A new PCSK9 gene promoter variant affects gene expression and causes autosomal dominant hypercholesterolemia.
BACKGROUND
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.


METHODS
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.
Laboratorio de Estudios Genéticos, Fundación de Investigación Hospital Clínico, Universitario de Valencia, Avda. Blasco Ibáñez 17, E-46010 Valencia, Spain.
Sebastian
S
Blesa
Santiago
S
Vernia
Ana-Barbara
AB
Garcia-Garcia
Sergio
S
Martinez-Hervas
Carmen
C
Ivorra
Veronica
V
Gonzalez-Albert
Juan Francisco
JF
Ascaso
Juan Carlos
JC
Martín-Escudero
Jose Tomas
JT
Real
Rafael
R
Carmena
Marta
M
Casado
Felipe Javier
FJ
Chaves
D000328:Adult; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D002478:Cells, Cultured; D015870:Gene Expression; D005787:Gene Frequency; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D041681:NIH 3T3 Cells; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000097:blood / Q000235:genetics*; D013030:Spain; D014162:Transfection
D050505:Mutant Proteins; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases