Recombinant Human PCSK9 (Asp374Tyr) Protein, C-His

Genetic variation in PCSK9 has an enormous impact on LDL-C concentration in humans and both gain-of-function (GOF) and loss-of-function (LOF) PCSK9 mutations have been described. While PCSK9 LOF mutations cause hypocholesterolemia, GOF mutations are a rare cause of familial hypercholesterolemia (FH), a monogenic disease characterized by very high levels of LDL-C and premature atherosclerotic cardiovascular disease (ASCVD) . PCSK9 GOF mutations are causative of FH, because the enhancement in PCSK9 function leads to increased LDLr degradation and reduced recycling to the cell surface. As a consequence, there is a reduction in LDL uptake and an increase in circulating LDL-C concentration. The best characterized PCSK9 GOF mutation is p. (Asp374Tyr) which produces a ten-fold increase in LDLr degradation by increasing the binding affinity of PCSK9 to the epidermal growth factor-like domain of LDLr. This variant was demonstrated to inhibit LDL uptake still at a concentration 25 times lower than the wild-type PCSK9.