PC9, A New Actor in Autosomal Dominant Hypercholesterolemia

Delphine      Allard; Marianne      Abifadel; Jean-Pierre      Rabes; Mathilde      Varret

doi:10.2174/138920205775067729

Abstract

First named Narc-1 (Neural apoptosis regulated convertase 1), PC9 is the ninth member of the family of proprotein convertases. This newly identified human subtilase contributes to cholesterol homeostasis and mutations in its gene, PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9), are responsible for Autosomal Dominant Hypercholesterolemia. This is the first example of a dominant disease associated with a defect in a member of the convertase family. Hypercholesterolemia is a main risk factor of atherosclerosis and its vascular complications. In the general population, about 1 person out of 20 presents high plasma LDL-cholesterol. In particular, familial forms with autosomal dominant transmission affect about 1 person out of 500. Until recently, mutations in only two genes were associated with the disease: the LDLR gene encoding a transmembrane receptor implicated in endocytosis and degradation of circulating LDL, and the APOB gene encoding the main ligand of this receptor present at LDL surface. Pathophysiology of these two main forms of the disease has been extensively studied and is well understood. In 1999, two teams simultaneously published hypercholesterolemic families presenting neither LDLR nor APOB defects and, in 2003, a third major gene involved in Autosomal Dominant Hypercholesterolemia, PCSK9, was identified. To date, no substrate of PC9 has been found except itself. The purpose of the present review is to compile all reported data and current knowledge on PC9 and hypotheses of its role in cholesterol homeostasis and in pathophysiology of hypercholesterolemia.

Keywords: Autosomal Dominant Hypercholesterolemia, PCSK9, PC9, Narc-1, proprotein convertase, LDL receptor, SREBP, VLDL