Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia

► We identified two new mutations of PCSK9: p.Leu108Arg and p.Asp35Tyr in two French families with hypercholesterolemia. ► In vitro studies of their consequences on the activity of PCSK9 on cell surface levels of LDLR were analyzed. ► p.Leu108Arg exhibited a ∼2-fold enhanced degrading activity towards the LDLR clearly resulting in a gain-of-function. ► p.Asp35Tyr created a novel Tyr-sulfation site, which may enhance the intracellular activity of PCSK9. ► These data further contribute to the characterization of PCSK9 mutations and to better understanding of their impact.