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The Proprotein Convertase Subtilisin/Kexin Type 9-resistant R410S Low Density Lipoprotein Receptor Mutation: A NOVEL MECHANISM CAUSING FAMILIAL HYPERCHOLESTEROLEMIA.
Susan-Resiga, Delia; Girard, Emmanuelle; Kiss, Robert Scott; Essalmani, Rachid; Hamelin, Josée; Asselin, Marie-Claude; Awan, Zuhier; Butkinaree, Chutikarn; Fleury, Alexandre; Soldera, Armand; Dory, Yves L; Baass, Alexis; Seidah, Nabil G.
Afiliação
  • Susan-Resiga D; From the Laboratory of Biochemical Neuroendocrinology, Montreal, Quebec H2W 1R7, Canada.
  • Girard E; From the Laboratory of Biochemical Neuroendocrinology, Montreal, Quebec H2W 1R7, Canada.
  • Kiss RS; the Department of Medicine, McGill University, Montreal, Quebec H3G 2M1, Canada.
  • Essalmani R; From the Laboratory of Biochemical Neuroendocrinology, Montreal, Quebec H2W 1R7, Canada.
  • Hamelin J; From the Laboratory of Biochemical Neuroendocrinology, Montreal, Quebec H2W 1R7, Canada.
  • Asselin MC; From the Laboratory of Biochemical Neuroendocrinology, Montreal, Quebec H2W 1R7, Canada.
  • Awan Z; From the Laboratory of Biochemical Neuroendocrinology, Montreal, Quebec H2W 1R7, Canada.
  • Butkinaree C; From the Laboratory of Biochemical Neuroendocrinology, Montreal, Quebec H2W 1R7, Canada.
  • Fleury A; the Laboratory of Supramolecular Chemistry, Department of Chemistry, University of Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada.
  • Soldera A; the Laboratory of Supramolecular Chemistry, Department of Chemistry, University of Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada.
  • Dory YL; the Laboratory of Supramolecular Chemistry, Department of Chemistry, University of Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada.
  • Baass A; Nutrition, Metabolism, and Atherosclerosis Clinic, Institut de Recherches Cliniques de Montréal, affiliated with University of Montreal, Montreal, Quebec H2W 1R7, Canada.
  • Seidah NG; From the Laboratory of Biochemical Neuroendocrinology, Montreal, Quebec H2W 1R7, Canada. Electronic address: seidahn@ircm.qc.ca.
J Biol Chem ; 292(5): 1573-1590, 2017 02 03.
Article em En | MEDLINE | ID: mdl-27998977
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Endossomos / Receptores de LDL / Pró-Proteína Convertase 9 / Hiperlipoproteinemia Tipo II / Lipoproteínas LDL / Lisossomos Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Endossomos / Receptores de LDL / Pró-Proteína Convertase 9 / Hiperlipoproteinemia Tipo II / Lipoproteínas LDL / Lisossomos Idioma: En Ano de publicação: 2017 Tipo de documento: Article