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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia
Atherosclerosis, Volume 223, No. 2, Year 2012
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Description
Background: The identification of mutations in PCSK9 (proprotein convertase subtilisin kexin9) in autosomal dominant hypercholesterolemia (ADH), has revealed the existence of a new player in cholesterol homeostasis. PCSK9 has been shown to enhance the degradation of the LDL receptor (LDLR) at the cell surface. Gain-of-function mutations of PCSK9 induce ADH and are very rare, but their identification is crucial in studying PCSK9's role in hypercholesterolemia, its detailed trafficking pathway and its impact on the LDLR. Methods: In order to identify new mutations and understand the exact mechanisms of action of mutated PCSK9, PCSK9 was sequenced in 75 ADH patients with no mutations in the LDLR or APOB genes. Functional analyses in cell culture were conducted and the impact of novel PCSK9 mutations on the quantitative and qualitative features of lipoprotein particles and on the HDL-mediated cellular cholesterol efflux was studied. Results: Among these 75 ADH probands with no mutations in the LDLR or APOB genes, four gain-of-function mutations of PCSK9 were identified, of which two were novel: the p.Leu108Arg and the p.Asp35Tyr substitutions. In vitro studies of their consequences on the activity of PCSK9 on cell surface levels of LDLR showed that the p.Leu108Arg mutation clearly results in a gain-of-function, while the p.Asp35Tyr mutation created a novel Tyr-sulfation site, which may enhance the intracellular activity of PCSK9. Conclusion: These data further contribute to the characterization of PCSK9 mutations and to better understanding of the impact on cholesterol metabolism of this new therapeutic target. © 2012 Elsevier Ireland Ltd.
Authors & Co-Authors
Abifadel, Marianne S.
France, Paris
Hôpital Bichat-claude-bernard Ap-hp
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Guérin, Maryse
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Sorbonne Université
Benjannet, Suzanne
Canada, Montreal
Institut de Recherches Cliniques de Montréal
Rabès, Jean Pierre H.
France, Paris
Hôpital Bichat-claude-bernard Ap-hp
France, Boulogne-billancourt
Hopital Ambroise Pare, Boulogne-billancourt
France, Versailles
Université de Versailles Saint-quentin-en-yvelines
Le Goff, Wilfried
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Sorbonne Université
Julia, Zélie
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Sorbonne Université
Hamelin, Josée
Canada, Montreal
Institut de Recherches Cliniques de Montréal
Carreau, Valérie
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Sorbonne Université
Varret, Mathilde
France, Paris
Hôpital Bichat-claude-bernard Ap-hp
Bruckert, Éric
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Sorbonne Université
Tosolini, Laurent
France, Paris
Hôpital Bichat-claude-bernard Ap-hp
Meilhac, Olivier
France, Paris
Hôpital Bichat-claude-bernard Ap-hp
Couvert, Philippe
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Sorbonne Université
Bonnefont-Rousselot, Dominique
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Université Paris Cité
Chapman, John
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Sorbonne Université
Carrié, Alain
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Sorbonne Université
Michel, Jean Baptiste L.
France, Paris
Hôpital Bichat-claude-bernard Ap-hp
Prat, Annik
Canada, Montreal
Institut de Recherches Cliniques de Montréal
Seidah, Nabil Georges
Canada, Montreal
Institut de Recherches Cliniques de Montréal
Boileau, Catherine R.
France, Paris
Hôpital Bichat-claude-bernard Ap-hp
France, Boulogne-billancourt
Hopital Ambroise Pare, Boulogne-billancourt
France, Versailles
Université de Versailles Saint-quentin-en-yvelines
Statistics
Citations: 96
Authors: 20
Affiliations: 8
Identifiers
Doi:
10.1016/j.atherosclerosis.2012.04.006
e-ISSN:
18791484
Research Areas
Cancer
Genetics And Genomics
Study Approach
Qualitative
Quantitative