Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients
| Autor: | Asma Omezzine, Lamia Rebhi, Faouzi Maatouk, Imen Jguirim, Maha Kacem, Mohamed Najah, Marianne Abifadel, Awatef Jelassi, Afef Slimani, Jean-Pierre Rabès, Catherine Boileau, Mustapha Rouis, Mathilde Varret, Khaldoun Ben Hamda, Mohamed Naceur Slimane |
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| Přispěvatelé: | Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tunisian Ministry of Higher Education and Scientific Research [PHC-Utique 10G0812 du CMCU], French Ministry of Higher Education and Scientific Research [PHC-Utique 10G0812 du CMCU], L'Agence Nationale de la Recherche [ANR-08-GENO-002-01], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2012 |
| Předmět: |
Adult
Male LDLR gene Apolipoprotein E Heterozygote Tunisia Adolescent Familial hypercholesterolemia Mutation Missense [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology medicine.disease_cause Frameshift mutation Hyperlipoproteinemia Type II PCSK9 Gene Apolipoproteins E Phenotypic variability Genetic variation medicine Humans Missense mutation Child Frameshift Mutation Gene Genetics Mutation Homozygote Serine Endopeptidases Cholesterol LDL Middle Aged Molecular biology Pedigree Phenotype Receptors LDL PCSK9 gene Child Preschool LDL receptor Female lipids (amino acids peptides and proteins) Proprotein Convertases Proprotein Convertase 9 Cardiology and Cardiovascular Medicine |
| Zdroj: | Atherosclerosis Atherosclerosis, 2012, 222 (1), pp.158-166. ⟨10.1016/j.atherosclerosis.2012.02.018⟩ Atherosclerosis, Elsevier, 2012, 222 (1), pp.158-166. ⟨10.1016/j.atherosclerosis.2012.02.018⟩ |
| ISSN: | 0021-9150 |
| DOI: | 10.1016/j.atherosclerosis.2012.02.018 |
| Popis: | Background Autosomal dominant hypercholesterolemia (ADH) is commonly caused by mutations in the low-density lipoprotein (LDL) receptor gene ( LDLR ), in the apolipoprotein B-100 gene ( APOB ), or in the proprotein convertase subtilisin kexine 9 gene ( PCSK9 ). ADH subjects carrying a mutation in LDLR present highly variable plasma LDL-cholesterol (LDL-C). This variability might be due to environmental factors or the effect of some modifying genes such as PCSK9 and APOE . Aims We investigated the molecular basis of thirteen Tunisian ADH families and attempted to determine the impact of PCSK9 and APOE gene variations on LDL-cholesterol levels and on the variable phenotypic expression of the disease. Methods and results Fifty six subjects were screened for mutations in the LDLR gene through direct sequencing. The causative mutation was found to segregate with the disease in each family and a new frameshift mutation, p.Met767CysfsX21, was identified in one family. The distribution of total- and LDL-cholesterol levels, adjusted for age and gender, among homozygous and heterozygous ADH patients varied widely. Within seven families, nine subjects presented low LDL-cholesterol levels despite carrying a mutation in the LDLR gene. To identify the molecular actors underlying this phenotypic variability, the PCSK9 gene was screened using direct sequencing and/or enzymatic restriction analysis, and the apo E genotypes were determined. A new missense variation (p.Pro174Ser) in the PCSK9 gene was identified and characterized as a new putative loss-of-function mutation. Conclusion Genetic variations in PCSK9 and APOE genes could explain only part of the variability observed in the phenotypic expression in Tunisian ADH patients carrying mutations in the LDLR gene. Other genetic variants and environmental factors very probably act to fully explain this phenotypic variability. |
| Databáze: | OpenAIRE |
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