ArticleFEBS open bio2014
Mutation G805R in the transmembrane domain of the LDL receptor gene causes familial hypercholesterolemia by inducing ectodomain cleavage of the LDL receptor in the endoplasmic reticulum.
Article in FEBS open bio, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 40 citations in OpenAlex.
- Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants in Patient Lymphocytes to Assess the Effect of Evinacumab in Homozygous Familial Hypercholesterolemia Patients With a Spectrum of LDLR Activity.Arteriosclerosis, thrombosis, and vascular biology · 2019Trial
- Associations of plasma level of soluble LDL receptor with cardiovascular events and mortality in a large prospective cohort study.Lipids in health and disease · 2026Article
- Functional analysis from ex-vivo characterization of LDLR exon 13-15 duplication associated to familial hypercholesterolemia.Frontiers in endocrinology · 2026Article
- Association of the rs688 Polymorphism in the Gene Encoding Low-Density Lipoprotein Receptor in Bangladeshi Population With Coronary Artery Disease.Genetics research · 2026Article
- Clinical exome sequencing identifies novel gene variants associated with ischemic stroke in the Saudi Tabuk population.Frontiers in human neuroscience · 2025Article
- Porcine low-density lipoprotein receptor plays an important role in classical swine fever virus infection.Emerging microbes & infections · 2024Article
- Acute Coronary Syndrome in a 9-Year-Old Girl With Homozygous Familial Hypercholesterolemia.JACC. Case reports · 2024Article
- Soluble LDL-receptor is induced by TNF-α and inhibits hepatocytic clearance of LDL-cholesterol.Journal of molecular medicine (Berlin, Germany) · 2023Article
- Novel Tools for Comprehensive Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants.International journal of molecular sciences · 2023Article
- Calling and Phasing of Single-Nucleotide and Structural Variants of theInternational journal of molecular sciences · 2023Article
- LDLR gene polymorphism (rs688) affects susceptibility to cardiovascular disease in end-stage kidney disease patients.BMC nephrology · 2021Article
- Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis.Nature communications · 2021Article
- Influence of interfacial tryptophan residues on an arginine-flanked transmembrane helix.Biochimica et biophysica acta. Biomembranes · 2020Article
- Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia.Frontiers in genetics · 2020Review
- LDLR Gene Polymorphisms (rs5925 and rs1529729) Are Associated with Susceptibility to Coronary Artery Disease in a South Indian Population.Medical sciences (Basel, Switzerland) · 2019Article
- Bladder drug mirabegron exacerbates atherosclerosis through activation of brown fat-mediated lipolysis.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- The UCL low-density lipoprotein receptor gene variant database: pathogenicity update.Journal of medical genetics · 2017Article
- A novel indel variant in LDLR responsible for familial hypercholesterolemia in a Chinese family.PloS one · 2017Article
- Protein traffic disorders: an effective high-throughput fluorescence microscopy pipeline for drug discovery.Scientific reports · 2015Article
- Association ofIndian journal of nephrologyArticle
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
More than 1700 mutations in the low density lipoprotein receptor (LDLR) gene have been found to cause familial hypercholesterolemia (FH). These are commonly divided into five classes based upon their effects on the structure and function of the LDLR. However, little is known about the mechanism by which mutations in the transmembrane domain of the LDLR gene cause FH. We have studied how the transmembrane mutation G805R affects the function of the LDLR. Based upon Western blot analyses of transfected HepG2 cells, mutation G805R reduced the amounts of the 120 kDa precursor LDLR in the endoplasmic reticulum. This led to reduced amounts of the mature 160 kDa LDLR at the cell surface. However, significant amounts of a secreted 140 kDa G805R-LDLR ectodomain fragment was observed in the culture media. Treatment of the cells with the metalloproteinase inhibitor batimastat largely restored the amounts of the 120 and 160 kDa forms in cell lysates, and prevented secretion of the 140 kDa ectodomain fragment. Together, these data indicate that a metalloproteinase cleaved the ectodomain of the 120 kDa precursor G805R-LDLR in the endoplasmic reticulum. It was the presence of the polar Arg805 and not the lack of Gly805 which led to ectodomain cleavage. Arg805 also prevented γ-secretase cleavage within the transmembrane domain. It is conceivable that introducing a charged residue within the hydrophobic membrane lipid bilayer, results in less efficient incorporation of the 120 kDa G805R-LDLR in the endoplasmic reticulum membrane and makes it a substrate for metalloproteinase cleavage.
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