The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes

Cenarro, Ana; Etxebarria, Aitor; Castro-Orós, Isabel De; Stef, Marianne; Bea, Ana M.; Palacios, Lourdes; Mateo-Gállego, Rocío; Benito‐Vicente, Asier; Ostolaza, Helena; Tejedor, T.; Martı́n, César; Civeira, Fernando

doi:10.1210/jc.2015-3874

Cited by 78 publications

(65 citation statements)

References 33 publications

(29 reference statements)

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“…Additional mechanisms include mutations affecting the apolipoprotein B ([ApoB], the key structural component of LDLs and very low‐density lipoproteins [VLDLs]), and the gene of pro‐protein convertase subtilisin‐kexin type 9 (PCSK9), which promotes the LDLR internalization and destruction in hepatocytes (Benn, Watts, Tybjærg‐Hansen, & Nordestgaard, ; Raal et al, ). Other rare forms of FH are due to mutation in the apolipoprotein E (ApoE) gene (Wiegman et al, ) and LDL receptor adaptor protein 1 (LDLRAP1), which encodes a protein required for clathrin‐mediated internalization of the LDLR (Cenarro et al, ). Nevertheless, in about 60% of patients the underlying mutation remains unrecognized.…”

Section: Introductionmentioning

confidence: 99%

Oxidative burden in familial hypercholesterolemia

Mollazadeh¹,

Carbone

Montecucco

et al. 2018

Journal Cellular Physiology

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Familial hypercholesterolemia (FH) is a genetic disorder characterized by high serum levels of low-density lipoprotein cholesterol (LDL-c). FH is characterized by accelerated development of atherosclerosis and represents the most frequent hereditary cause of premature coronary heart disease. Mutations of the LDL receptor gene are the genetic signature of FH, resulting in abnormal levels of circulating LDLs. Moreover, FH promotes the generation of reactive oxygen species (ROS) which is another key mechanism involved in atherosclerosis development and progression. The aim of this narrative review is to update the current knowledge on the pathophysiological mechanisms linking FH to ROS generation and their detrimental impact on atherosclerotic pathophysiology. With this purpose, we reviewed experimental and clinical data on the association between FH and OS and the functional role of OS as a promoter of inflammation and atherosclerosis. In this regard, oxidant species such as oxidized LDL, malondialdehyde, ROS, and isoprostanes emerged as leading mediators of the oxidative injury in FH. In conclusion, targeting oxidative stress may be a promising therapeutic strategy to reduce atherogenesis in patients with FH.

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Section: Introductionmentioning

confidence: 99%

Oxidative burden in familial hypercholesterolemia

Mollazadeh¹,

Carbone

Montecucco

et al. 2018

Journal Cellular Physiology

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“…Heterozygous familial hypercholesterolemia (HeFH), the most frequent monogenic disorder of human metabolism caused by some mutations in the genes that encode for the low-density lipoprotein (LDL) receptor, apolipoprotein (apo) B, proprotein convertase subtilisin/kexin-type 9 (PCSK9) or apo E 1, 2 , entails an increased risk of premature cardiovascular disease 2 .…”

Section: Introductionmentioning

confidence: 99%

Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia

Climent

Pérez-Calahorra

Marco-Benedí

et al. 2017

Sci Rep

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Patients with heterozygous familial hypercholesterolemia (HeFH) have been reported to be less vulnerable to type 2 diabetes mellitus (T2DM), although the mechanism is unknown. The aims of the present study were to assess the effects of low density lipoprotein (LDL) cholesterol concentration and the presence of FH-causing mutations on T2DM prevalence in HeFH. Data were collected from the Dyslipidemia Registry of the Spanish Arteriosclerosis Society. Inclusion criteria were definite or probable HeFH in patients aged ≥18 years. T2DM prevalence in HeFH patients was compared with data of the general population. 1732 patients were included. The prevalence of T2DM was lower in patients with HeFH compared with the general population (5.94% vs 9.44%; OR: 0.606, 95% CI 0.486–0.755, p < 0.001). Risk factors for developing T2DM were male sex, age, body mass index, hypertension, baseline triglyceride levels and years on statin therapy. The prevalence of T2DM in HeFH patients was 40% lower than that observed in the general population. Gene mutations and LDL cholesterol concentrations were not risk factors associated with the prevalence of T2DM in patients with HeFH. The prevalence of T2DM in patients with HeFH was 40% lower than in the general population matched for age and sex.

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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]. This variant was found to segregate with FH phenotype among index cases' family members.…”

Section: Discussionmentioning

confidence: 92%

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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The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes

Cited by 78 publications

References 33 publications

Oxidative burden in familial hypercholesterolemia

Oxidative burden in familial hypercholesterolemia

Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia

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

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