title: 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.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Research Unit of Genetic and Biological Factors of Atherosclerosis, Faculty of Medicine, Monastir 5000, Tunisia. afefslimani@yahoo.com
authors.forename: Afef
authors.initials: A
authors.lastname: Slimani
authors.forename: Awatef
authors.initials: A
authors.lastname: Jelassi
authors.forename: Imen
authors.initials: I
authors.lastname: Jguirim
authors.forename: Mohamed
authors.initials: M
authors.lastname: Najah
authors.forename: Lamia
authors.initials: L
authors.lastname: Rebhi
authors.forename: Asma
authors.initials: A
authors.lastname: Omezzine
authors.forename: Faouzi
authors.initials: F
authors.lastname: Maatouk
authors.forename: Khaldoun Ben
authors.initials: KB
authors.lastname: Hamda
authors.forename: Maha
authors.initials: M
authors.lastname: Kacem
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rabès
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Mustapha
authors.initials: M
authors.lastname: Rouis
authors.forename: Mohamed Naceur
authors.initials: MN
authors.lastname: Slimane
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
mesh_terms: D000293:Adolescent; D000328:Adult; D001057:Apolipoproteins E / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D014416:Tunisia
chemical_list: D001057:Apolipoproteins E; D008078:Cholesterol, LDL; C573412:LDLR protein, human; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases