PCSK9 Gene

The PCSK9 gene (PCSK9 stands for "Proprotein Convertase Subtilisin/Kexin Type 9") is a protein coding gene located on chromosome 1p32.3. Alternative splicing results in multiple transcript variants.

The PCSK9 gene encodes a member of the subtilisin-like proprotein convertase family, the proprotein convertase subtilisin/kexin type 9, which is an enzyme belonging to the serine proteases.

Proprotein convertases activate inactive precursor forms of proteins (proproteins) by removing a prosegment, thus releasing the active protein (e.g. hormone or receptor). Nine proprotein convertases have been characterized to date, including most recently PCSK9.

The encoded protein undergoes autocatalytic processing with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestinal and renal tissues and escorts specific receptors for lysosomal degradation. The proprotein convertase subtilisin/kexin type 9 has clinical significance because it decreases the number of LDL receptors on the cell membrane of liver cells and consequently increases the concentration of LDL cholesterol in the blood.

Mutations of the PCSK9 gene represent the third most common cause of hypercholesterolemia in patients with homozygous autosomal dominant hypercholesterolemia (ADH).

Familial hypercholesterolemia is an autosomal dominant disease characterized by elevated plasmatic LDL levels, xanthomas and early coronary artery disease. Causes discovered to date are mutations in three genes, all three of which affect LDL receptor function: These are mutations in the following genes:

• LDLR gene (LDL receptor gene)
• ApoB gene
• PCSK9 gene.

The development of PCSK9 inhibitors is one approach to reduce LDL cholesterol. Gene correction techniques are in clinical trials. These use a genetic engineering approach, CRISPR technology. Here, a single nucleotide in DNA is transformed into another using base editing. More specifically, a nucleotide in the PCSK9 gene is exchanged. Thus, hepatogenic PCSK9 expression is permanently suppressed. As a result, LDL cholesterol concentrations decrease and so does cardiovascular risk. The "base editing technique" is similar to the technology used in the mRA vaccine for COVID-19. Just as in that vaccine, RNA molecules packaged in nanoparticles are introduced into cells. While the Corona vaccine dictates cells to produce a component of the SARS-CoV2 virus, the base-editing technique particles instruct cells to synthesize a base-altered protein so that no PCSK9 protein is subsequently produced.

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2. Bertolini S et al (2013) Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis 227:342-348.
3. Marianne Abifadel et al (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics 34: 154-156.
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7. Stawowy P et al.(2014) PCSK9 as a new target in the therapy of hypercholesterolemia.Heart 39: 466-469.