Monogenic Hypercholesterolemia: Genetics


Several specific genes, when mutated, cause high blood cholesterol levels, with consequent early atherosclerosis and coronary events. The classical example and commonest defects involves the low‐density lipoprotein receptor (LDLR) gene, haploinsufficiency of which leads to slow LDL‐cholesterol clearance and homozygous mutation of which leads to extreme hypercholesterolaemia and coronary disease during childhood. Familial defective apolipoprotein B (FDB) involving APOB transmits as an autosomal dominant trait with incomplete penetrance and affects ApoB, the ligand within LDL particles for the receptor. PCSK9 also transmits as an autosomal dominant trait, with high penetrance. PCSK9, proprotein convertase subtilisin kexin type‐9, is secreted and by binding to the LDL receptor promotes receptor degradation, gain‐of‐function mutations increasing binding and reducing receptor availability. LDLRAP1, a clathrin adaptor protein, if defective on both alleles, causes autosomal recessive hypercholesterolaemia in which there is failure to internalise the receptor. Knowledge of these new genes has identified new targets for pharmaceutical developments and mutation analysis has contributed diagnostically to cascade screening now in use to identify and offer preventive treatment.

Key Concepts:

  • Single gene mutations can cause inherited familial patterns of hypercholesterolaemia.

  • The monogenic hypercholesterolaemias all involve genes encoding products participating in the pathway of LDL particle clearance by the LDL receptor.

  • LDLR defects represent a genocopy for the phenotype of dietary hypercholesterolaemia and offer inference about the causal role of population hypercholesterolaemia in coronary risk.

  • Four genes are known which can cause an inherited hypercholesterolaemia, these are LDLR, APOB, PCSK9 and LDLRAP1.

  • The patterns of inheritance differ, LDLR, APOB and PCSK9 causing autosomal dominant hypercholesterolaemia, LDLRAP1 causing autosomal recessive hypercholesterolaemia.

  • Mutations in PCSK9 mutations involve gain‐of‐function, whereas LDLR, APOB and LDLRAP1mutations involve loss of function.

  • PCSK9 in particular represents a potential novel target for new pharmaceutical development of cholesterol lowering drugs.

  • Mutation knowledge and mutation identification now support cascade screening to identify and offer treatment to individuals at high risk of early coronary disease.

Keywords: hypercholesterolaemia; LDL receptor; apolipoprotein B; atherosclerosis; coronary disease


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Web Links

Apolipoprotein B (Including Ag(x) Antigen) (APOB); Locus ID: 338. LocusLink:

Apolipoprotein B (Including Ag(x) Antigen) (APOB); MIM Number: 107730. OMIM:‐post/Omim/dispmim?107730

Apolipoprotein E (APOE); Locus ID: 348.

Apolipoprotein E (APOE); MIM number: 107741. OMIM:‐post/Omim/dispmim?107741

Low Density Lipoprotein Receptor (Familial Hypercholesterolemia) (LDLR); Locus ID: 3949. LocusLink:

Low Density Lipoprotein Receptor (Familial Hypercholesterolemia) (LDLR); MIM Number: 606945. OMIM:‐post/Omim/dispmim?606945

The Low Density Lipoprotein Receptor (LDLR) Gene in Familial Hypercholesterolemia. Compilation of LDLR Sequence, Structure, Mutations, Polymorphisms and other Molecular Genetic Data and Links.

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Day, Ian N M(Aug 2011) Monogenic Hypercholesterolemia: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005940.pub2]