Descriptor: "MESH : DNA Mutational Analysis" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"MESH : DNA Mutational Analysis"' showing total 25 results

Start Over Descriptor "MESH : DNA Mutational Analysis"

25 results on '"MESH : DNA Mutational Analysis"'

1. A quality control program for mutation detection in KIT and PDGFRA in gastrointestinal stromal tumours

Author: Fabienne Escande, Jean Michel Coindre, Silvana Pilotti, Sébastien Forget, Paolo Dei Tos, Pierre Paul Bringuier, Maria Debiec-Rychter, Elena Tamborini, David Gonzalez, Nicolas Faur, L Morzuch, Isabelle Hostein, Louisa Toffolati, Sylvianne Olschwang, Jean-François Emile, Département de pathologie, Institut Bergonié - CRLCC Bordeaux, university of leuven, Department of Human Genetics, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CA foncello Hospital, Department of pathology, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Laboratoire de Physique des Lasers ( LPL ), Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut Galilée-Centre National de la Recherche Scientifique ( CNRS ), biology and pathological laboratory, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Service de Pathologie, Institut Bergonié, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, UNICANCER, Radboud University Medical Center [Nijmegen], Centre de Recherche en Cancérologie de Marseille (CRCM / U891 Inserm), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique des Lasers (LPL), Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), Medical University of Gdańsk, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay
Subjects: Oncology, Receptor, Platelet-Derived Growth Factor alpha, MESH : Polymorphism, Genetic, MESH: Receptor, Platelet-Derived Growth Factor alpha, DNA Mutational Analysis, MESH: Quality Control, MESH : Genotype, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genotype, MESH : Exons, 0302 clinical medicine, Surgical oncology, Genotype, MESH: DNA Mutational Analysis, 0303 health sciences, Mutation, MESH : Gastrointestinal Stromal Tumors, GiST, Gastroenterology, MESH : Quality Control, DNA, Neoplasm, Exons, 3. Good health, MESH: Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-kit, 030220 oncology & carcinogenesis, MESH: Laboratories, MESH : DNA, Neoplasm, MESH : Mutation, MESH: Gastrointestinal Stromal Tumors, Quality Control, medicine.medical_specialty, MESH: Mutation, Gastrointestinal Stromal Tumors, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, PDGFRA, Biology, MESH : Laboratories, MESH : Proto-Oncogene Proteins c-kit, 03 medical and health sciences, Internal medicine, MESH: Polymorphism, Genetic, medicine, Humans, Genotyping, 030304 developmental biology, MESH: Humans, Polymorphism, Genetic, MESH : Humans, Hepatology, digestive system diseases, Immunology, MESH : Receptor, Platelet-Derived Growth Factor alpha, MESH: Exons, Laboratories
Abstract: International audience; BACKGROUND: Although most gastrointestinal stromal tumours (GIST) carry oncogenic mutations in KIT exons 9, 11, 13 and 17, or in platelet-derived growth factor receptor alpha (PDGFRA) exons 12, 14 and 18, around 10% of GIST are free of these mutations. Genotyping and accurate detection of KIT/PDGFRA mutations in GIST are becoming increasingly useful for clinicians in the management of the disease. METHOD: To evaluate and improve laboratory practice in GIST mutation detection, we developed a mutational screening quality control program. Eleven laboratories were enrolled in this program and 50 DNA samples were analysed, each of them by four different laboratories, giving 200 mutational reports. RESULTS: In total, eight mutations were not detected by at least one laboratory. One false positive result was reported in one sample. Thus, the mean global rate of error with clinical implication based on 200 reports was 4.5%. Concerning specific polymorphisms detection, the rate varied from 0 to 100%, depending on the laboratory. The way mutations were reported was very heterogeneous, and some errors were detected. CONCLUSION: This study demonstrated that such a program was necessary for laboratories to improve the quality of the analysis, because an error rate of 4.5% may have clinical consequences for the patient.
Published: 2011
Full Text: View/download PDF

2. ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences

Author: Xavier Bertagna, Francoise Doullay, Ludivine Drougat, E. Sonnet, Jérôme Bertherat, Joël Coste, Lionel Groussin, Rossella Libé, Françoise Borson-Chazot, Stéphanie Espiard, F. Brucker-Davis, Florence Torremocha, Guillaume Assié, Felix Beuschlein, Constantine A. Stratakis, Bruno Ragazzon, Marie-Laure Raffin-Sanson, G. Barrande, Stephanie Lopez, Karine Perlemoine, Nathalie Chabbert-Buffet, Denis Pinsard, Laurence Guignat, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional d'Orléans (CHRO), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Diabétologie-Endocrinologie (NICE - Endocrino), Centre Hospitalier Universitaire de Nice (CHU Nice), Endocrinologie, diabète, maladies métaboliques (CHU Marseille, AP-HM), Assistance Publique - Hôpitaux de Marseille (APHM), Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Service Endocrinologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'endocrinologie diabétologie et nutrition [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, Gynécologie-obstétrique et médecine de la reproduction - Maternité [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’endocrinologie et nutrition [AP-HP Ambroise-Paré], Hôpital Ambroise Paré [AP-HP], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupement hospitalier lyon Est (Hospices Civils de Lyon), Hospices Civils de Lyon (HCL), Unité d’Epidémiologie et de Biostatistiques [APHP Cochin-Broca-Hôtel Dieu], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Klinikum der Universitat Munchen, Ludwig-Maximilians-Universität München (LMU), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de référence des maladies rares de la surrénale [Cochin], Centre Hospitalier Régional d'Orléans ( CHR ), Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Diabétologie-Endocrinologie ( NICE - Endocrino ), CHU Nice, Assistance Publique - Hôpitaux de Marseille ( APHM ), Hôpital de la Cavale Blanche - CHRU Brest ( CHU - BREST ), CHU de Poitiers, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, Service d'obstétrique gynécologie et médecine reproductive [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service d’endocrinologie et nutrition [AP-HP Hôpital Ambroise-Paré], AP-HP Hôpital Ambroise-Paré [Boulogne-Billancourt], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Groupement hospitalier lyon Est ( Hospices Civils de Lyon ), Hospices Civils de Lyon ( HCL ), Maladies chroniques, santé perçue, et processus d'adaptation. Approches épidémiologiques et psychologiques. ( APEMAC - EA 4360 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Université de Lorraine ( UL ), Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ), Klinikum Grosshadern, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), CHU Cochin [AP-HP], Centre Hospitalier Régional d'Orléans (CHR), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, DNA Mutational Analysis, MESH : Aged, MESH : Adrenal Cortex Diseases, Biochemistry, Cohort Studies, MESH: Cushing Syndrome, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Adrenal Glands, Missense mutation, MESH : Female, MESH: Adrenal Glands, MESH: DNA Mutational Analysis, Cushing Syndrome, MESH: Cohort Studies, Cells, Cultured, MESH : Cushing Syndrome, Subclinical infection, MESH: Genetic Association Studies, MESH: Aged, 0303 health sciences, Aldosterone, MESH: Middle Aged, JCEM Online: Advances in Genetics, MESH : Tumor Suppressor Proteins, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Middle Aged, MESH : Adult, 3. Good health, Dexamethasone suppression test, Female, MESH: Cells, Cultured, Adrenal Cortex Diseases, Adult, medicine.medical_specialty, endocrine system, MESH : Male, Mutation, Missense, MESH : Cohort Studies, 030209 endocrinology & metabolism, Context (language use), MESH : DNA Mutational Analysis, Biology, MESH : Adrenal Glands, 03 medical and health sciences, Germline mutation, Internal medicine, MESH : Hyperplasia, Renin–angiotensin system, MESH : Cells, Cultured, medicine, Humans, MESH : HeLa Cells, MESH : Middle Aged, MESH: Tumor Suppressor Proteins, Genetic Association Studies, 030304 developmental biology, Aged, Armadillo Domain Proteins, MESH: Mutation, Missense, Hyperplasia, MESH: Humans, MESH: Hyperplasia, Tumor Suppressor Proteins, MESH: Adrenal Cortex Diseases, Biochemistry (medical), MESH : Humans, MESH: Adult, MESH : Genetic Association Studies, MESH: Male, chemistry, Macronodular Adrenal Hyperplasia, MESH: HeLa Cells, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Female, MESH : Mutation, Missense, HeLa Cells
Abstract: International audience; CONTEXT:Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH.OBJECTIVE:To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation in a large cohort of unrelated PBMAH patients with subclinical or clinical CS.PATIENTS AND METHODS:ARMC5 was sequenced in 98 unrelated PBMAH index cases. PBMAH was identified by bilateral adrenal nodular enlargement on computed tomography scan. The effect on apoptosis of ARMC5 missense mutants was tested in H295R and HeLa cells. Clinical and hormonal data were collected including midnight and urinary free cortisol levels, ACTH, androgens, renin/aldosterone ratio, cortisol after overnight dexamethasone suppression test, cortisol and 17-hydroxyprogesterone after ACTH 1-24 stimulation and illegitimate receptor responses. Computed tomography and histological reports were analyzed.RESULTS:ARMC5-damaging mutations were identified in 24 patients (26%). The missense mutants and the p.F700del deletion were unable to induce apoptosis in both H295R and HeLa cell lines, unlike the wild-type gene. ARMC5-mutated patients showed an overt CS more frequently, compared to wild-type patients: lower ACTH, higher midnight plasma cortisol, urinary free cortisol, and cortisol after dexamethasone suppression test (P = .003, .019, .006, and
Published: 2015
Full Text: View/download PDF

3. Focal adhesion kinase is involved in rabies virus infection through its interaction with viral phosphoprotein P

Author: Jovan Nikolic, Hervé Bourhy, Cécile Lagaudrière-Gesbert, Danielle Blondel, Christoph Wirblich, Florence Larrous, Baptiste Fouquet, Rhabdovirus (RHABDO), Département Virologie (Dpt Viro), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence de la Rage-Dynamique des Lyssavirus et adaptation à l'hôte (CNR), Institut Pasteur [Paris], Centre Collaborateur de l'OMS pour la Rage - Dynamique des lyssavirus et adaptation à l'hôte (CC-OMS), Thomas Jefferson University, Philadelphia, This work was supported by a grant from Fondation pour la Recherche Médicale (FRM DEQ20120323711). Confocal microscopy was performed on the 'Plate-forme Imagerie et Biologie Cellulaire' of the CNRS campus, supported by the Institut Fédératif de Recherche 87 'La plante et son environnement' and the program ASTRE of the Conseil Général de l’Essonne, Rhabdovirus ( RHABDO ), Département Virologie ( Dpt Viro ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Centre National de Référence de la Rage-Dynamique des Lyssavirus et adaptation à l'hôte ( CNR ), Centre Collaborateur de l'OMS pour la Rage - Dynamique des lyssavirus et adaptation à l'hôte ( CC-OMS ), and Institut Pasteur [Paris] (IP)
Subjects: MESH : Cell Line, DNA Mutational Analysis, MESH : Focal Adhesion Protein-Tyrosine Kinases, medicine.disease_cause, Virus Replication, Inclusion Bodies, Viral, MESH : Protein Interaction Mapping, Interferon, MESH : Rabies virus, Protein Interaction Mapping, MESH: Microscopy, Confocal, MESH: Animals, MESH: DNA Mutational Analysis, MESH : Host-Pathogen Interactions, Microscopy, Confocal, MESH: Focal Adhesion Protein-Tyrosine Kinases, MESH : Viral Structural Proteins, MESH : Protein Binding, 3. Good health, Cell biology, Virus-Cell Interactions, MESH : Mutagenesis, Site-Directed, MESH: Rabies virus, MESH : Virus Replication, MESH: Mutagenesis, Site-Directed, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH : Inclusion Bodies, Viral, medicine.drug, Protein Binding, Viral protein, Immunoprecipitation, Immunology, MESH : DNA Mutational Analysis, MESH: Viral Structural Proteins, Biology, MESH: Two-Hybrid System Techniques, Microbiology, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Phosphoproteins, Virus, Cell Line, MESH : Immunoprecipitation, Focal adhesion, Virology, Two-Hybrid System Techniques, medicine, Animals, Humans, MESH: Protein Binding, MESH : Microscopy, Confocal, Viral Structural Proteins, MESH: Humans, MESH: Immunoprecipitation, Rabies virus, MESH : Humans, MESH: Protein Interaction Mapping, MESH: Virus Replication, MESH: Host-Pathogen Interactions, Phosphoproteins, Molecular biology, MESH: Cell Line, Viral replication, MESH : Two-Hybrid System Techniques, Insect Science, Phosphoprotein, Focal Adhesion Protein-Tyrosine Kinases, Mutagenesis, Site-Directed, MESH: Inclusion Bodies, Viral, MESH : Animals, MESH : Phosphoproteins, Molecular Chaperones
Abstract: The rabies virus (RABV) phosphoprotein P is a multifunctional protein: it plays an essential role in viral transcription and replication, and in addition, RABV P has been identified as an interferon antagonist. Here, a yeast two-hybrid screen revealed that RABV P interacts with the focal adhesion kinase (FAK). The binding involved the 106-to-131 domain, corresponding to the dimerization domain of P and the C-terminal domain of FAK containing the proline-rich domains PRR2 and PRR3. The P-FAK interaction was confirmed in infected cells by coimmunoprecipitation and colocalization of FAK with P in Negri bodies. By alanine scanning, we identified a single mutation in the P protein that abolishes this interaction. The mutant virus containing a substitution of Ala for Arg in position 109 in P (P.R109A), which did not interact with FAK, is affected at a posttranscriptional step involving protein synthesis and viral RNA replication. Furthermore, FAK depletion inhibited viral protein expression in infected cells. This provides the first evidence of an interaction of RABV with FAK that positively regulates infection. IMPORTANCE Rabies virus exhibits a small genome that encodes a limited number of viral proteins. To maintain efficient virus replication, some of them are multifunctional, such as the phosphoprotein P. We and others have shown that P establishes complex networks of interactions with host cell components. These interactions have revealed much about the role of P and about host-pathogen interactions in infected cells. Here, we identified another cellular partner of P, the focal adhesion kinase (FAK). Our data shed light on the implication of FAK in RABV infection and provide evidence that P-FAK interaction has a proviral function.
Published: 2015
Full Text: View/download PDF

4. Mutational founder effect in recessive dystrophic epidermolysis bullosa families from Southern Tunisia

Author: Nizar Ben Halim, Mbarka Bchetnia, Khaled Lasram, Daniele Castiglia, Nadia Laroussi, Sonia Abdelhak, Lilia Romdhane, Rym Kefi, Mounira Meddeb Cherif, Houyem Ouragini, Mohamed Samir Boubaker, Hamida Turki, Ahlem Sabrine Ben Brick, Alain Hovnanian, Salaheddine Marrakchi, Hela Mesrati, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Department of Dermatology, Hedi Chaker Hospital [Sfax], Laboratory of Medical Genetics, Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IRCCS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the Tunisian Ministry of Higher Education and Scientific Research (Laboratory on ‘‘Biomedical Genomics and Oncogenetics’’ LR11IPT05) and the Tunisian Ministry of Public Health, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory ( LR11IPT05 ), Université Tunis El Manar ( UTM ) -Institut Pasteur de Tunis-Réseau International des Instituts Pasteur ( RIIP ), Hedi Chaker Hospital, Istituto Dermopatico dell'Immacolata ( IRCCS ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université Tunis El Manar (UTM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, MESH: Founder Effect, 030207 dermatology & venereal diseases, Consanguinity, 0302 clinical medicine, Recessive dystrophic epidermolysis bullosa, COL7A1, MESH : Epidermolysis Bullosa Dystrophica/genetics, MESH : Female, MESH : Skin/pathology, MESH: DNA Mutational Analysis, MESH : Collagen Type VII/genetics, Skin, Genetics, 0303 health sciences, MESH: Epidermolysis Bullosa Dystrophica/genetics, MESH: Collagen Type VII/genetics, General Medicine, Founder effect, Novel mutations, MESH: Epidermolysis Bullosa Dystrophica/pathology, 3. Good health, Epidermolysis Bullosa Dystrophica, Pedigree, [ SDV.GEN.GPO ] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Codon, Nonsense, Mutation (genetic algorithm), Carcinoma, Squamous Cell, Female, MESH : Mutation, MESH: Tunisia, Collagen Type VII, Tunisia, MESH: Mutation, MESH: Pedigree, MESH : Male, MESH : Founder Effect, Genes, Recessive, Dermatology, MESH : DNA Mutational Analysis, Biology, MESH : Epidermolysis Bullosa Dystrophica/pathology, MESH : Carcinoma, Squamous Cell/complications, 03 medical and health sciences, MESH : Tunisia, MESH : Consanguinity, Humans, Allele, Gene, MESH : Haplotypes, Alleles, MESH: Genes, Recessive, 030304 developmental biology, MESH: Consanguinity, MESH: Skin/pathology, MESH: Codon, Nonsense/genetics, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [ SDV ] Life Sciences [q-bio], MESH: Alleles, Haplotype, MESH : Humans, MESH : Genes, Recessive, MESH: Haplotypes, MESH: Male, MESH : Codon, Nonsense/genetics, MESH: Carcinoma, Squamous Cell/complications, Haplotypes, MESH : Pedigree, Mutation, MESH : Alleles, [ SDV.MHEP.DERM ] Life Sciences [q-bio]/Human health and pathology/Dermatology, Recessive dystrophic epidermolysis bullosa severe generalized, MESH: Female, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; Dystrophic epidermolysis bullosa (DEB) is a group of heritable bullous skin disorders caused by mutations in the COL7A1 gene. One of the most severe forms of DEB is the severe generalized [recessive dystrophic epidermolysis bullosa (RDEB-SG)] subtype, which is inherited in an autosomal recessive manner. This subtype is most often due to COL7A1 mutations resulting in a premature termination codon on both alleles. We report here, the molecular investigation of 15 patients belonging to 14 nuclear families from the city of Sfax in Southern Tunisia, with clinical features of RDEB-SG complicated by squamous cell carcinoma in 3 patients. We identified two novel mutations, p.Val769LeufsX1 and p.Ala2297SerfsX91, in addition to one previously reported mutation (p.Arg2063Trp). The p.Val769LeufsX1 mutation was shared by 11 families and haplotype analysis indicated that it is a founder mutation. The p.Ala2297SerfsX91 mutation was a private mutation found in only one family. Together with the previously described recurrent mutations in Tunisia, screening for the founder p.Val769LeufsX1 mutation should provide a rapid molecular diagnosis tool for mutation screening in RDEB patients from Southern Tunisia and possibly from other Mediterranean populations sharing the same genetic background.
Published: 2014
Full Text: View/download PDF

5. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

Author: Raouf Ben Abdelali, Véronique Lhéritier, Jean-Yves Cahn, Françoise Huguet, Norbert Ifrah, Agnès Buzyn, Noémie de Gunzburg, Elizabeth Macintyre, Vahid Asnafi, Dominique Payet-Bornet, Sébastien Maury, Jonathan Bond, Thibaud Leguay, Amélie Trinquand, Bertrand Nadel, André Delannoy, Kheira Beldjord, Hervé Dombret, Xavier Thomas, Jérôme Lambert, Ludovic Lhermitte, Hossein Mossafa, Etienne Lengliné, Yves Chalandon, Caroline Bonmati, Aline Tanguy-Schmidt, Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Cytogénétique - Pasteur-Cerba, Laboratoire Pasteur-Cerba, Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ), Hôpital de Jolimont, Haine-Saint-Paul and Cliniques Universitaires St Luc, Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'hématologie clinique [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Toulouse III - Paul Sabatier (UT3), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Recherche en Cancérologie de Lyon (CRCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Ras Proteins/genetics, Oncology, Pathology, MESH : F-Box Proteins, DNA Mutational Analysis, Cell Cycle Proteins, MESH : Gene Deletion, MESH: Receptor, Notch1, 0302 clinical medicine, MESH : Cell Cycle Proteins, Receptor, Notch1, MESH: DNA Mutational Analysis, Young adult, ddc:616, 0303 health sciences, Hazard ratio, PTEN Phosphohydrolase/genetics, hemic and immune systems, 3. Good health, MESH : Phenotype, MESH: Young Adult, 030220 oncology & carcinogenesis, Predictive value of tests, Cohort, F-Box Proteins/genetics, MESH : Proto-Oncogene Proteins, MESH: Membrane Proteins, MESH: ras Proteins, medicine.medical_specialty, MESH : Young Adult, MESH : DNA Mutational Analysis, MESH: Phenotype, MESH: PTEN Phosphohydrolase, Disease-Free Survival, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Cell Cycle Proteins, Humans, PTEN, Ubiquitin-Protein Ligases/genetics, MESH : Predictive Value of Tests, MESH: Kaplan-Meier Estimate, Cell Cycle Proteins/genetics, Receptor, Notch1/genetics, [ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Humans, Proportional hazards model, F-Box Proteins, MESH : Humans, MESH: Adult, MESH : Proportional Hazards Models, MESH: Ubiquitin-Protein Ligases, MESH : Membrane Proteins, MESH: Disease-Free Survival, Mutation, ras Proteins, Adult Acute Lymphoblastic Leukemia, MESH : Genetic Predisposition to Disease, MESH : Ubiquitin-Protein Ligases, MESH : GTP Phosphohydrolases, MESH: Female, Gene Deletion, Cancer Research, F-Box-WD Repeat-Containing Protein 7, Time Factors, MESH : Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Kaplan-Meier Estimate, MESH : PTEN Phosphohydrolase, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, GTP Phosphohydrolases, MESH: Proportional Hazards Models, MESH: Risk Factors, Risk Factors, hemic and lymphatic diseases, MESH : Female, biology, MESH : Receptor, Notch1, MESH: Genetic Predisposition to Disease, MESH : Adult, MESH : Risk Factors, MESH: Predictive Value of Tests, MESH: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Phenotype, MESH : Disease-Free Survival, Female, MESH : Mutation, MESH : Time Factors, Adult, MESH: Mutation, MESH: GTP Phosphohydrolases, Ubiquitin-Protein Ligases, MESH : Male, MESH: F-Box Proteins, MESH: Multivariate Analysis, MESH : Kaplan-Meier Estimate, Young Adult, Predictive Value of Tests, Proto-Oncogene Proteins, Internal medicine, medicine, Genetic Predisposition to Disease, Membrane Proteins/genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/classification/genetics/mortality/therapy, Proportional Hazards Models, 030304 developmental biology, business.industry, MESH: Time Factors, PTEN Phosphohydrolase, Membrane Proteins, MESH : Multivariate Analysis, GTP Phosphohydrolases/genetics, MESH: Male, MESH: Proto-Oncogene Proteins, Proto-Oncogene Proteins/genetics, MESH: Gene Deletion, Multivariate Analysis, biology.protein, MESH : ras Proteins, business
Abstract: Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Published: 2013
Full Text: View/download PDF

6. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia

Author: Véronique Bonnet, Hervé Crehalet, Gérald Luc, Lawrence P. Aggerbeck, Mathilde Di Filippo, Marie Elisabeth Samson-Bouma, Frédéric Gottrand, Jean-Pierre Rabès, Agnès Sassolas, Dominique Bozon, Service de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon (HCL)-Centre de Biologie et de pathologie Est, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Pharmacologie, toxicologie et signalisation cellulaire (U747), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Inflammation: mécanismes et régulation et interactions avec la nutrition et les candidoses, Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Interne, PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hospices Civils de Lyon ( HCL ) -Centre de Biologie et de pathologie Est, Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Physiologie Cellulaire des Regulations Hormonales, Nutritionnelles et Pharmacologiques, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biochimie et de Génétique Moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré-GHU Paris Ile-de-France Ouest, Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale ( INSERM ), PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: dyslipidemias, familial hypocholesterolemia, chylomicrons, lipoprotein/assembly, hepatosteatosis, genetics, gene expression, genotype-phenotype correlation, splicing, TRIGLYCERIDE-TRANSFER-PROTEIN, DISULFIDE-ISOMERASE, MTP GENE, SPLICING SIGNALS, APOLIPOPROTEIN-B, IDENTIFICATION, SUBUNIT, SITE, HYPOBETALIPOPROTEINEMIA, PHENOTYPE, MESH : Abetalipoproteinemia, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, DNA Mutational Analysis, 030204 cardiovascular system & hematology, Gene mutation, MESH : Child, Preschool, Compound heterozygosity, medicine.disease_cause, Biochemistry, Microsomal triglyceride transfer protein, 0302 clinical medicine, Endocrinology, Missense mutation, MESH : Female, MESH: DNA Mutational Analysis, Genetics, 0303 health sciences, Mutation, MESH: Genetic Predisposition to Disease, Abetalipoproteinemia, 3. Good health, Child, Preschool, RNA splicing, Female, MESH : Carrier Proteins, MESH : Mutation, MESH: Mutation, MESH: Carrier Proteins, QD415-436, MESH : DNA Mutational Analysis, Biology, functional analysis, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, MESH: Humans, MESH : Humans, MESH: Child, Preschool, MESH: Abetalipoproteinemia, Cell Biology, medicine.disease, Molecular biology, biology.protein, MESH : Genetic Predisposition to Disease, Carrier Proteins, Patient-Oriented and Epidemiological Research, MESH: Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Minigene
Abstract: Abetalipoproteinemia (ABL) is an inherited disease characterized by the defective assembly and secretion of apolipoprotein B-containing lipoproteins caused by mutations in the microsomal triglyceride transfer protein large subunit (MTP) gene (MTTP). We report here a female patient with an unusual clinical and biochemical ABL phenotype. She presented with severe liver injury, low levels of LDL-cholesterol, and subnormal levels of vitamin E, but only mild fat malabsorption and no retinitis pigmentosa or acanthocytosis. Our objective was to search for MTTP mutations and to determine the relationship between the genotype and this particular phenotype. The subject exhibited compound heterozygosity for two novel MTTP mutations: one missense mutation (p.Leu435His) and an intronic deletion (c.619-5_619-2del). COS-1 cells expressing the missense mutant protein exhibited negligible levels of MTP activity. In contrast, the minigene splicing reporter assay showed an incomplete splicing defect of the intronic deletion, with 26% of the normal splicing being maintained in the transfected HeLa cells. The small amount of MTP activity resulting from the residual normal splicing in the patient explains the atypical phenotype observed. Our investigation provides an example of a functional analysis of unclassified variations, which is an absolute necessity for the molecular diagnosis of atypical ABL cases.-Di Filippo, M., H. Crehalet, M. E. Samson-Bouma, V. Bonnet, L. P. Aggerbeck, J-P. Rabes, F. Gottrand, G. Luc, D. Bozon, and A. Sassolas. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia. J. Lipid Res. 2012. 53: 548-555.
Published: 2012
Full Text: View/download PDF

7. Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes

Author: Sandrine Boyault, Thomas Bachelot, Alain Puisieux, Christine Lasset, Claudine Navarro, Isabelle Treilleux, Youenn Drouet, Eric Tabone, Qing Wang, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Biologie Fonctionnelle, Insectes et Interactions (BF2I), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA), Luzhou Medical college, Department of spinal surgery, Eq 11, Oncogénèse et progression tumorale, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-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)-Département de Médecine Nucléaire, Eq 09, Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biopathologie, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Eq 02, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)-Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)-Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-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)-Département de Médecine Nucléaire, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biopathologie, Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)-Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Genomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -IFR105-Université Paris Diderot - Paris 7 ( UPD7 ), Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-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 ) -Département de Médecine Nucléaire, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Département de Biopathologie, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ) -Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ), Biologie Fonctionnelle, Insectes et Interactions ( BF2I ), Institut National de la Recherche Agronomique ( INRA ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ), Institut Universitaire de France ( IUF ), Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ) -Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: MESH: Signal Transduction, Receptors, Steroid, Cancer Research, DNA Mutational Analysis, MESH : Aged, AKT1, Kaplan-Meier Estimate, MESH : PTEN Phosphohydrolase, MESH : Breast Neoplasms, Gene mutation, MESH: Cadherins, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, CDH1, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, MESH: Carcinoma, Lobular, MESH : Female, MESH: DNA Mutational Analysis, MESH: Tumor Suppressor Protein p53, MESH: Genetic Association Studies, Genetics, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Carcinoma, Ductal, Breast, MESH : Carcinoma, Lobular, Middle Aged, MESH : Adult, Cadherins, 3. Good health, MESH : Proto-Oncogene Proteins c-akt, Oncology, 030220 oncology & carcinogenesis, Female, MESH : Cadherins, Signal Transduction, Adult, Class I Phosphatidylinositol 3-Kinases, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, Biology, MESH: PTEN Phosphohydrolase, MESH : Kaplan-Meier Estimate, 03 medical and health sciences, Breast cancer, Antigens, CD, medicine, Humans, PTEN, MESH : Middle Aged, Gene, Genetic Association Studies, PI3K/AKT/mTOR pathway, MESH: Kaplan-Meier Estimate, Aged, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, MESH: Proto-Oncogene Proteins c-akt, MESH : Humans, PTEN Phosphohydrolase, MESH : Carcinoma, Ductal, Breast, MESH : Phosphatidylinositol 3-Kinases, MESH: Adult, MESH : Genetic Association Studies, medicine.disease, MESH: Carcinoma, Ductal, Breast, Carcinoma, Lobular, MESH : Tumor Suppressor Protein p53, MESH: Phosphatidylinositol 3-Kinases, biology.protein, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-akt, MESH : Receptors, Steroid, MESH: Female, MESH: Breast Neoplasms, MESH: Receptors, Steroid
Abstract: International audience; Understanding how cancer genes are mutated in individual tumors is an important issue with potential clinical and therapeutic impact. This is especially relevant with recently developed targeted therapies since mutated genes can be targets and/or predictors. However, to date, gene mutation profiling in individual tumors is still underexplored. Breast cancer is composed of various subtypes. We presumed that this heterogeneity reflected the involvement of different molecular mechanisms including gene mutations that affect defined signaling pathways. Unlike the majority of published mutational studies, this study was aimed to draw a mutation profile in individual tumors by screening a panel of cancer genes in the same tumor. Thus, five genes frequently mutated in breast cancers: TP53, PIK3CA, PTEN, CDH1, and AKT1 were screened in each of 120 human primary breast tumors. Mutations in at least one of these genes were found in 62.5% of the tumors, of which the majority carried a single-gene mutation. Interestingly, a substantial proportion of tumors carried mutations either in TP53 or in genes of the PI3K pathway (PIK3CA or PTEN or AKT1). These two distinct mutation patterns were significantly associated to hormone receptor expression but independent of HER2 status.
Published: 2012
Full Text: View/download PDF

8. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation

Author: Sylvie Salenave, Jessica Zucman-Rossi, Emmanuelle Jeannot, Gabrielle Couchy, Philippe Chanson, Paulette Bioulac-Sage, Jean-Charles Nault, Charles Balabaud, Marie-José Redon, Camilla Pilati, Sophie Prevot, Marie-Christine Saint-Paul, Philippe Labrune, Jeanne Tran Van Nhieu, Anne de Muret, Monique Fabre, Jean-Yves Scoazec, Catherine Buffet, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pôle Digestif, Hôpital Archet 2 [Nice] (CHU), Service d'hépato-gastro-entérologie, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et de Cytologie Pathologiques [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Antoine-Béclère, Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie [Béclère], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anipath, UFR Médecine Lyon-RTH Laennec-UFR Médecine Lyon-RTH Laennec, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service d'Endocrinologie et Maladies de la reproduction, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine-Béclère, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Anipath, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Hôpital Archet 2 [Nice] ( CHU ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine-Béclère, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Anipath, Université Paris-Sud - Paris 11 ( UP11 ) -IFR93-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre
Subjects: Male, MESH: Signal Transduction, MESH : Liver Neoplasms, MESH : GTP-Binding Protein alpha Subunits, Gs, DNA Mutational Analysis, MESH : Aged, MESH : Models, Biological, Gene mutation, MESH: Base Sequence, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Adenoma, Liver Cell, 0302 clinical medicine, MESH: Liver Neoplasms, MESH : STAT3 Transcription Factor, GTP-Binding Protein alpha Subunits, Gs, MESH : Female, MESH: DNA Mutational Analysis, MESH: Carcinoma, Hepatocellular, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Liver Neoplasms, MESH: STAT3 Transcription Factor, DNA, Neoplasm, MESH : Adult, Middle Aged, 3. Good health, HNF1A, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Female, MESH : DNA, Neoplasm, MESH : Mutation, Signal Transduction, MESH : Carcinoma, Hepatocellular, Adult, STAT3 Transcription Factor, musculoskeletal diseases, Carcinoma, Hepatocellular, MESH: Mutation, MESH: Fibrous Dysplasia, Polyostotic, MESH : Male, MESH : Fibrous Dysplasia, Polyostotic, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, Biology, Fibrous Dysplasia, Polyostotic, Models, Biological, Adenoma, Liver Cell, 03 medical and health sciences, MESH : Adenoma, Liver Cell, Chromogranins, medicine, GNAS complex locus, Humans, MESH : Middle Aged, Aged, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, Base Sequence, Hepatology, Oncogene, MESH : Humans, MESH: Models, Biological, MESH: Adult, Hepatocellular adenoma, MESH: GTP-Binding Protein alpha Subunits, Gs, medicine.disease, MESH: Male, Mutation, Inflammatory Hepatocellular Adenoma, biology.protein, Cancer research, MESH : Base Sequence, Carcinogenesis, MESH: Female
Abstract: Background & Aims Mosaic G-protein alpha-subunit ( GNAS )-activating mutations are responsible for the McCune–Albright (MCA) syndrome. This oncogene that activates the adenylate cyclase is also mutated in various tumor types leading to the accumulation of cyclic-AMP. Identification of a hepatocellular adenoma (HCA) in two MCA patients led us to search for GNAS activation in benign and malignant hepatocellular carcinogenesis. Methods GNAS mutations were screened by sequencing 164 HCA, 245 hepatocellular carcinoma (HCC), and 17 fibrolamellar carcinomas. Tumors were characterized by quantitative RT-PCR, gene mutation screening and pathological reviewing. The consequences of wild type and mutant GNAS expression were analyzed in hepatocellular cell lines. Results A somatic GNAS -activating mutation was identified in 5 benign tumors and in 2 HCC. In benign tumors, GNAS mutations were exclusive from HNF1A , CTNNB1 , and IL6ST mutations whereas one HCC demonstrated both CTNNB1 and GNAS mutations. Quantitative RT-PCR showed an activation of the IL-6 and interferon pathways in GNAS -mutated tumor tissues. Accordingly, pathological reviewing identified in GNAS -mutated tumors an inflammatory phenotype characterized by fibrosis and STAT3 activation. We further demonstrated in HCC cell lines that GNAS mutant expression induced inflammatory response and STAT3 activation. Conclusions We identified for the first time the association between two rare diseases, MCA syndrome and HCA occurrence, but also that somatic GNAS -activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype. These results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis.
Published: 2012
Full Text: View/download PDF

9. Zidovudine (AZT) has a bactericidal effect on enterobacteria and induces genetic modifications in resistant strains

Author: M.-A. Mazoyer, Anne Doléans-Jordheim, Emmanuelle Bergeron, F. Bereyziat, F. Morfin, S. Ben-Larbi, Jean Freney, Oana Dumitrescu, Charles Dumontet, Lars Petter Jordheim, Ecologie microbienne ( EM ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Vétérinaire de Lyon ( ENVL ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique ( INRA ) -VetAgro Sup ( VAS ), Centre National de Référence des Staphylocoques, INSERM U851, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Microbiologie UNITE RTI2B, Institut des Sciences Pharmaceutiques et Biologiques ( ISPB ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon, Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Equipe 14, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon, Virologie et Pathologie Humaine (VirPath), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie et Pathogénèse Humaine, Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Oddrun Mjalands Stiftelse For Kreftforskning, Immunité infection vaccination ( I2V ), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR128-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Sequence Analysis, DNA, MESH : Escherichia coli, Time Factors, DNA Mutational Analysis, Antibiotics, Drug resistance, medicine.disease_cause, MESH : Drug Resistance, Bacterial, MESH: Drug Synergism, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Staphylococcus aureus, MESH : Bacterial Proteins, MESH: DNA Mutational Analysis, MESH : Anti-Bacterial Agents, MESH: Bacterial Proteins, MESH: Microbial Viability, 0303 health sciences, MESH: Microbial Sensitivity Tests, MESH: Escherichia coli, MESH : Amikacin, MESH : Staphylococcus aureus, Aminoglycoside, MESH: Zidovudine, Drug Synergism, General Medicine, Antimicrobial, Anti-Bacterial Agents, 3. Good health, MESH: Shigella dysenteriae, MESH : Thymidine Kinase, Infectious Diseases, MESH : Mutagens, MESH: Amikacin, Gentamicin, MESH : Mutation, Zidovudine, medicine.drug, MESH : Time Factors, Microbiology (medical), MESH: Thymidine Kinase, Staphylococcus aureus, MESH: Gentamicins, MESH: Mutation, Shigella dysenteriae, MESH : Drug Synergism, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Microbial Sensitivity Tests, MESH : DNA Mutational Analysis, Biology, Thymidine Kinase, Microbiology, 03 medical and health sciences, Bacterial Proteins, MESH: Anti-Bacterial Agents, MESH: Mutagens, Drug Resistance, Bacterial, MESH: Drug Resistance, Bacterial, Escherichia coli, medicine, Humans, MESH : Gentamicins, Amikacin, 030304 developmental biology, MESH : Zidovudine, [ SDE.BE ] Environmental Sciences/Biodiversity and Ecology, Microbial Viability, MESH: Humans, 030306 microbiology, MESH: Time Factors, MESH : Humans, MESH : Microbial Viability, Sequence Analysis, DNA, biochemical phenomena, metabolism, and nutrition, MESH : Shigella dysenteriae, Virology, Thymidine kinase, Mutation, MESH : Microbial Sensitivity Tests, Gentamicins, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Mutagens, MESH : Sequence Analysis, DNA
Abstract: International audience; The spread of multiresistant bacteria increases the need for new antibiotics. The observation that some nucleoside analogues have antibacterial activity led us to further investigate the antimicrobial activity and resistance of zidovudine (AZT). We determined the minimum inhibition concentration (MIC), studied time-kill curves, induced resistant bacteria and sequenced the gene for thymidine kinase. We demonstrate that AZT has a bactericidal effect on some enterobacteria. However, AZT could induce resistance in Escherichia coli. These resistances were associated with various modifications in the thymidine kinase gene. In particular, we observed the presence in this gene of an insertion sequence (IS) similar to IS911 of Shigella dysenteriae in two resistant clones. No cross-resistance with classical antibiotics in strains with modified thymidine kinase gene was observed. Finally, an additive or synergistic activity between AZT and the two aminoglycoside antibiotics amikacin and gentamicin was observed. We demonstrate the bactericidal activity of AZT and show synergy in association with gentamicin. Genetic modifications in resistant bacteria were identified. Our results indicate that AZT could potentially be added in the treatment of infections with enterobacteria or represent the basis for the development of derivatives with better activity and inducing less resistance.
Published: 2011
Full Text: View/download PDF

10. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias

Author: Angela F. Brady, Louise Zylberberg, Yasemin Alanay, Gwenaëlle Collod-Béroud, Andrea Superti-Furga, Sally Ann Lynch, Michel Polak, Avinash Abhyankar, André Mégarbané, Martine Le Merrer, Suneel S. Apte, Marie-Pierre Cordier, Carine Le Goff, Arnold Munnich, Clémentine Mahaut, David Sillence, Sacha A. Jensen, Pelin Özlem Şimşek Kiper, Christine Bole-Feysot, Lauren W. Wang, David L. Rimoin, Vicken Topouchian, Patrick Nitschke, Slimane Allali, Koenraad Devriendt, Penny A. Handford, Catherine Boileau, Sylvie Odent, Deborah Krakow, Irene Stolte-Dijkstra, Damien Bonnet, Geert Mortier, Valérie Cormier-Daire, Sheila Unger, Jean-Laurent Casanova, Bernhard Zabel, Marianne Rohrbach, Hiroshi Kitoh, David Geneviève, Çocuk Sağlığı ve Hastalıkları, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Department of Biochemistry [Oxford], University of Oxford, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Pediatrics, Hacettepe University = Hacettepe Üniversitesi, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Institute of Child Health, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Department of Orthopaedic Surgery, Nagoya University, Department of Molecular Cellular and Developmental Biology, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-Howard Hughes Medical Institute (HHMI), Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Genetics, Universiteit Gent = Ghent University (UGENT), hôpital Sud, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Clinical Genetics, Academic Department of Medical Genetics, Westmead Hospital [Sydney], Department of Clinical Genetics, Service de Pédiatrie, Université de Lausanne = University of Lausanne (UNIL), Service de chirurgie orthopédique pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Service de Génétique humaine, Centre for Pediatrics and Adolescent Medicine, University of Freiburg [Freiburg]-University Hospital Freiburg, Endocrinologie moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Génétique Humaine des Maladies Infectieuses (Inserm U980), Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), COLLOD-BEROUD, Gwenaëlle, Department of Biomedical Engineering, Cleveland Clinic-Lerner Research Institute, University of Oxford [Oxford], Institut des Sciences de la Terre de Paris (iSTeP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de Référence Malformations Cardiaques Congénitales Complexes, North West Thames Regional Genetics, Northwick Park Hospital, Service de Génétique, Hospices Civils de Lyon (HCL), Center for Human Genetics, Université Catholique de Louvain (UCL)-Cliniques Universitaires Saint-Luc [Bruxelles], Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departments of Orthopedic Surgery and Human Genetics, University of California-University of California, National Centre for Medical Genetics, Antwerp University Hospital [Edegem] (UZA), Service de Génétique Clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), service d'endocrinologie, gynécologie, diabétologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Division of Metabolism, University Children's Hospital, Clinical genetics, University Medical Center Groningen [Groningen] (UMCG), Université de Lausanne (UNIL), Medical Genetics Institute, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Bioinformatique, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré [AP-HP], Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche génomique et physiologie de la lactation (GPL), Institut National de la Recherche Agronomique (INRA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of California-University of California-Howard Hughes Medical Institute (HHMI), Universiteit Gent = Ghent University [Belgium] (UGENT), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Génomique et Physiologie de la Lactation (GPL), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, rockefeller university, Ghent University [Belgium] (UGENT), Hôpital Sud, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cleveland Clinic Foundation-Lerner Research Institute, St Giles laboratory of Human Genetics and Infectious Diseases, Institut des Sciences de la Terre de Paris ( iSTeP ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hospices Civils de Lyon ( HCL ), Université Catholique de Louvain ( UCL ) -Cliniques Universitaires Saint-Luc [Bruxelles], Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of California at Los Angeles [Los Angeles] ( UCLA ), Université Saint-Joseph de Beyrouth ( USJ ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), University Hospital Antwerp, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Sud, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], The Children's Hospital at Westmead, University Medical Center Groningen, Université de Lausanne ( UNIL ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris Descartes - Paris 5 ( UPD5 ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, University of Zurich, and Cormier-Daire, V
Subjects: MESH: Extracellular Matrix Proteins, DNA Mutational Analysis, Fluorescent Antibody Technique, Marfan Syndrome, MESH : Dwarfism, MESH: Protein Structure, Tertiary, Arachnodactyly, 0302 clinical medicine, MESH : Child, MESH: Child, Acromicric dysplasia, Genetics(clinical), Eye Abnormalities, MESH: DNA Mutational Analysis, MESH: Dwarfism, Child, MESH: Fluorescent Antibody Technique, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Exome sequencing, Genetics & Heredity, Inclusion Bodies, 0303 health sciences, Mutation, Extracellular Matrix Proteins, MESH: Middle Aged, 3. Good health, MESH : Connective Tissue, MESH : Phenotype, MESH: Young Adult, Child, Preschool, MESH : Protein Structure, Tertiary, musculoskeletal diseases, MESH : Heterozygote, MESH: Connective Tissue, MESH : Young Adult, Limb Deformities, Congenital, Dwarfism, MESH : DNA Mutational Analysis, MESH: Phenotype, Fibrillins, Article, 03 medical and health sciences, 1311 Genetics, MESH : Adolescent, Genetics, Humans, MESH : Middle Aged, MESH: Adolescent, MESH: Bone Diseases, Developmental, [SDV.GEN]Life Sciences [q-bio]/Genetics, Bone Diseases, Developmental, MESH : Bone Diseases, Developmental, MESH: Humans, MESH : Humans, MESH: Child, Preschool, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Protein Structure, Tertiary, MESH : Microfibrils, MESH : Fluorescent Antibody Technique, Human medicine, MESH : Transforming Growth Factor beta1, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, MESH: Signal Transduction, Candidate gene, Fibrillin-1, MESH : Child, Preschool, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, MESH: Transforming Growth Factor beta1, MESH : Exons, Genetics (clinical), MESH: Heterozygote, Microfilament Proteins, Exons, MESH : Adult, Middle Aged, MESH: Eye Abnormalities, Weill–Marchesani syndrome, MESH: Microfibrils, Phenotype, Connective Tissue, MESH : Mutation, medicine.symptom, Fibrillin, Signal Transduction, MESH : Limb Deformities, Congenital, Adult, 2716 Genetics (clinical), congenital, hereditary, and neonatal diseases and abnormalities, Heterozygote, MESH: Limb Deformities, Congenital, MESH: Mutation, MESH : Microfilament Proteins, Adolescent, 610 Medicine & health, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Short stature, MESH: Marfan Syndrome, Transforming Growth Factor beta1, MESH: Microfilament Proteins, Young Adult, MESH : Extracellular Matrix Proteins, MESH : Eye Abnormalities, medicine, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, 030304 developmental biology, MESH : Signal Transduction, MESH : Marfan Syndrome, MESH: Inclusion Bodies, GENE, MESH : Inclusion Bodies, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 10036 Medical Clinic, Microfibrils, MESH: Exons, MATRIX
Abstract: International audience; Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFb-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFb signaling were consistent features in GD and AD fibro-blasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFb signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.
Published: 2011
Full Text: View/download PDF

11. Immunoglobulin heavy chain V-D-J gene rearrangement and mutational status in Uruguayan patients with chronic lymphocytic leukemia

Author: Guillermo Dighiero, Sergio Bianchi, Hugo Naya, Pilar Moreno, Raul Gabus, Ana Inés Landoni, Otto Pritsch, Pablo Oppezzo, Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur ( RIIP ) -Institut Pasteur de Montevideo, Departamento de Fisiopatología, Universidad de la República-Hospital de Clinicas, Servicio de Hematología, Hospital Maciel, Departamento de Inmunobiología, and Universidad de la República-Facultad de Medicina
Subjects: Male, Cancer Research, Chronic lymphocytic leukemia, DNA Mutational Analysis, MESH : Aged, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Immunoglobulin Variable Region, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Gene Frequency, hemic and lymphatic diseases, MESH : Female, MESH : Gene Frequency, MESH : Immunoglobulin Variable Region, MESH : Uruguay, Phylogeny, Genetics, education.field_of_study, Geography, Incidence (epidemiology), MESH : Geography, Hematology, MESH : Adult, MESH : Leukemia, Lymphocytic, Chronic, B-Cell, Middle Aged, Oncology, Chronic leukemia, Female, MESH : Mutation, IGHV@, Adult, MESH : Male, Genes, Immunoglobulin Heavy Chain, Population, MESH : Genes, Immunoglobulin Heavy Chain, MESH : DNA Mutational Analysis, Biology, MESH : Gene Rearrangement, B-Lymphocyte, Heavy Chain, medicine, Humans, MESH : Middle Aged, education, Gene, Aged, MESH : Humans, MESH : Phylogeny, Gene rearrangement, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Immunology, Mutation, Immunoglobulin heavy chain, Uruguay, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived circulating clonal leukemic B-cells, although the etiopathogenesis remains unclear. The incidence of CLL is variable in different regions around the world. While it is the most frequent chronic leukemia in Western countries, it has a low incidence in Asia. In this work we have investigated the immunoglobulin heavy chain gene rearrangements and mutational status in 80 Uruguayan patients with CLL, and compared these results with those obtained in other geographic regions. Our results demonstrate that Uruguayan patients with CLL display an IGHV gene usage which resembles that observed in Mediterranean countries and exhibits certain differences compared with Brazilian and Asian series, as expected, considering the ethnic basis of the Uruguayan population. This suggests that genetic influences could be important in the development and etiopathogenesis of CLL, but larger studies are necessary to substantiate this possibility.
Published: 2010
Full Text: View/download PDF

12. Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome

Author: Ilmay Bilge, Corinne Antignac, Zelal Z. Bircan, Marie-Claire Gubler, Marie-Alice Macher, Olivier Gribouval, Olivia Boyer, Lisa M. Guay-Woodford, Fabien Nevo, Geneviève Benoit, Robert R. Weiss, Chantal Loirat, Kenza Soulami, Constantinos J. Stefanidis, Audrey Pawtowski, Georges Deschênes, Michelle Hall, Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Department of Pediatrics, Istanbul Faculty of Medicine, Department of Pediatric Nephrology, Kocaeli University Hospital, AP-HP, Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris, Department of Genetics, UAB Center for Clinical and Translational Science, Birmingham, Department of Pediatric Nephrology, Hôpital Universitaire des Enfants - Reine Fabiola, Brussels, Service de Néphrologie Dialyse Transplantation, CHU Ibn Rochd, Casablanca, Department of Pediatric Nephrology, Department of Pediatric Nephrology, Maria Fareri Children's Hospital, Valhalla, New York, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie pédiatrique, Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Department of Pediatrics, Istanbul University, Kocaeli University Hospital, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Genetics, UAB Center for Clinical and Translational Science, Université libre de Bruxelles (ULB)-Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Service de Néphrologie Dialyse Transplantation, CHU Ibn Rochd [Casablanca], 'P. & A. Kyriakou' Children's Hospital, Maria Fareri Children's Hospital, Financial support for this work was provided by grants from the Programme Hospitalier de Recherche Clinique (PHRC) AOM02123 (to C.A), the Association pour l'utilisation du Rein Artificiel (AURA) (to C.A), PodoNet (Clinical, Genetic and Experimental Research into Hereditary Diseases of the Podocyte) - project of the 2007 E-RARE program (to CA) and Fonds de la Recherche en Santé Québec (FRSQ) (Fellowship training Award to G.B.)., CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), New York Medical College (NYMC), Gribouval, Olivier, Néphropathies héréditaires et rein en développement ( UMR_S 983 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], Université de Montréal-CHU Sainte Justine [Montréal], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), and Université Libre de Bruxelles [Bruxelles] ( ULB ) -Hôpital Universitaire des Enfants - Reine Fabiola
Subjects: Male, Candidate gene, Nephrotic Syndrome, DNA Mutational Analysis, MESH : Aged, 030232 urology & nephrology, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH : Child, Preschool, medicine.disease_cause, Compound heterozygosity, Cohort Studies, 0302 clinical medicine, Focal segmental glomerulosclerosis, MESH: Aged, 80 and over, Phosphoinositide Phospholipase C, MESH : Child, PLCE1, MESH: Child, Missense mutation, MESH : Female, Molecular genetics, MESH: DNA Mutational Analysis, Child, MESH: Cohort Studies, Genetics (clinical), Genetics, MESH: Aged, Aged, 80 and over, 0303 health sciences, Mutation, MESH: Statistics, Nonparametric, MESH : Phosphoinositide Phospholipase C, MESH: Middle Aged, Renal Medicine, Glomerulosclerosis, Focal Segmental, MESH: Genetic Predisposition to Disease, MESH : Infant, MESH : Adult, Middle Aged, MESH: Infant, 3. Good health, MESH : Phenotype, Phenotype, Child, Preschool, Screening, Female, Steroids, MESH : Mutation, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Glomerulosclerosis, Focal Segmental, MESH : Male, MESH : Nephrotic Syndrome, MESH : Cohort Studies, MESH : DNA Mutational Analysis, Biology, MESH: Phenotype, Statistics, Nonparametric, 03 medical and health sciences, MESH : Adolescent, medicine, MESH: Phosphoinositide Phospholipase C, Humans, MESH : Middle Aged, Genetic Predisposition to Disease, MESH : Aged, 80 and over, MESH : Statistics, Nonparametric, 030304 developmental biology, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Humans, MESH: Child, Preschool, Infant, MESH: Adult, medicine.disease, mutations, MESH: Male, MESH: Steroids, Steroid-resistant nephrotic syndrome, MESH : Glomerulosclerosis, Focal Segmental, MESH : Genetic Predisposition to Disease, MESH: Nephrotic Syndrome, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, MESH : Steroids
Abstract: International audience; BACKGROUND: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCepsilon1) have been recently described in patients with early onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. METHOD: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, mutational analysis was performed in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid resistant NS presenting at a median age of 23.0 months (range 0-373). RESULTS: Homozygous or compound heterozygous mutations were identified in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, three unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. CONCLUSION: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF,IQGAP1 and NPHS1) were not identified, it is speculated that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.
Published: 2010
Full Text: View/download PDF

13. Comparative analysis of oncogenic properties and nuclear factor-kappaB activity of latent membrane protein 1 natural variants from Hodgkin's lymphoma's Reed-Sternberg cells and normal B-lymphocytes

