9 results on '"Jean-Pierre Rabès"'
Search Results
2. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia
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Wilfried Le Goff, Josée Hamelin, Jean-Pierre Rabès, Zélie Julia, Dominique Bonnefont-Rousselot, Valérie Carreau, Olivier Meilhac, Mathilde Varret, Marianne Abifadel, Philippe Couvert, Nabil G. Seidah, Laurent Tosolini, Alain Carrié, John Chapman, Suzanne Benjannet, Eric Bruckert, Maryse Guerin, Jean-Baptiste Michel, Catherine Boileau, and Annik Prat
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Male ,Paris ,Apolipoprotein B ,DNA Mutational Analysis ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Transfection ,medicine.disease_cause ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,PCSK9 Gene ,0302 clinical medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Apolipoproteins B ,030304 developmental biology ,Genetics ,0303 health sciences ,Mutation ,biology ,PCSK9 ,Cholesterol, HDL ,Serine Endopeptidases ,nutritional and metabolic diseases ,Hep G2 Cells ,Proprotein convertase ,medicine.disease ,Phenotype ,Pedigree ,HEK293 Cells ,Receptors, LDL ,LDL receptor ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,Proprotein Convertases ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,Biomarkers - Abstract
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.
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- 2012
3. Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients
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Asma Omezzine, Lamia Rebhi, Faouzi Maatouk, Imen Jguirim, Maha Kacem, Mohamed Najah, Marianne Abifadel, Awatef Jelassi, Afef Slimani, Jean-Pierre Rabès, Catherine Boileau, Mustapha Rouis, Mathilde Varret, Khaldoun Ben Hamda, Mohamed Naceur Slimane, Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tunisian Ministry of Higher Education and Scientific Research [PHC-Utique 10G0812 du CMCU], French Ministry of Higher Education and Scientific Research [PHC-Utique 10G0812 du CMCU], L'Agence Nationale de la Recherche [ANR-08-GENO-002-01], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Adult ,Male ,LDLR gene ,Apolipoprotein E ,Heterozygote ,Tunisia ,Adolescent ,Familial hypercholesterolemia ,Mutation, Missense ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,medicine.disease_cause ,Frameshift mutation ,Hyperlipoproteinemia Type II ,PCSK9 Gene ,Apolipoproteins E ,Phenotypic variability ,Genetic variation ,medicine ,Humans ,Missense mutation ,Child ,Frameshift Mutation ,Gene ,Genetics ,Mutation ,Homozygote ,Serine Endopeptidases ,Cholesterol, LDL ,Middle Aged ,Molecular biology ,Pedigree ,Phenotype ,Receptors, LDL ,PCSK9 gene ,Child, Preschool ,LDL receptor ,Female ,lipids (amino acids, peptides, and proteins) ,Proprotein Convertases ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine - Abstract
Background Autosomal dominant hypercholesterolemia (ADH) is commonly caused by mutations in the low-density lipoprotein (LDL) receptor gene ( LDLR ), in the apolipoprotein B-100 gene ( APOB ), or in the proprotein convertase subtilisin kexine 9 gene ( PCSK9 ). ADH subjects carrying a mutation in LDLR present highly variable plasma LDL-cholesterol (LDL-C). This variability might be due to environmental factors or the effect of some modifying genes such as PCSK9 and APOE . Aims We investigated the molecular basis of thirteen Tunisian ADH families and attempted to determine the impact of PCSK9 and APOE gene variations on LDL-cholesterol levels and on the variable phenotypic expression of the disease. Methods and results Fifty six subjects were screened for mutations in the LDLR gene through direct sequencing. The causative mutation was found to segregate with the disease in each family and a new frameshift mutation, p.Met767CysfsX21, was identified in one family. The distribution of total- and LDL-cholesterol levels, adjusted for age and gender, among homozygous and heterozygous ADH patients varied widely. Within seven families, nine subjects presented low LDL-cholesterol levels despite carrying a mutation in the LDLR gene. To identify the molecular actors underlying this phenotypic variability, the PCSK9 gene was screened using direct sequencing and/or enzymatic restriction analysis, and the apo E genotypes were determined. A new missense variation (p.Pro174Ser) in the PCSK9 gene was identified and characterized as a new putative loss-of-function mutation. Conclusion Genetic variations in PCSK9 and APOE genes could explain only part of the variability observed in the phenotypic expression in Tunisian ADH patients carrying mutations in the LDLR gene. Other genetic variants and environmental factors very probably act to fully explain this phenotypic variability.
