404

The low-density lipoprotein (LDL) receptor mediates the specific uptake of LDL from the circulation and its intracellular degradation by a process known as the LDL receptor pathway. LDL receptor gene expression is regulated by intracellular sterol content, and is limited mainly to the liver in vivo. Mutations in LDLR, the gene encoding the LDL receptor, cause familial hypercholesterolaemia (FH), a dominantly inherited disease where accumulation of LDL in the circulation increases the risk of coronary heart disease. Defects in other genes, including APOB, encoding the ligand for the LDL receptor, ARH, encoding a protein required for its internalisation and proprotein convertase subtilisin/kexin type 9 (PCSK9), encoding a protein that reduces LDL receptor protein levels, cause a similar disorder because the encoded proteins are involved in the LDL receptor pathway. FH can readily be treated with cholesterol-lowering drugs to reduce cardiovascular risk effectively, and identification of the causal genetic defect allows unequivocal and early diagnosis.

Key Concepts:

  • The LDL receptor mediates specific uptake and intracellular degradation of serum LDL.
  • Inherited defects in the LDL receptor pathway cause familial hypercholesterolaemia (FH), characterised by increased serum LDL and increased risk of coronary heart disease.
  • Most FH patients have mutations in LDLR, but defects in other genes cause a similar disorder.
  • A recessive form of FH is caused by null mutations in ARH, a clathrin adaptor protein required for LDL receptor internalisation.
  • A dominant form of FH is caused by gain-of-function mutations in PCSK9, which encodes a protein that promotes degradation of LDL receptor protein.
  • Dominant loss-of-function mutations in PCSK9 reduce serum cholesterol and risk of coronary heart disease.
  • One relatively common dominant mutation in APOB, encoding the ligand for the LDL receptor, causes familial defective apoB (FDB).
  • LDLR transcription is regulated by sterol response element-binding proteins (SREBP) in a complex mechanism involving several other proteins.
  • FH can readily be treated with cholesterol-lowering drug therapy to abolish the increased risk of coronary disease, but is currently under-diagnosed.
  • Identifying causal mutations in known patients and screening their relatives should identify more affected individuals.

Keywords: LDL receptor; familial hypercholesterolaemia; coronary heart disease; receptor-mediated endocystosis; autosomal dominant; sterol-mediated regulation; PCSK9; autosomal recessive hypercholesterolaemia; apolipoprotein B; lipoprotein metabolism

