Context: Autosomal Dominant Hypercholesterolemia is a genetic disorder characterized by increased LDL-cholesterol levels leading to high risk of premature cardiovascular disease. More than 900 mutations in LDLR, 6 in APOB and 10 in PCSK9 have been identified as a cause of the disease in different populations. All known mutations in PCSK9 causing hypercholesterolemia produce an increase in the enzymatic activity of this protease. Up to now, there are data about the implication of PCSK9 in ADH in a low number of populations, not including Spanish population.

Objective: To study the prevalence of PCSK9 mutations in ADH Spanish population.

Participants: We have screened PCSK9 gene in 42 independent ADH patients in whom mutations in LDLR and APOB genes had been excluded.

Results: None of the known mutations causing ADH was detected in our sample, but we have found two variations in the promoter region that could cause ADH, c.-288G>A and c.-332C>A, (each one of them in one proband). The analysis of the effect of these two variations on the transcription activity of the PCSK9 promoter showed that c.-288G>A did not modify the transcription while c.-332C>A variant caused a 2.5 fold increase when compared to the wild type sequence, either with or without Lovastatin.

Conclusions: PCSK9 is a rare cause of ADH in Spanish population and, up to what we know; none of the previously described mutations has been detected. We have identified a new mutation that could cause ADH by increasing the transcription of PCSK9.