Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease

Abstract

Hypercholesterolemia is one of the major causes of coronary heart disease (CHD). The genes encoding the low-density lipoprotein receptor and its ligand apolipoprotein B, have been the two genes classically implicated in autosomal dominant hypercholesterolemia (ADH). Our discovery in 2003 of the first mutations of the proprotein convertase subtilisin kexin 9 gene (PCSK9) causing ADH shed light on an unknown actor in cholesterol metabolism that since then has been extensively investigated. Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a decreased risk of CHD. In this review, we focus on reported variants, and their biological, clinical, and functional relevance. We also highlight the spectrum of hypercholesterolemia or hypobetalipoproteinemia phenotypes that are already associated with mutations in PCSK9. Finally, we present future prospects concerning this therapeutic target that might constitute a new approach to reduce cholesterol levels and CHD, and enhance the effectiveness of other lipid-lowering drugs.

Novel Domain Interaction Regulates Secretion of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Protein

“…Human genetic studies have suggested that the residues in this region modulate PCSK9 function (6,13,42). Experimental data further showed that deletion of residues 31-53 significantly increases the affinity of PCSK9 for LDLR (30) and that the acidic residues in this region contribute to the effect (32).…”

Pcsk9

“…6,7,15,16 After the discovery of PCSK9 and its relationship to circulating levels of LDL-cholesterol (LDL-C), 12,14 a race was sparked around the world to find not only new gain-of-function (GOF) mutations causing hypercholesterolemia 14,17 but also loss-of-function (LOF) mutations compatible with hypocholesterolemia. 18,19 The highly active Anglo-Saxon D374Y PCSK9 variant is the most remarkable GOF mutation,…”

Chemical Modification of Oligonucleotides: A Novel Approach Towards Gene Targeting

“…We also show the biological application of 2',4'-BNA NC -modified oligonucleotides to reduce expression level of target mRNA in mammalian cells [14]. PCSK9 is a serine protease involved in the degradation of LDL receptor [15][16][17]. Suppression of PCSK9 by reducing expression level of PCSK9 mRNA may cause an increase in the amount of the LDL receptor, resulting in the reduction of serum LDL cholesterol level.…”