The mechanism by which the PCSK9 (S127R) protein results in hypercholesterolemia has been suggested to be mediated by an intracellular binding with LDLR [78], because this amino acid substitution delays autocatalytic cleavage and secretion [5], and there is only a modest increase in affinity for the LDLR [7, 55]. This evidence concerns the gene PCSK9 and familial hypercholesterolemia.