Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia.
OBJECTIVE
Autosomal dominant hypercholesterolemia is a genetic disease in which patients have elevated LDL cholesterol levels and premature atherosclerosis. Mutations in the LDL receptor and its ligand apolipoprotein B are causative for autosomal dominant hypercholesterolemia, and the study of this pathway has been crucial to understanding LDL metabolism and receptor-mediated endocytosis in general. Recently, families were identified with a clinical diagnosis of autosomal dominant hypercholesterolemia, but without linkage to the LDL receptor or apolipoprotein B genes. Identification and study of the causative genes in these families should provide additional insights into LDL metabolism.


RESULTS
Recent microarray studies and database searches identified a novel member of the proprotein convertase family called proprotein convertase subtilisin kexin 9 (PCSK9). A role for PCSK9 in cholesterol metabolism was proposed from the expression studies and confirmed by the discovery that PCSK9 missense mutations were associated with a form of autosomal dominant hypercholesterolemia, Hchola3. The cellular role for PCSK9 and the mechanism behind its mutations are under study, and a role for PCSK9 in regulating LDL receptor protein levels has been demonstrated.


CONCLUSIONS
PCSK9 is the third locus implicated in autosomal dominant hypercholesterolemia (Hchola3), and it appears to play an important role in cellular cholesterol metabolism. Understanding the function of PCSK9 will be important for broadening our knowledge of LDL metabolism and may aid in the development of novel hypocholesterolemic agents.
Maxwell
Kara N
KN
Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY 10021, USA.
Breslow
Jan L
JL
D001055:Apolipoproteins B / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D013261:Sterols / Q000378:metabolism
D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D013261:Sterols; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases