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Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the APOE p. L eu167del Mutation
Author(s) -
Marduel Marie,
Ouguerram Khadija,
Serre Valérie,
BonnefontRousselot Dominique,
MarquesPinheiro Alice,
Erik Berge Knut,
Devillers Martine,
Luc Gérald,
Lecerf JeanMichel,
Tosolini Laurent,
Erlich Danièle,
Peloso Gina M.,
Stitziel Nathan,
Nitchké Patrick,
Jaïs JeanPhilippe,
Abifadel Marianne,
Kathiresan Sekar,
Leren Trond Paul,
Rabès JeanPierre,
Boileau Catherine,
Varret Mathilde
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22215
Subject(s) - biology , genetics , apolipoprotein e , apolipoprotein b , gene , mutation , mutant , allele , hyperlipidemia , exome sequencing , familial hypercholesterolemia , candidate gene , cholesterol , endocrinology , medicine , diabetes mellitus , disease
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_502del TCC /p. L eu167del, previously reported associated with sea‐blue histiocytosis and familial combined hyperlipidemia. We confirmed the involvement of the APOE p. L eu167del in ADH , with (1) a predicted destabilization of an alpha‐helix in the binding domain, (2) a decreased apo E level in LDL s, and (3) a decreased catabolism of LDL s. Our results show that mutations in the APOE gene can be associated with bona fide ADH .