Figure 1. The LDL receptor pathway. The LDL receptor is synthesised in the ER and transported to the Golgi where cotranslationally added O- and N-linked sugars are modified (1), after which the LDL receptor is translocated and inserted on the basolateral surface of the hepatocyte (2). On the cell surface, the receptor binds LDL (3) and the ligand/receptor complex is internalised via clathrin-coated vesicles into endosomes (4). In the acidic environment of the endosomes, the complex dissociates (5) and the receptor recycles to the cell surface (6), whereas the LDL is degraded in lysosomes. LDL receptors on the cell surface can also bind circulating PCSK9 (8), and the complex is internalised (9); PCSK9 does not dissociate in the late endosomes and the entire receptor ligand complex is degraded (10). See text for further details.
Figure 2. Diagram of the LDL receptor gene and protein. (a) The LDL receptor gene (LDLR) comprises 18 exons (vertical black bars), the last of which encodes a long 3¢-untranslated region (UTR). The primary RNA transcript is spliced to form a 5.3 Kb mRNA (b), of which about half encodes the LDL receptor protein. The 3¢ UTR of the mRNA contains AU-rich elements that interact with RNA-binding proteins to stabilise the mRNA. The mRNA is translated to produce a protein of 837 amino acid residues (c), composed of five distinct structural and functional domains, as indicated below the protein. Each domain is encoded by an exon or group of exons, as indicated by horizontal arrows above the gene. The signal peptide directs the newly synthesised protein for export, and is cleaved from the mature protein. The ligand-binding domain contains seven similar repeats, in which structural integrity is maintained by three disulfide links. The epidermal growth factor (EGF)-precursor-like domain contains three growth factor repeats, each with three internal disulfide links; these are similar to but distinct from the repeats in the binding domain. The central part of the EGF-precursor-like domain contains five repeats characterised by the motif YWTD, that fold to form a -propeller structure. The serine- and threonine-rich O-linked sugars domain is the site of O-linked glycosylation. The cytoplasmic domain contains the NPVY motif required for internalisation of the receptor, and three potential ubiquitination sites. Sterol-regulated transcription of the LDL receptor gene requires an intact proximal promoter (d), comprising three imperfect direct repeats, two of which bind the general transcription factor SP1, whereas repeat two binds SREBP via the sterol response element (SRE), indicated in bold.
Figure 3. A mutation and a rare silent variant in LDLR in the same family. The proband in the family, indicated with an arrow in the pedigree (a), has severe hypercholesterolaemia (total serum cholesterol values shown below each symbol), as does her sister and three of her four sons. All of them have inherited a mutant allele of LDLR that is predicted to cause the substitution L458P in the protein (b). This residue is strongly conserved in all species (c). The spouse of the index patient carries a rare variant allele of LDLR that is predicted to cause the substitution G198D (b) that has been inherited by two of his sons (a). This allele was first identified in one of the sons and was thought to be casual of defective LDL receptor function; however, although very rare and causing a nonconservative substitution, it does not co-segregate with hypercholesterolaemia in the family (a) and is not conserved between species (c). Modified from Naoumova et al. (2004b).
Figure 4. A splicing defect caused by a ‘silent’ coding mutation. Diagram of exons 8–10 of the LDLR, indicating the splice acceptor site between intron 8 and exon 9 (a). A patient with a clinical diagnosis of heterozygous FH was found by sequencing of genomic DNA to have a variant of LDLR (CGG to AGG) that was not predicted to cause an amino acid substitution because both code for Arg (b). However, analysis of mRNA from cultured cells from the patient revealed a heterozygous deletion of 31 bp at the start of the region encoded by exon 9 of the LDLR mRNA (modified from Bourbon et al., 2007). The single base substitution introduces a new splice site that is used exclusively in preference to the normal splice site at the start of exon 9; the consensus sequence surrounding the site has a higher calculated ‘score’ for splicing (http://rulai.cshl.edu/new_alt_exon_db2/HTML/score.html).
Figure 5. Mutations in ARH and PCSK9 in FH patients. (a) Diagram of ARH protein, indicating its different functional domains: the phosphotyrosine-binding (PTB) domain binds to the cytoplasmic tail of the LDL receptor, although it does not require it to be phosphorylated. (b) Diagram of the ARH (LDLRAP1) gene, which comprises 9 exons, indicated as black boxes. Mutations identified in ARH patients are indicated above and below the gene; most of these introduce premature termination codons, either directly or as the result of a frameshift caused by an insertion (ins) or deletion (del); one splice site mutation results in an in-frame deletion of 26 amino acid residues in the PTB domain (grey text) (modified from Soutar and Naoumova, 2007). (c) Diagram showing functional domains of PCSK9 protein. Newly synthesised PCSK9 undergoes intracellular autocleavage and is then secreted from the cell; the cleaved prodomain remains tightly associated. Genetic variants associated with hypercholesterolaemia are shown above; those in bold type were found in patients with FH. Variants associated with reduced serum cholesterol are shown below the protein; those shown in bold type have strong effects on serum cholesterol in all carriers (see Horton et al., 2009 for references).
