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Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme which in humans is encoded by the PCSK9 gene with orthologs found across many species.

Function
This gene encodes a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase.

This protein plays a major regulatory role in cholesterol homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation. Reduced LDLR levels result in decreased metabolism of low-density lipoproteins, which could lead to hypercholesterolemia.

PCSK9 may also have a role in the differentiation of cortical neurons.

Clinical significance
Several variants of PCSK9 have also been shown to significantly reduce circulating cholesterol. Some variants, which only reduce cholesterol by 15% in whites, has been shown to produce a concurrent reduction in coronary heart disease by 50%, which has major implications for public health.

Inhibition of PCSK9 function is currently being explored as a means of lowering cholesterol levels.

Alnylam Pharmaceuticals has recently shown, in initial clinical trials, positive results of ALN-PCS, which acts by means of RNA interference, as an effective means of PCSK9 inhibition.

Mutations in this gene have been associated with a rare form of autosomal dominant familial hypercholesterolemia (HCHOLA3). The mutations appear to cause the disease by increasing its protease activity, reducing LDL receptor levels and thereby preventing the uptake of cholesterol into the cells.