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- 2012
4. Limited mutational heterogeneity in the LDLR gene in familial hypercholesterolemia in Tunisia
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A.M. Abid, Mathilde Varret, Imen Jguirim, Awatef Jelassi, L. Boughamoura, Mohamed Najah, Jean-Pierre Rabès, Mohamed Naceur Slimane, F. Maatouk, Catherine Boileau, and M. Rouis
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Adult ,Male ,Heterozygote ,Tunisia ,Adolescent ,DNA Mutational Analysis ,Population ,Nonsense mutation ,Familial hypercholesterolemia ,Biology ,Frameshift mutation ,Hyperlipoproteinemia Type II ,Exon ,medicine ,Humans ,Missense mutation ,education ,Aged ,Family Health ,Genetics ,education.field_of_study ,Polymorphism, Genetic ,Autosomal dominant trait ,Exons ,medicine.disease ,Pedigree ,Receptors, LDL ,Mutation ,Mutation (genetic algorithm) ,Female ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine - Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the low-density lipoprotein receptor ( LDLR ), apolipoprotein B ( APOB ), and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) genes. In previous studies, we have identified novel mutations in Tunisian FH families. In this study, we have extended our investigation to additional families. Five unrelated probands were screened for mutations in the LDLR and APOB genes, using direct sequencing and enzymatic restriction. We identified two novel LDLR mutations: a missense mutation in exon 7: p.Gly343Cys (c.1027G>T), and a nonsense mutation in exon 17: p.Lys816X (c.2446A>T). Using the PolyPhen and SIFT prediction computer programs the p.Gly343Cys is predicted to have a deleterious effect on LDL receptor activity. The missense mutation we found in exon 3, p.Cys89Trp (c.267C>G), has previously been identified in patients from United Kingdom and Spain, and is reported here for the first time in the Tunisian population. Finally, the framshift mutation in exon 10, p.Ser493ArgfsX44, is reported here for the fourth and fifth time in Tunisian families. The latter is the most frequent FH-causing mutation in Tunisia. These LDLR gene mutations enrich the spectrum of mutations causing FH in the Tunisian population. The framshift mutation, p.Ser493ArgfsX44, seems to be a founder mutation in this population.
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- 2009
5. Usefulness of the genetic risk score to identify phenocopies in families with autosomal dominant hypercholesterolemia?
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Youmna Ghaleb, Sandy Elbitar, Catherine Boileau, Petra El Khoury, Mathilde Varret, Marianne Abifadel, and Jean-Pierre Rabès
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Phenocopy ,Genetics ,Biology ,Genetic risk ,Cardiology and Cardiovascular Medicine - Published
- 2017
6. Identification of a new mutation in the N-terminal region of the apolipoprotein B gene in familial hypercholesterolemia
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Sekar Kathiresan, Marianne Abifadel, Y. Ghaleb, Eric Bruckert, Mathilde Varret, N. Stitziel, S. Elbitar, Gina M. Peloso, Valérie Carreau, Jean-Pierre Rabès, P. El Khoury, and Catherine Boileau
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Genetics ,Apolipoprotein B ,biology ,Terminal (electronics) ,New mutation ,biology.protein ,medicine ,Identification (biology) ,Familial hypercholesterolemia ,Cardiology and Cardiovascular Medicine ,medicine.disease ,Gene - Published
- 2016
7. Phenotypical and molecular characterization of familial heterozygous hypobetalipoproteinemia (fhbl)
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M. Lapoirie, Alain Lachaux, Agnès Sassolas, M. Nouvel, M. Di Filippo, S. Chebel-Dumont, Noël Peretti, Marie-Elisabeth Samson-Bouma, P. Moulin, Pascale Benlian, Alain Carrié, and Jean-Pierre Rabès
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Genetics ,medicine ,Hypobetalipoproteinemia ,Biology ,Cardiology and Cardiovascular Medicine ,medicine.disease ,Phenotype - Published
- 2014
8. Analysis of the 525 point mutations in the human LDL receptor gene database
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Ludovic Villéger, Catherine Boileau, Claudine Junien, Christophe Béroud, Mathilde Varret, and Jean-Pierre Rabès
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Genetics ,Ldl receptor gene ,Point mutation ,Biology ,Cardiology and Cardiovascular Medicine - Published
- 1999
9. 1.P.275 Results of the molecular analysis of the 220 point mutations in the human LDL receptor gene database
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Gwenaëlle Collod-Béroud, Christophe Béroud, Catherine Boileau, Claudine Junien, Jean-Pierre Rabès, and Mathilde Varret
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Ldl receptor gene ,Genetics ,Point mutation ,Biology ,Cardiology and Cardiovascular Medicine ,Molecular analysis - Published
- 1997
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