title: 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.
authors: Lipoprotein Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK. anne.soutar@csc.mrc.ac.uk
authors: Anne K
authors: AK
authors: Soutar
authors: Rossi P
authors: RP
authors: Naoumova
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D053299:Apolipoprotein B-100 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D015994:Incidence; D008077:Lipoproteins, LDL / Q000032:analysis / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011379:Prognosis; D011973:Receptors, LDL / Q000235:genetics*; D018570:Risk Assessment; D012720:Severity of Illness Index; D012737:Sex Factors
chemical_list: D053299:Apolipoprotein B-100; D008077:Lipoproteins, LDL; D011973:Receptors, LDL