title: APOE p.Leu167del mutation in familial hypercholesterolemia.
abstract: BACKGROUND
  Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the low density lipoprotein receptor (LDLR), its ligand apoB (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Yet DNA sequencing does not identify mutations in these genes in a significant number of cases, suggesting that ADH has multiple genetic etiologies.
  
  
  METHODS
  Through a combination of clinical examination, biochemical analysis, candidate gene approach and next-generation exome sequencing we investigated the genetic basis of an ADH phenotype in a proband of an Italian origin.
  
  
  RESULTS
  The proband presented with an acute myocardial infarction at age 43. He had tendinous xanthomas, xanthelasmas and elevated levels of total and LDL cholesterol, at 11.2 and 9.69 mmol/L, respectively, with normal levels of HDL cholesterol and triglycerides at 1.62 and 1.13 mmol/L, respectively. HPLC lipoprotein profile showed selective increase in LDL-C. DNA sequencing did not identify any mutation in the LDLR, PCSK9, LDLRAP1 and APOB gene. We then performed exome sequencing on three individuals from the family. The strongest evidence of association was found for the previously identified apolipoprotein E mutation (APOE, chromosome 19:45412053-55) known as APOE Leu167del, an in-frame three base-pair deletion. Computational biology confirmed the deleterious nature of this mutation. The Leu167del mutation is predicted to alter the protein structure of apoE near the α-helix within the receptor binding domain.
  
  
  CONCLUSIONS
  This report confirms a previous report that ADH can be caused by mutations within the APOE gene and represents the 4th loci causing ADH. Standard screening for ADH should include APOE gene.
authors.affiliation: The Research Institute of the McGill University Health Centre, Faculty of Medicine, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, QC H3A 1A1, Canada; Institut de Recherches Cliniques (IRCM) Affiliated to Université de Montréal, 110 Pine Avenue West, Montréal, QC, Canada.
authors.forename: Zuhier
authors.initials: Z
authors.lastname: Awan
authors.forename: Hong Y
authors.initials: HY
authors.lastname: Choi
authors.forename: Nathan
authors.initials: N
authors.lastname: Stitziel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ruel
authors.forename: Mary Aderayo
authors.initials: MA
authors.lastname: Bamimore
authors.forename: Regina
authors.initials: R
authors.lastname: Husa
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Gagnon
authors.forename: Rui-Hao L
authors.initials: RH
authors.lastname: Wang
authors.forename: Gina M
authors.initials: GM
authors.lastname: Peloso
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D007930:Leucine / Q000235:genetics*; D008024:Ligands; D008297:Male; D009154:Mutation; D009203:Myocardial Infarction / Q000235:genetics; D010375:Pedigree; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D012306:Risk; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics; D014973:Xanthomatosis / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D008024:Ligands; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D007930:Leucine
keywords: APOE gene; Autosomal dominant hypercholesterolemia; Familial hypercholesterolemia