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

Marduel, Marie; Ouguerram, Khadija; Serre, Valérie; Bonnefont‐Rousselot, Dominique; Marques-Pinheiro, Alice; Berge, Knut Erik; Devillers, Martine; Luc, Gérald; Lecerf, Jean‐Michel; Tosolini, Laurent; Erlich, D.; Peloso, Gina M.; Stitziel, Nathan O.; Nitchké, Patrick; Jaı̈s, Jean-Philippe; Abifadel, Marianne; Kathiresan, Sekar; Leren, Trond P.; Rabès, Jean-Pierre; Boileau, Cathérine; Varret, Mathilde

doi:10.1002/humu.22215

Cited by 114 publications

(101 citation statements)

References 27 publications

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“…This APOE variant was predicted to have a destabilizing effect on the protein structure here, and this has been confi rmed experimentally recently for the E4 isoform ( 40 ); our patient carried precisely the E4 isoform (patient #3). The p.(Leu167del) found in patient #2 was previously described in ADH patients ( 4,5 ), and our in silico structural analyses suggest that this apoE variant will have impaired LDLR binding properties. The binding defect of p.(Leu167del) was, however, not demonstrated ( 4 ).…”

Section: Discussionsupporting

confidence: 75%

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Wintjens

Bozon²,

Belabbas

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identifi ed APOE sequence changes were predicted to impact protein function. Abstract Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor ( LDLR ), APOB , and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADHassociated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR , 3.1% in APOB , and 1.7% in PCSK9 . We identifi ed 18 new variants in LDLR and 2 in PCSK9 . Three LDLR variants, including two newly identifi ed, were studied by minigene reporter assay confi rming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identifi ed in three patients with isolated severe hypercholesterolemia giving a

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Section: Discussionsupporting

confidence: 75%

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Wintjens

Bozon²,

Belabbas

et al. 2016

Journal of Lipid Research

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“…The decrease in HDL cholesterol (HDL-C) in pcsk9 Ϫ / Ϫ mice has been attributed to the binding of ApoE containing HDL to the upregulated LDLR ( 11 ). Even with a functional LDLR and ApoB, mutations in APOE in humans can lead to hypercholesterolemia (43)(44)(45)(46). To date the role of ApoE in the lipid lowering and athero-protective effects of PCSK9 inhibition is unclear.…”

Section: In Vivomentioning

confidence: 99%

PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE

Ason

Hoorn²,

Chan

et al. 2014

Journal of Lipid Research

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“…We found only one patient heterozygous for a known apoE variant [p.(Leu167del)], considered the cause of FH with dominant transmission [3]. Recently a large study conducted in 228 Spanish FH patients in whom the LDLR, APOB and PCSK9 pathogenic variants had been excluded, showed that nine patients (3.1%) were carriers of the p.(Leu167del) variant [20].…”

Section: Discussionmentioning

confidence: 91%

“…Gain-of-function (GOF) mutations of PCSK9 causing FH are exceedingly rare [6]. Only a single mutation in APOE gene [p.(Leu167del)] was found to be the cause of a dominant FH phenotype [3]. FH-like phenotypes with a recessive transmission are extremely rare.…”

Section: Introductionmentioning

confidence: 99%

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Pirillo¹,

Garlaschelli²,

Arca³

et al. 2017

Atherosclerosis Supplements

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Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDLcholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality.Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods: We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1). Results: A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype. Conclusions: This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress.

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Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with theAPOEp.Leu167del Mutation

Cited by 114 publications

References 27 publications

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France

PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

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