Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia

Autor: Dilip D. Patel, Livia Pisciotta, Claudio Priore Oliva, Sebastiano Calandra, Maurizio Averna, A. Bellocchio, Alfredo Cantafora, Davide Noto, R. Fresa, Stefano Bertolini, Angelo B. Cefalù, Patrizia Tarugi
Přispěvatelé: Pisciotta, L, Priore Oliva, C, Cefalù, AB, Noto, D, Bellocchio, A, Fresa, R, Cantafora, A, Patel, D, Averna , M, Tarurgi, P, Calandra, S, Bertolini, S, PISCIOTTA, L, PRIORE OLIVA, C, CEFALU', AB, NOTO, D, BELLOCCHIO, A, FRESA, R, CANTAFORA, A, PATEL, D, AVERNA, MR, TARUGI, P, CALANDRA, S, BERTOLINI, S
Rok vydání: 2005
Předmět:
Proband
LDLR gene
Adult
Male
Settore MED/09 - Medicina Interna
Apolipoprotein B
Familial hypercholesterolemia (FH)
Autosomal dominant hypercholesterolemia 3 (ADH3)
PCSK9 gene
Premature coronary artery disease
LDLR
PCSK9
Mutation
Missense
Familial hypercholesterolemia
Compound heterozygosity
medicine.disease_cause
Hyperlipoproteinemia Type II
Familial hypercholesterolemia (FH)
Autosomal dominant hypercholesterolemia 3 (ADH3)
LDLR gene
PCSK9 gene
Premature coronary artery disease
medicine
Missense mutation
Humans
Cells
Cultured
Genetics
Mutation
biology
business.industry
Serine Endopeptidases
Heterozygote advantage
Middle Aged
medicine.disease
Pedigree
Phenotype
Settore MED/03 - Genetica Medica
Amino Acid Substitution
Receptors
LDL
LDL receptor
biology.protein
lipids (amino acids
peptides
and proteins)
Female
Proprotein Convertases
Proprotein Convertase 9
Cardiology and Cardiovascular Medicine
business
Zdroj: Atherosclerosis. 186(2)
ISSN: 0021-9150
Popis: 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 all 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 I 10 controls and 80 patients with co-dominant hypercholesterolemia. These observations indicate that Fare missense Mutations of PCSK9 may worsen the clinical phenotype of patients carrying LDLR mutations.
Databáze: OpenAIRE
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