The mutation that we used to induce hypercholesterolemia in mice, analogous to amino-acid substitution of Asp374 by Tyr (D374Y) in humans [23, 24], increases the affinity of PCSK9 for the LDL receptor in vitro by ≥10-fold [25], and is the mutation described in PCSK9 with the greatest effect, resulting in cholesterol levels above 500 mg/dl in affected subjects. The gene discussed is PCSK9; the disease is Hypercholesterolemia.