Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients - Biological Adaptation and Ageing Accéder directement au contenu
Article Dans Une Revue Atherosclerosis Année : 2012

Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients

Afef Slimani
  • Fonction : Auteur
Awatef Jelassi
  • Fonction : Auteur
Imen Jguirim
  • Fonction : Auteur
Mohamed Najah
Lamia Rebhi
  • Fonction : Auteur
Asma Omezzine
  • Fonction : Auteur
Faouzi Maatouk
  • Fonction : Auteur
Khaldoun Ben Hamda
  • Fonction : Auteur
Maha Kacem
  • Fonction : Auteur
Jean-Pierre Rabes
  • Fonction : Auteur
Marianne Abifadel
  • Fonction : Auteur
Catherine Boileau
Mohamed Naceur Slimane
  • Fonction : Auteur
Mathilde Varret

Résumé

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.

Dates et versions

hal-01544070 , version 1 (21-06-2017)

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Citer

Afef Slimani, Awatef Jelassi, Imen Jguirim, Mohamed Najah, Lamia Rebhi, et al.. Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients. Atherosclerosis, 2012, 222 (1), pp.158-166. ⟨10.1016/j.atherosclerosis.2012.02.018⟩. ⟨hal-01544070⟩
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