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

Abstract

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.

• Authors: Afef Slimani, Awatef Jelassi, Imen Jguirim, Mohamed Najah, Lamia Rebhi, Asma Omezzine, Faouzi Maatouk, Khaldoun Ben Hamda, Maha Kacem, Jean-Pierre Rabès, Marianne Abifadel, Catherine Boileau, Mustapha Rouis, Mohamed Naceur Slimane, Mathilde Varret
• Journal: Atherosclerosis (Atherosclerosis) Vol. 222 Issue 1 Pg. 158-66 (May 2012) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 22417841 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apolipoproteins E
• Cholesterol, LDL
• LDLR protein, human
• Receptors, LDL
• PCSK9 protein, human
• Proprotein Convertase 9
• Proprotein Convertases
• Serine Endopeptidases

Topics

• Adolescent
• Adult
• Apolipoproteins E (genetics)
• Child
• Child, Preschool
• Cholesterol, LDL (blood)
• Female
• Frameshift Mutation
• Heterozygote
• Homozygote
• Humans
• Hyperlipoproteinemia Type II (blood, genetics)
• Male
• Middle Aged
• Mutation, Missense
• Pedigree
• Phenotype
• Proprotein Convertase 9
• Proprotein Convertases (genetics)
• Receptors, LDL (genetics)
• Serine Endopeptidases (genetics)
• Tunisia