title: Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia.
abstract: 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.
authors.affiliation: INSERM UR383, Hôpital Necker-Enfants Malades.
authors.forename: Delphine
authors.initials: D
authors.lastname: Allard
authors.forename: Sabine
authors.initials: S
authors.lastname: Amsellem
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.forename: Mélanie
authors.initials: M
authors.lastname: Trillard
authors.forename: Martine
authors.initials: M
authors.lastname: Devillers
authors.forename: Gérald
authors.initials: G
authors.lastname: Luc
authors.forename: Michel
authors.initials: M
authors.lastname: Krempf
authors.forename: Yves
authors.initials: Y
authors.lastname: Reznik
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girardet
authors.forename: Alexandre
authors.initials: A
authors.lastname: Fredenrich
authors.forename: Claudine
authors.initials: C
authors.lastname: Junien
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Pascale
authors.initials: P
authors.lastname: Benlian
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rabès
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D006937:Hypercholesterolemia / Q000175:diagnosis* / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020161:Physical Chromosome Mapping; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D001055:Apolipoproteins B; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases