title: Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia.
abstract: OBJECTIVE
  Rare mutations in the APOE gene, undetectable with the usual genotyping technique, are responsible for dominant familial dysbetalipoproteinemia (FD) and therefore could be easily misclassified as familial combined hyperlipidemia (FCHL). We aimed to identify APOE mutations associated with dominant combined hyperlipoproteinemia and to establish their frequency in subjects with a clinical diagnosis of FCHL.
  
  
  RESULTS
  In 279 unrelated subjects with FCHL in whom a functional LDLR mutation was excluded, sequencing of the entire APOE gene detected 9 carriers of a rare mutation: 5 subjects (1.8%) with the R136S mutation (arginine at residue 136 changed to serine) and 4 subjects (1.4%) with the p.Leu149del mutation, a 3-bp inframe deletion that results in the loss of leucine at position 149. Both genetic defects were detected with similar frequency (2.5% and 1.3%, respectively) in an independent group of 160 FCHL subjects from other locations in Spain. Family studies demonstrated cosegregation of these APOE mutations with hyperlipoproteinemia. R136S carriers showed dysbetalipoproteinemia, while the lipid phenotype of p.Leu149del carriers was IIa or IIb.
  
  
  CONCLUSIONS
  Rare APOE mutations are responsible for approximately 3.5% of FCHL cases in our population. APOE R136S and p.Leu149del induce autosomal dominant FD and a phenotype indistinguishable from FCHL, respectively.
authors.affiliation: Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (I+CS), Zaragoza, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Solanas-Barca
authors.forename: Isabel
authors.initials: I
authors.lastname: de Castro-Orós
authors.forename: Rocío
authors.initials: R
authors.lastname: Mateo-Gallego
authors.forename: Montserrat
authors.initials: M
authors.lastname: Cofán
authors.forename: Nuria
authors.initials: N
authors.lastname: Plana
authors.forename: José
authors.initials: J
authors.lastname: Puzo
authors.forename: Elena
authors.initials: E
authors.lastname: Burillo
authors.forename: Paula
authors.initials: P
authors.lastname: Martín-Fuentes
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.forename: Luis
authors.initials: L
authors.lastname: Masana
authors.forename: Miguel
authors.initials: M
authors.lastname: Pocoví
authors.forename: Fernando
authors.initials: F
authors.lastname: Civeira
authors.forename: Ana
authors.initials: A
authors.lastname: Cenarro
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000235:genetics*; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000175:diagnosis / Q000235:genetics*; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D010375:Pedigree; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics; D013030:Spain
chemical_list: D001057:Apolipoproteins E; C573412:LDLR protein, human; D011973:Receptors, LDL