Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the APOE p.Leu167del Mutation. Issue 1 (11th October 2012)

• Record Type: Journal Article
• Authors: Marduel, Marie; Ouguerram, Khadija; Serre, Valérie; Bonnefont‐Rousselot, Dominique; Marques‐Pinheiro, Alice; Erik Berge, Knut; Devillers, Martine; Luc, Gérald; Lecerf, Jean‐Michel; Tosolini, Laurent; Erlich, Danièle; Peloso, Gina M.; Stitziel, Nathan; Nitchké, Patrick; Jaïs, Jean‐Philippe; Abifadel, Marianne; Kathiresan, Sekar; Leren, Trond Paul; Rabès, Jean‐Pierre; Boileau, Catherine; Varret, Mathilde
• Is Part Of: Human mutation. Volume 34:Issue 1(2013:Jan.)
• Page Start: 83
• Page End: 87
• Publication Date: 2012-10-11
• Subjects: Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22215
• Languages: English
• ISSNs: 1059-7794

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>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 <italic>LDLR</italic>, <italic>APOB</italic>, or <italic>PCSK9</italic> 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 <italic>APOE</italic> gene, c.500_502delTCC/p.Leu167del, previously reported associated with sea‐blue histiocytosis and familial combined hyperlipidemia. We confirmed the involvement of the <italic>APOE</italic> 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 <italic>APOE</italic> gene can be associated with bona fide ADH.</p> </abstract>