Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the APOE p.Leu167del Mutation

被引：96

作者：

Marduel, Marie ^{[1
,2
,3
]}

Ouguerram, Khadija ^{[4
]}

Serre, Valerie ^{[2
,5
]}

Bonnefont-Rousselot, Dominique ^{[3
,6
,7
]}

Marques-Pinheiro, Alice ^{[2
]}

Berge, Knut Erik ^{[8
]}

Devillers, Martine ^{[2
]}

Luc, Gerald ^{[9
,10
]}

Lecerf, Jean-Michel ^{[10
]}

Tosolini, Laurent ^{[1
]}

Erlich, Daniele ^{[5
]}

Peloso, Gina M. ^{[11
]}

Stitziel, Nathan ^{[11
]}

Nitchke, Patrick ^{[3
,12
]}

Jais, Jean-Philippe ^{[3
,12
]}

Abifadel, Marianne ^{[1
,13
]}

Kathiresan, Sekar ^{[11
]}

Leren, Trond Paul ^{[8
]}

Rabes, Jean-Pierre ^{[1
,14
,15
]}

Boileau, Catherine ^{[1
,14
,15
]}

Varret, Mathilde ^{[1
,5
]}

机构：

[1] INSERM, U698, Paris, France

[2] INSERM, U781, Paris, France

[3] Univ Paris 05, Paris, France

[4] Univ Nantes, INSERM, Inst Thorax, U915, Nantes, France

[5] Univ Paris Denis Diderot, Paris, France

[6] Fac Pharm, EA 4466, Paris, France

[7] CHU Pitie Salpetriere, AP HP, Serv Biochim Metab, Paris, France

[8] Univ Oslo, Rikshosp, Oslo Univ Hosp, Med Genet Lab, N-0027 Oslo, Norway

[9] Univ Lille Nord France, Fac Pharm, Lille, France

[10] Univ Hosp Lille, Dept Internal Med, Lille, France

[11] Broad Inst, Cambridge, MA USA

[12] CHU Necker, AP HP, Serv Biostat & Informat Med, Paris, France

[13] Univ St Joseph, Fac Pharm, Beirut, Lebanon

[14] Hop Ambroise Pare, AP HP, Lab Biochim & Genet Mol, Boulogne, France

[15] Univ Versailles St Quentin En Yvelines, UFR Med Paris Ile France Ouest, Guyancourt, France

来源：

HUMAN MUTATION | 2013年 / 34卷 / 01期

关键词：

apolipoprotein E; APOE; hypercholesterolemia; ADH; LDL; SEA-BLUE HISTIOCYTOSIS; RECEPTOR-BINDING ACTIVITY; NIEMANN-PICK-DISEASE; APOLIPOPROTEIN-E; COMBINED HYPERLIPIDEMIA; CLINICAL-DIAGNOSIS; STORAGE DISEASE; GENE-MUTATIONS; LOW-DENSITY; HYPERLIPOPROTEINEMIA;

D O I：

10.1002/humu.22215

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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. Hum Mutat 34:83-87, 2013. (C) 2012 Wiley Periodicals, Inc.

引用

页码：83 / 87

页数：5

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