ArticleThe Journal of biological chemistry2017
The Proprotein Convertase Subtilisin/Kexin Type 9-resistant R410S Low Density Lipoprotein Receptor Mutation: A NOVEL MECHANISM CAUSING FAMILIAL HYPERCHOLESTEROLEMIA.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 31 citations in OpenAlex.
- Pharmacogenomics of Atherosclerotic Plaque: Pathophysiological Background and Therapeutic Perspectives.Current atherosclerosis reports · 2026Review
- Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.Signal transduction and targeted therapy · 2024Review
- Pharmacogenomics of Cardiovascular Drugs for Atherothrombotic, Thromboembolic and Atherosclerotic Risk.Genes · 2023Review
- Endocrine Regulation of Microvascular Receptor-Mediated Transcytosis and Its Therapeutic Opportunities: Insights by PCSK9-Mediated Regulation.Pharmaceutics · 2023Review
- Resistin Modulates Low-Density Lipoprotein Cholesterol Uptake in Human Placental Explants via PCSK9.Reproductive sciences (Thousand Oaks, Calif.) · 2022Article
- Proprotein convertase subtilisin/kexin type 9 inhibitor non responses in an adult with a history of coronary revascularization: A case report.World journal of clinical cases · 2022Article
- Article
- The Multifaceted Biology of PCSK9.Endocrine reviews · 2022Review
- Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies.Journal of the American College of Cardiology · 2021Article
- Montreal-FH-SCORE Predicts Coronary Artery Calcium Score in Patients With Familial Hypercholesterolemia.CJC open · 2021Article
- The motif EThe Journal of biological chemistry · 2020Article
- Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia.Frontiers in genetics · 2020Review
- Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor).Arteriosclerosis, thrombosis, and vascular biology · 2019Article
- New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Familial hypercholesterolemia (FH) is characterized by severely elevated low density lipoprotein (LDL) cholesterol. Herein, we identified an FH patient presenting novel compound heterozygote mutations R410S and G592E of the LDL receptor (LDLR). The patient responded modestly to maximum rosuvastatin plus ezetimibe therapy, even in combination with a PCSK9 monoclonal antibody injection. Using cell biology and molecular dynamics simulations, we aimed to define the underlying mechanism(s) by which these LDLR mutations affect LDL metabolism and lead to hypercholesterolemia. Our data showed that the LDLR-G592E is a class 2b mutant, because it mostly failed to exit the endoplasmic reticulum and was degraded. Even though LDLR-R410S and LDLR-WT were similar in levels of cell surface and total receptor and bound equally well to LDL or extracellular PCSK9, the LDLR-R410S was resistant to exogenous PCSK9-mediated degradation in endosomes/lysosomes and showed reduced LDL internalization and degradation relative to LDLR-WT. Evidence is provided for a tighter association of LDL with LDLR-R410S at acidic pH, a reduced LDL delivery to late endosomes/lysosomes, and an increased release in the medium of the bound/internalized LDL, as compared with LDLR-WT. These data suggested that LDLR-R410S recycles loaded with its LDL-cargo. Our findings demonstrate that LDLR-R410S represents an LDLR loss-of-function through a novel class 8 FH-causing mechanism, thereby rationalizing the observed phenotype.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.