close
 References
    Abifadel M, Varret M, Rabes JP et al. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolaemia. Nature Genetics 34: 154–156.
    Bilheimer DW, Grundy SM, Brown MS and Goldstein JL (1983) Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolaemia heterozygotes. Procedings of the National Academy of Sciences of the USA 80: 4124–4128.
    Bourbon M, Sun XM and Soutar AK (2007) A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing. Atherosclerosis 195: e17–e20.
    Bradley WA, Hwang SL, Karlin JB et al. (1984) Low-density lipoprotein receptor binding determinants switch from apolipoprotein E to apolipoprotein B during conversion of hypertriglyceridemic very-low-density lipoprotein to low-density lipoproteins. Journal of Biological Chemistry 259: 14728–14735.
    Brown MS and Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–47.
    Cohen J, Pertsemlidis A, Kotowski IK et al. (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genetics 37: 161–165.
    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.
    Cummings RD, Kornfeld S, Schneider WJ et al. (1983) Biosynthesis of N- and O-linked oligosaccharides of the low density lipoprotein receptor. Journal of Biological Chemistry 258: 15261–15273.
    Cunningham D, Danley DE, Geoghegan KF et al. (2007) Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolaemia. Nature Structural and Molecular Biology 14: 413–419.
    Davis CG, van Driel IR, Russell DW, Brown MS and Goldstein JL (1987) The low density lipoprotein receptor. Identification of amino acids in cytoplasmic domain required for rapid endocytosis. Journal of Biological Chemistry 262: 4075–4082.
    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 hypercholesterolaemia. Arteriosclerosis, Thrombosis and Vascular Biology 24: 1454–1459.
    Duff CJ, Scott MJ, Kirby IT et al. (2009) Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor. Biochemical Journal 419: 577–584.
    Fasano T, Sun XM, Patel DD and Soutar AK (2009) Degradation of LDLR protein mediated by ‘gain of function’ PCSK9 mutants in normal and ARH cells. Atherosclerosis 203: 166–171.
    Frank-Kamenetsky M, Grefhorst A, Anderson NN et al. (2008) Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Procedings of the National Academy of Sciences of the USA 105: 11915–11920.
    Goldstein JL, Brown MS, Anderson RG, Russell DW and Schneider WJ (1985) Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annual Reviews of Cell Biology 1: 1–39.
    Goldstein JL, DeBose-Boyd RA and Brown MS (2006) Protein sensors for membrane sterols. Cell 124: 35–46.
    Graham CA, McIlhatton BP, Kirk CW et al. (2005) Genetic screening protocol for familial hypercholesterolaemia which includes splicing defects gives an improved mutation detection rate. Atherosclerosis 182: 331–340.
    Graham MJ, Lemonidis KM, Whipple CP et al. (2007) Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. Journal of Lipid Research 48: 763–767.
    Hobbs HH, Brown MS, Goldstein JL and Russell DW (1986) Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolaemia. Journal of Biological Chemistry 261: 13114–13120.
    Hobbs HH, Russell DW, Brown MS and Goldstein JL (1990) The LDL receptor locus in familial hypercholesterolaemia: mutational analysis of a membrane protein. Annual Reviews of Genetics 24: 133–170.
    Hooper AJ, Marais AD, Tanyanyiwa DM and Burnett JR (2007) The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193: 445–448.
    Horton JD, Cohen JC and Hobbs HH (2009) PCSK9: a convertase that coordinates LDL catabolism. Journal of Lipid Research 50(suppl.): S172–S177.
    Horton JD, Goldstein JL and Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. Journal of Clinical Investigation 109: 1125–1131.
    Humphries SE, Whittall RA, Hubbart CS et al. (2006) Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. Journal of Medical Genetics 43: 943–949.
    Jeon H and Blacklow SC (2005) Structure and physiologic function of the low density lipoprotein receptor. Annual Review of Biochemistry 74: 535–562.
    Jeon H, Meng W, Takagi J et al. (2001) Implications for familial hypercholesterolaemia from the structure of the LDL receptor YWTD-EGF domain pair. Nature Structural Biology 8: 499–504.
    Leigh SE, Foster AH, Whittall RA, Hubbart CS and Humphries SE (2008) Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolaemia database. Annals of Human Genetics 72: 485–498.
    Li H, Chen W, Zhou Y et al. (2009) Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements. Journal of Lipid Research 50: 820–831.
    Marks D, Wonderling D, Thorogood M et al. (2000) Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis. Health Technology Assessment 4: 1–123.
    May P, Woldt E, Matz RL and Boucher P (2007) The LDL receptor-related protein (LRP) family: an old family of proteins with new physiological functions. Annals of Medicine 39: 219–228.
    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.
    Miettinen TA (2001) Cholesterol absorption inhibition: a strategy for cholesterol-lowering therapy. International Journal of Clinical Practice 55: 710–716.
    Minhas R, Humphries SE, Qureshi N and Neil HA (2009) Controversies in familial hypercholesterolaemia: recommendations of the NICE Guideline Development Group for the identification and management of familial hypercholesterolaemia. Heart 95: 584–587.
    Myant NB (1993) Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis 104: 1–18.
    Naoumova RP, Neuwirth C, Lee P et al. (2004c) Autosomal recessive hypercholesterolaemia: long-term follow up and response to treatment. Atherosclerosis 174: 165–172.
    Naoumova RP, Neuwirth C, Pottinger B et al. (2004b) Genetic diagnosis of familial hypercholesterolaemia: a mutation and a rare non-pathogenic amino acid variant in the same family. Atherosclerosis 174: 67–71.
    Naoumova RP, Thompson GR and Soutar AK (2004a) Current management of severe homozygous hypercholesterolaemias. Current Opinion in Lipidology 15: 413–422.
    North CL and Blacklow SC (2000) Solution structure of the sixth LDL-A module of the LDL receptor. Biochemistry 39: 2564–2571.
    Olsson PA, Korhonen L, Mercer EA and Lindholm D (1999) MIR is a novel ERM-like protein that interacts with myosin regulatory light chain and inhibits neurite outgrowth. Journal of Biological Chemistry 274: 36288–36292.
    Soutar AK (2009) Regulation of the LDL receptor in familial hypercholesterolaemia. Clinical Lipidology 4: 755–765.
    Soutar AK and Naoumova RP (2007) Mechanisms of disease: genetic causes of familial hypercholesterolaemia. 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 hypercholesterolaemia. Arteriosclerosis, Thrombosis and Vascular Biology 23: 1963–1970.
    Stalder L and Muhlemann O (2008) The meaning of nonsense. Trends in Cell Biology 18: 315–321.
    Sudhof TC, Goldstein JL, Brown MS and Russell DW (1985) The LDL receptor gene: a mosaic of exons shared with different proteins. Science 228: 815–822.
    Sun XM, Eden ER, Tosi I et al. (2005) Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Human Molecular Genetics 14: 1161–1169.
    Sun XM, Patel DD, Bhatnagar D, Knight BL and Soutar AK (1995) Characterization of a splice-site mutation in the gene for the LDL receptor associated with an unpredictably severe clinical phenotype in English patients with heterozygous FH. Arteriosclerosis, Thrombosis and Vascular Biology 15: 219–227.
    van der Westhuyzen DR, Stein ML, Henderson HE et al. (1991) Deletion of two growth-factor repeats from the low-density-lipoprotein receptor accelerates its degradation. Biochemical Journal 277: 677–682.
    Villeger L, Abifadel M, Allard D et al. (2002) The UMD-LDLR database: additions to the software and 490 new entries to the database. Human Mutation 20: 81–87.
    Webb JC, Patel DD, Shoulders CC, Knight BL and Soutar AK (1996) Genetic variation at a splicing branch point in intron 9 of the low density lipoprotein (LDL)-receptor gene: a rare mutation that disrupts mRNA splicing in a patient with familial hypercholesterolaemia and a common polymorphism. Human Molecular Genetics 5: 1325–1331.
    Whittall RA, Matheus S, Cranston T, Miller GJ and Humphries SE (2002) The intron 14 2140+5G>A variant in the low density lipoprotein receptor gene has no effect on plasma cholesterol levels. Journal of Medical Genetics 39: e57.
    Zelcer N, Hong C, Boyadjian R and Tontonoz P (2009) LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325: 100–104.
 Further Reading
    Abifadel M, Rabès JP, Devillers M et al. (2009) Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Human Mutation 30: 520–529.
    Brown MS and Goldstein JL (2009) Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL. Journal of Lipid Research 50(suppl.): S15–S27.
    book Brown MS, Hobbs HH and Goldstein JL (2001) "Familial hypercholesterolemia". In: Valle D, Scriver CR, Beaudet A, Sly WS, Childs B, Kinzler KW and Volgestein B (eds) The Metabolic and Molecular Bases of Inherited Disease pp. 2863–2913. Or see http://www.ommbid.com/ for The Online Metabolic and Molecular Bases of Inherited Diseases. New York: McGraw Hill.
    Fouchier SW, Kastelein JJ and Defesche JC (2005) Update of the molecular basis of familial hypercholesterolemia in the Netherlands. Human Mutation 26: 550–556.
    Goldstein JL and Brown MS (2009) The LDL receptor. Arteriosclerosis, Thrombosis and Vascular Biology 29: 431–438.

Related Sub-Topics:

Intracellular and Extracellular Signalling | Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders | Posttranslational Modification | Mechanisms of Cell Death, Senescence and Metabolism | General Molecular Biology | Proteins: Structure, Function, Metabolism | Lipids: Structure, Function, Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: LDL Receptor and Its Role in Inherited Disease
 
How to Cite close
Soutar, Anne K(Sep 2010) LDL Receptor and Its Role in Inherited Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022404]