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A New PCSK9 Gene Promoter Variant Affects Gene Expression and Causes Autosomal Dominant Hypercholesterolemia

Laboratorio de Estudios Genéticos (S.B., A.-B.G.-G., S.M.-H., C.I., V.G.-A., F.J.C.), Fundación Investigación Hospital Clínico Universitario de Valencia, and Instituto de Biomedicina de Valencia (S.V., M.C.), E-46010 Valencia, Spain; Servicio de Endocrinología (S.M.-H., J.F.A., J.T.R., R.C.), Hospital Clínico Universitario de Valencia, Universidad de Valencia, E-46022 Valencia, Spain; Servicio de Medicina Interna (J.C.M.-E.), Hospital Rio Hortega, E-47005 Valladolid, Spain; and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (S.B., A.-B.G.-G., S.M.-H., V.G.-A., J.F.A., J.T.R., R.C., F.J.C.)

Address all correspondence and requests for reprints to: F. Javier Chaves, Fundación de Investigación Hospital Clínico, Universitario de Valencia, Avda. Blasco Ibáñez 17, E-46010 Valencia, Spain. E-mail: felipe.chaves{at}uv.es.

Context: Autosomal dominant hypercholesterolemia (ADH) is a genetic disorder characterized by increased low-density lipoprotein (LDL)-cholesterol levels, leading to high risk of premature cardiovascular disease. More than 900 mutations in LDL receptor, six 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 a Spanish population.

Objective: The objective of the study was to study the prevalence of PCSK9 mutations in ADH Spanish population.

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

Results: None of the known mutations causing ADH was detected in our sample, but we found two variations in the promoter region that could cause ADH, c.-288G>A and c.-332C>A (each 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, whereas c.-332C>A variant caused a 2.5-fold increase when compared with 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.