title: Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation.
abstract: Apolipoprotein (apo) E mutants are associated with type III hyperlipoproteinemia characterized by high cholesterol and triglycerides levels. Autosomal dominant hypercholesterolemia (ADH), due to the mutations in the LDLR, APOB, or PCSK9 genes, is characterized by an isolated elevation of cholesterol due to the high levels of low-density lipoproteins (LDLs). We now report an exceptionally large family including 14 members with ADH. Through genome-wide mapping, analysis of regional/functional candidate genes, and whole exome sequencing, we identified a mutation in the APOE gene, c.500_502delTCC/p.Leu167del, previously reported associated with sea-blue histiocytosis and familial combined hyperlipidemia. We confirmed the involvement of the APOE p.Leu167del in ADH, with (1) a predicted destabilization of an alpha-helix in the binding domain, (2) a decreased apo E level in LDLs, and (3) a decreased catabolism of LDLs. Our results show that mutations in the APOE gene can be associated with bona fide ADH.
authors.affiliation: INSERM U698, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Marduel
authors.forename: Khadija
authors.initials: K
authors.lastname: Ouguerram
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnefont-Rousselot
authors.forename: Alice
authors.initials: A
authors.lastname: Marques-Pinheiro
authors.forename: Knut
authors.initials: K
authors.lastname: Erik Berge
authors.forename: Martine
authors.initials: M
authors.lastname: Devillers
authors.forename: Gérald
authors.initials: G
authors.lastname: Luc
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Lecerf
authors.forename: Laurent
authors.initials: L
authors.lastname: Tosolini
authors.forename: Danièle
authors.initials: D
authors.lastname: Erlich
authors.forename: Gina M
authors.initials: GM
authors.lastname: Peloso
authors.forename: Nathan
authors.initials: N
authors.lastname: Stitziel
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitchké
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jaïs
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Trond Paul
authors.initials: TP
authors.lastname: Leren
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rabès
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
mesh_terms: D000293:Adolescent; D000328:Adult; D001057:Apolipoproteins E / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014280:Triglycerides / Q000378:metabolism; D055815:Young Adult
chemical_list: D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides; D002784:Cholesterol