Research progress of genetic causes of familial hypercholesterolemia(FH)

Familial hypercholesterolemia(FH) is characterized by raised serum low density lipoprotein cholesterol(LDL-c) levels,which result in excess deposition of cholesterol in tissues,and then lead to atherosclerosis and premature coronary heart disease.The mutations of LDL receptor or apoB play main roles in this disease.FH results from defects in the uptake and degradation of LDL via the LDL receptor pathway.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 LDL receptor adaptor protein 1(LDLRAP1),which encodes a protein required for internalization of the LDL receptor(LDLR).Rare gain-of-function mutations in proprotein convertase subtilisin/kexin type 9(PCSK9) cosegregate with hypercholesterolemia,and one mutation is associated with a particularly severe FH phenotype.Expression of PCSK9 normally down-regulates the LDLR pathway by indirectly causing degradation of LDLR protein,and loss-of-function mutations in PCSK9 result in low plasma LDL levels.Thus,PCSK9 is an attractive target for hypolipidemic drugs.