title: Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia.
abstract: Patients homozygous or compound heterozygous for LDLR mutations or double heterozygous for LDLR and apo B R3500Q mutation have higher LDL-C levels, more extensive xanthomatosis and more severe premature coronary disease (pCAD) than simple heterozygotes for mutations in either these genes or for missense mutations in PCSK9 gene. It is not known whether combined mutations in LDLR and PKCS9 are associated with such a severe phenotype. We sequenced Apo B and PCSK9 genes in two patients with the clinical diagnosis of homozygous FH who were heterozygous for LDLR gene mutations. Proband Z.P. (LDL-C 13.39 mmol/L and pCAD) was heterozygous for an LDLR mutation (p.E228K) inherited from her father (LDL-C 8.07 mmol/L) and a PCSK9 mutation (p.R496W) from her mother (LDL-C 5.58 mmol/L). Proband L.R. and her sister (LDL-C 11.51 and 10.47 mmol/L, xanthomatosis and carotid atherosclerosis) were heterozygous for an LDLR mutation (p.Y419X) inherited from their mother (LDL-C 6.54 mmol/L) and a PCSK9 mutation (p.N425S) probably from their deceased father. The LDL-C levels in double heterozygotes of these two families were 56 and 44% higher than those found in simple heterozygotes for the two LDLR mutations, respectively. The two PCSK9 mutations are novel and were not found in 110 controls and 80 patients with co-dominant hypercholesterolemia. These observations indicate that rare missense mutations of PCSK9 may worsen the clinical phenotype of patients carrying LDLR mutations.
authors.affiliation: Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, I-16132 Genoa, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Pisciotta
authors.forename: Claudio
authors.initials: C
authors.lastname: Priore Oliva
authors.forename: Angelo Baldassare
authors.initials: AB
authors.lastname: Cefalù
authors.forename: Davide
authors.initials: D
authors.lastname: Noto
authors.forename: Antonella
authors.initials: A
authors.lastname: Bellocchio
authors.forename: Raffaele
authors.initials: R
authors.lastname: Fresa
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cantafora
authors.forename: Dilip
authors.initials: D
authors.lastname: Patel
authors.forename: Maurizio
authors.initials: M
authors.lastname: Averna
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tarugi
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases