LDL Receptor and Its Role in Inherited Disease


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′‐ (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 β‐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. .

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., ). 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, ). (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., for references).



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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.

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.

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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]