Structural analysis of APOB variants, p.(Arg3527Gln), p.(Arg1164Thr) and p.(Gln4494del), causing Familial Hypercholesterolaemia provides novel insights into variant pathogenicity

Fernández-Higuero, José Ángel; Etxebarria, Aitor; Benito‐Vicente, Asier; Alves, Ana Catarina; Arrondo, José Luis R.; Ostolaza, Helena; Bourbon, Mafalda; Martín, César

doi:10.1038/srep18184

Cited by 32 publications

(19 citation statements)

References 39 publications

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“…The mean particle diameter obtained at neutral pH was 29.4 ± 0.2 nm in concordance as previously described24. Figure 1A shows there was no alteration of the mean particle diameter at pH 5.0, as 29.8 ± 0.4 nm value was obtained.…”

Section: Resultssupporting

confidence: 90%

Structural changes induced by acidic pH in human apolipoprotein B-100

Fernández-Higuero

Benito‐Vicente

Etxebarria

et al. 2016

Sci Rep

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Acidification in the endosome causes lipoprotein release by promoting a conformational change in the LDLR allowing its recycling and degradation of LDL. Notwithstanding conformational changes occurring in the LDLR have expanded considerably, structural changes occurring in LDL particles have not been fully explored yet. The objectives of the present work were to study structural changes occurring in apoB100 by infrared spectroscopy (IR) and also LDL size and morphology by dynamic light scattering (DLS) and electron microscopy (EM) at both pH 7.4 and 5.0. We determined by IR that pH acidification from 7.4 to 5.0, resembling that occurring within endosomal environment, induces a huge reversible structural rearrangement of apoB100 that is characterized by a reduction of beta-sheet content in favor of alpha-helix structures. Data obtained from DLS and EM showed no appreciable differences in size and morphology of LDL. These structural changes observed in apoB100, which are likely implied in particle release from lipoprotein receptor, also compromise the apoprotein stability what would facilitate LDL degradation. In conclusion, the obtained results reveal a more dynamic picture of the LDL/LDLR dissociation process than previously perceived and provide new structural insights into LDL/LDLR interactions than can occur at endosomal low-pH milieu.

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Section: Resultssupporting

confidence: 90%

Structural changes induced by acidic pH in human apolipoprotein B-100

Fernández-Higuero

Benito‐Vicente

Etxebarria

et al. 2016

Sci Rep

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“…39 Of note, there are case studies reporting mutations in the non-hot spot of APOB. 40,41 Therefore, it may be beneficial to undertake sequencing of the entire APOB gene because other rare variants in the gene may be responsible for the patient's clinical phenotype. 36,39 In the present study, we screened the whole exons in APOB and found some mutations in nonhot region.…”

Section: Discussionmentioning

confidence: 99%

Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography

Zhu

et al. 2017

ATVB

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Large-scale clinical studies of FH have been reported from many countries, 2,7-16 but the features of FH in China are largely unknown. 17 Furthermore, the actual prevalence of FH is likely to be underestimated in the past, and the FH trait is masked by the CAD phenotype or more common risk factors without the genetically elevated cholesterol levels.3 Hence, the aim of present study was to investigate patients with FH phenotype and further provide molecular data on mutations for patients with FH in the Division of Dyslipidemia of Fu Wai Hospital, the only national center of dyslipidemia in China.© 2016 American Heart Association, Inc. Objective-Familial hypercholesterolemia (FH) is characterized by an elevated low-density lipoprotein cholesterol and increased risk of premature coronary artery disease. However, the general picture and mutational spectrum of FH in China are far from recognized, representing a missed opportunity for the investigation. Approach and Results-A total of 8050 patients undergoing coronary angiography were enrolled. The diagnosis of clinical FH was made using Dutch Lipid Clinic Network criteria, and the information of relatives was obtained by inquiring for the probands or from their own medical records of certain clinics/hospitals. Molecular analysis of FH was performed using target exome sequencing in LDLR (low-density lipoprotein cholesterol receptor gene), APOB (apolipoprotein B gene), and PCSK9 (proprotein convertase subtilisin/kexin type 9 gene). As a result, 3.5% of the patients with definite/ probable FH phenotype (definite 1.0% and probable 2.5%) were identified. Women FH had fewer premature coronary artery disease (women <60, or men <55 years of age) when compared with men FH (70.6% versus 82.7%; P<0.001), whereas angiographic extension of coronary artery disease was significantly increased with FH diagnosis in both men and women (P<0.001). Patterns of medication use in definite/probable FH were as follows: nontreated, 20.6%; low intensity, 6.0%; moderate intensity, 68.3%; and high intensity, 5.0%. However, none of them had achieved the lowdensity lipoprotein cholesterol <100 mg/dL. Additionally, mutational analysis was performed in 245 definite/probable FH cases, and risk variants were identified in 115 patients, giving a detection rate of 46.9%. Conclusions-We showed firsthand a common identification but poor treatment of patients with FH phenotype in Chinese coronary angiography patients. Genetic data in our FH cases might contribute to update the frequency and spectrum of Chinese FH scenarios. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Prevalence of FHBasic characteristics of the study population are summarized in Table 1. The mean (±SD) age of the participants was 57.2±10.5 years, of whom 68.7% were men and 83.8% were with CAD and 37.8% with pCAD (<55 years for men and <60 years for women). The mean total cholesterol and LDL-C were 165.25±50.58 and 101.54±43.63 mg/dL, respectively. In the sample, there were 1.0% def...

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“…APOB gene variants can change secondary structure of the human ApoB and the LDL particle size in comparison with the wild type LDL particle [94]. These changes may also impact the LDL oxidation.…”

Section: Resultsmentioning

confidence: 99%

Multiple rare and common variants in APOB gene locus associated with oxidatively modified low-density lipoprotein levels

et al. 2019

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Oxidatively modified low-density lipoproteins (oxLDL) play an important role in the occurrence and progression of atherosclerosis. To identify the genetic factors influencing the oxLDL levels, we have genotyped 776 DNA samples of Russian individuals for 196,725 single-nucleotide polymorphisms (SNPs) using the Cardio-MetaboChip (Illumina, USA) and conducted genome-wide association study (GWAS). Fourteen common variants in the locus including APOB gene were significantly associated with the oxLDL levels ( P < 2.18 × 10 −7 ). These variants explained only 6% of the variation in the oxLDL levels. Then, we assessed the contribution of rare coding variants of APOB gene to the oxLDL levels. Individuals with the extreme oxLDL levels (48 with the lowest and 48 with the highest values) were selected for targeted sequencing of the region including APOB gene. To evaluate the contribution of the SNPs to the oxLDL levels we used various statistical methods for the association analysis of rare variants: WST, SKAT, and SKAT-O. We revealed that both synonymous and nonsynonymous SNPs affected the oxLDL levels. For the joint analysis of the rare and common variants, we conducted the SKAT-C testing and found a group of 15 SNPs significantly associated with the oxLDL levels ( P = 2.14 × 10 −9 ). Our results indicate that the oxLDL levels depend on both common and rare variants of the APOB gene.

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Structural analysis of APOB variants, p.(Arg3527Gln), p.(Arg1164Thr) and p.(Gln4494del), causing Familial Hypercholesterolaemia provides novel insights into variant pathogenicity

Cited by 32 publications

References 39 publications

Structural changes induced by acidic pH in human apolipoprotein B-100

Structural changes induced by acidic pH in human apolipoprotein B-100

Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography

Multiple rare and common variants in APOB gene locus associated with oxidatively modified low-density lipoprotein levels

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