Autosomal dominant hypercholesterolemia (ADH) is a frequent (1/500) monogenic inherited disorder characterized by isolated elevation of
LDL leading to premature
cardiovascular disease. ADH is known to result from mutations at two main loci: LDLR (encoding the
low density lipoprotein receptor), and
APOB (encoding
apolipoprotein B100), its natural
ligand. We previously demonstrated that ADH is also caused by mutations of the PCSK9 (
proprotein convertase subtilisin/kexin type 9) gene that encodes Narc-1 (
neural apoptosis-regulated convertase 1). However, the role of this novel disease locus as a cause of
hypercholesterolemia remains unclear. In the present study, we analysed the PCSK9 coding region and intronic junctions in 130 adult or pediatric patients with ADH, previously found as being non LDLR/non
APOB mutation carriers. Four novel heterozygous missense variations were found: c.654A>T (p.R218S), c.1070G>A (p.R357H), c.1405C>T (p.R469W), and c.1327G>A (p.A443T). All mutations were absent in 340 normolipidemic controls. Except for the A443T, all mutations are nonconservative and modify a highly conserved residue. Segregation with
hypercholesterolemia is incomplete in one pedigree. Type and severity of
hyperlipidemia and of
cardiovascular disease could vary among subjects from the same family. Finally, the proband carrying the R357H mutation exhibited very high plasma
cholesterol during pregnancy, whereas the proband carrying the p.R469W mutation exhibited a severe phenotype of
hypercholesterolemia in combination with a LDLR mutation resulting from a frameshift at residue
F382 (1209delC). These observations suggest that variations in PCSK9 are a rare cause of non LDLR/non
APOB ADH (approximately 2.3%) and that additional environmental or genetic factors may contribute to the phenotype caused by PCSK9 missense mutations in humans.