Mutations in the Type 9 Proprotein Convertase Gene and New Therapeutic Approaches for Familial Hypercholesterolemia: A Literature Review

Abstract

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated serum levels of low-density lipoprotein (LDL), which is usually the result of mutations in the LDL receptor, apolipoprotein B100 and pro-convertase subtilisin / kexine type 9 (PCSK9), which causes failure in the cellular uptake of circulating LDL. PCSK9 originates a protein that promotes the degradation of the LDL receptor within the cell, resulting in a lower return of receptors to the cell surface and, consequently, a reduction in cellular uptake and clearance of circulating LDL, leading to an increase in levels of serum LDL. This literature review aimed to analyze the structure of PCSK9, the mechanism of action of this protein, mutations in the gene that encodes it that are associated with the development of HF and new therapeutic strategies for HF that involve the use of PCSK9 inhibitors. Function gain mutations in the PCSK9 gene are associated with elevated serum LDL levels and increased risk of cardiovascular disease, while function loss ones are associated with reduced serum LDL levels and lower risk of cardiovascular disease. Treatment of FH is performed with the use of statins, which inhibit hepatic cholesterol synthesis. However, this therapeutic approach is not always effective. In this context, PCSK9 inhibitors, such as monoclonal antibodies, are a very promising therapeutic strategy for FH treatment, since they have been shown to be efficient for the reduction of serum LDL and, consequently, to reduce the risk of cardiovascular diseases in patients with FH.