Mechanisms of Disease: genetic causes of familial hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, commonly caused by a loss-of-function mutation in the LDL-receptor gene (LDLR) or by a mutation in the gene encoding apolipoprotein B (APOB). FH is primarily an autosomal dominant disorder with a gene–dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDLRAP1, which encodes a protein required for clathrin-mediated internalization of the LDL receptor by liver cells, has also been documented. The most recent addition to the database of genes in which defects cause FH is one encoding a member of the proprotein convertase family, PCSK9. Rare dominant gain-of-function mutations in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally downregulates the LDL-receptor pathway by indirectly causing degradation of LDL-receptor protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus, PCSK9 is an attractive target for new drugs aimed at lowering serum LDL cholesterol, which should have additive lipid-lowering effects to the statins currently used.

Key Points

  • Familial hypercholesterolemia (FH) is usually inherited as an autosomal dominant disorder caused by defective clearance of LDL from the circulation that occurs with a frequency of about 1/500

  • Pioneering studies by Brown and Goldstein revealed that FH was usually caused by defective function of a cell-surface receptor for LDL caused by mutations in LDLR

  • Subsequent work has revealed that there are numerous different mutations in the LDL-receptor protein, but these do not explain the variability in the severity of clinical symptoms in heterozygous patients, and the fact that environmental factors are also important

  • Not all patients with clinical FH have mutations in LDLR; mutations in APOB, PCSK9 and LDLRAP1 can affect LDL-receptor function in vivo

  • Diagnosis of FH is important to reduce premature coronary heart disease, but genetic screening for FH is hampered by the large number of different mutations

  • Cascade screening of affected relatives of index patients has already increased rates of diagnosis and treatment of FH in some countries; population screening, however, is probably not cost-effective

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Figure 1: Dominant pattern of inheritance of familial hypercholesterolemia due to mutations in the LDL-receptor gene (LDLR)
Figure 2: The LDL-receptor pathway for uptake and degradation of LDL
Figure 3: The LDLR gene
Figure 4: Autosomal recessive hypercholesterolemia
Figure 5: Severe phenotype in patients heterozygous for the Asp374Tyr mutation in the PCSK9 protein
Figure 6: PCSK9 variants associated with plasma LDL cholesterol concentration

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Correspondence to Anne K Soutar.

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Soutar, A., Naoumova, R. Mechanisms of Disease: genetic causes of familial hypercholesterolemia. Nat Rev Cardiol 4, 214–225 (2007). https://doi.org/10.1038/ncpcardio0836

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