Author: Fabienne Meggetto, Alan Bénard, Nadine Cogne, Aurélie Chanut, Nathalie Faumont, Georges Delsol, Jean Feuillard, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations ( PMRIL ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Centre National de la Recherche Scientifique ( CNRS ), Ecologie microbienne ( EM ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Vétérinaire de Lyon ( ENVL ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique ( INRA ) -VetAgro Sup ( VAS ), Centre de Physiopathologie Toulouse Purpan, and Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH : Cell Line, MESH : Molecular Sequence Data, DNA Mutational Analysis, MESH: NF-kappa B, Apoptosis, MESH: Base Sequence, medicine.disease_cause, 0302 clinical medicine, MESH : Tumor Cells, Cultured, MESH: Luciferases, Renilla, immune system diseases, hemic and lymphatic diseases, MESH : Hodgkin Disease, Tumor Cells, Cultured, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH : Viral Matrix Proteins, MESH: Genetic Variation, Reed-Sternberg Cells, MESH: DNA Mutational Analysis, MESH : Immunoblotting, MESH: Reed-Sternberg Cells, Oncogene Proteins, Genetics, B-Lymphocytes, 0303 health sciences, Mutation, MESH: Immunoblotting, MESH : Oncogene Proteins, NF-kappa B, Hematology, Transfection, Hodgkin Disease, MESH: Hodgkin Disease, MESH : NF-kappa B, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : Mutation, MESH : Transfection, MESH: Mutation, MESH : Recombinant Fusion Proteins, Recombinant Fusion Proteins, Immunoblotting, Molecular Sequence Data, MESH : Luciferases, Renilla, MESH : DNA Mutational Analysis, Biology, MESH: Sequence Homology, Nucleic Acid, MESH : B-Lymphocytes, Cell Line, Viral Matrix Proteins, 03 medical and health sciences, MESH: Oncogene Proteins, stomatognathic system, MESH : Genetic Variation, Sequence Homology, Nucleic Acid, MESH: B-Lymphocytes, medicine, otorhinolaryngologic diseases, MESH: Recombinant Fusion Proteins, Animals, Humans, Hodgkin's Lymphoma, MESH : Sequence Homology, Nucleic Acid, MESH: Tumor Cells, Cultured, Luciferases, Renilla, 030304 developmental biology, MESH: Viral Matrix Proteins, MESH: Molecular Sequence Data, MESH: Humans, MESH : Reed-Sternberg Cells, Base Sequence, MESH: Apoptosis, MESH: Transfection, MESH : Humans, Genetic Variation, medicine.disease, Hodgkin's lymphoma, Epstein–Barr virus, Lymphoma, MESH: Cell Line, stomatognathic diseases, Reed–Sternberg cell, Cell culture, Cancer research, MESH : Base Sequence, MESH : Animals, Carcinogenesis, MESH : Apoptosis
Abstract: International audience; BACKGROUND: In Epstein-Barr virus-associated Hodgkin's lymphomas, neoplastic Reed-Sternberg cells and surrounding non-tumor B-cells contain different variants of the LMP1-BNLF1 oncogene. In this study, we raised the question of functional properties of latent membrane protein 1 (LMP1) natural variants from both Reed-Sternberg and non-tumor B-cells. DESIGN AND METHODS: Twelve LMP1 natural variants from Reed-Sternberg cells, non-tumor B-cells of Hodgkin's lymphomas and from B-cells of benign reactive lymph nodes were cloned, sequenced and stably transfected in murine recombinant interleukin-3-dependent Ba/F3 cells to search for relationships between LMP1 cellular origin and oncogenic properties as well as nuclear factor-kappaB activation, and apoptosis protection. RESULTS: LMP1 variants of Reed-Sternberg cell origin were often associated with increased mutation rate and with recurrent genetic events, such as del15bp associated with S to N replacement at codon 309, and four substitutions I85L, F106Y, I122L, and M129I. Oncogenic potential (growth factor-independence plus clonogenicity) was consistently associated with LMP1 variants from Reed-Sternberg cells, but inconstantly for LMP1-variants from non-tumor B-cells. Analysis of LMP1 variants from both normal B-cells and Reed-Sternberg cells indicates that protection against apoptosis through activation of nuclear factor-kappaB - whatever the cellular origin of LMP1 - was maintained intact, regardless of the mutational pattern. CONCLUSIONS: Taken together, our results demonstrate that preserved nuclear factor-kappaB activity and protection against apoptosis would be the minimal prerequisites for all LMP1 natural variants from both normal and tumor cells in Hodgkin's lymphomas, and that oncogenic potential would constitute an additional feature for LMP1 natural variants in Reed-Sternberg cells.
Published: 2009
Full Text: View/download PDF

14. The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations

Author: Christine Binquet, Christine Monino, Laurence Faivre, Gwenaëlle Collod-Béroud, Dalil Hamroun, Guillaume Jondeau, Christophe Béroud, Luitgard M. Neumann, Prateek Gupta, Catherine Boileau, Mireille Claustres, Dianna M. Milewicz, Elodie Gautier, Maurice Godfrey, Christoph Marschall, Hanns Georg Klein, Cheryl L. Maslen, Mélissa Yana Frédéric, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Charité Campus Virchow-Klinikum (CVK), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Molecular and Medical Genetics, Oregon Health and Science University, Center for Human Molecular Genetics, University of Nebraska Omaha, Department of Internal Medicine and Neurosurgery, The University of Texas Medical School, Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, UFR Paris-Ile-de-France-Ouest (PIFO), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Montpellier 1, INSERM, GIS-Institut des Maladies Rares 2004, Contract grant sponsor: Association Française contre les Myopathies (AFM), Grant number: AFM-R07017FF, Contract grant sponsor: Agence Nationale pour la Recherche (ANR), Grant number: ANR-05PCOD-14-02., Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oregon Health and Science University [Portland] (OHSU), University of Nebraska System-University of Nebraska System, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), COLLOD-BEROUD, Gwenaëlle, IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, and University of Nebraska [Omaha]
Subjects: Fibrillin-2, MESH : Polymorphism, Genetic, Fibrillin-1, DNA Mutational Analysis, MESH : Genotype, [SDV.GEN] Life Sciences [q-bio]/Genetics, computer.software_genre, MESH: Genotype, 0302 clinical medicine, Genotype, Databases, Genetic, Missense mutation, Congenital contractural arachnodactyly, MESH: DNA Mutational Analysis, Genetics (clinical), MESH: Databases, Genetic, Regulation of gene expression, Genetics, 0303 health sciences, Database, MESH : Gene Expression Regulation, Microfilament Proteins, Phenotype, MESH: Gene Expression Regulation, Beals-Hecht syndrome, 3. Good health, INC, MESH : Phenotype, MESH : Mutation, Fibrillin, musculoskeletal diseases, MESH: Mutation, MESH : Microfilament Proteins, database OFFICIAL JOURNAL wwwhgvsorg & 2008 WILEY-LISS, Locus (genetics), fibrillin, MESH : DNA Mutational Analysis, Biology, Fibrillins, MESH: Phenotype, MESH: Sequence Homology, Nucleic Acid, congenital contractural arachnodactyly, 03 medical and health sciences, MESH: Microfilament Proteins, Sequence Homology, Nucleic Acid, MESH: Polymorphism, Genetic, medicine, Humans, MESH : Sequence Homology, Nucleic Acid, FBN2, CCA, MESH : Databases, Genetic, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, MESH : Humans, medicine.disease, Gene Expression Regulation, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, computer, 030217 neurology & neurosurgery
Abstract: International audience; Congenital contractural arachnodactyly (CCA) is an extremely rare disease, due to mutations in the FBN2 gene encoding fibrillin-2. Another member of the fibrillin family, the FBN1 gene, is involved in a broad phenotypic continuum of connective-tissue disorders including Marfan syndrome. Identifying not only what is in common but also what differentiates these two proteins should enable us to better comprehend their respective functions and better understand the multitude of diseases in which these two genes are involved. In 1995 we created a locus-specific database (LSDB) for FBN1 mutations with the Universal Mutation Database (UMD) tool. To facilitate comparison of identified mutations in these two genes and search for specific functional areas, we created an LSDB for the FBN2 gene: the UMD-FBN2 database. This database lists 26 published and six newly identified mutations that mainly comprise missense and splice-site mutations. Although the number of described FBN2 mutations was low, the frequency of joint dislocation was significantly higher with missense mutations when compared to splice site mutations.
Published: 2009
Full Text: View/download PDF

15. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders

Author: Clarisse Baumann, Henri Plauchu, Didier Lacombe, Valérie Cormier-Daire, Marc Sznajder, Guillaume Jondeau, Stanislas Lyonnet, Chantal Stheneur, Bertrand Moura, Catherine Boileau, Mireille Claustres, Gwenaëlle Collod-Béroud, Christine Muti, Bertrand Chevallier, Claudine Junien, Marlène Rio, David Attias, Laurence Faivre, Laurent Gouya, Gilles Sultan, Jean-Marie Le Parc, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Physiologie Cellulaire des Regulations Hormonales, Nutritionnelles et Pharmacologiques, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de biochimie, d'hormonologie et de génétique moléculaire, UFR Paris-Ile-de-France-Ouest, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Interactions de l'épithelium intestinal avec le système immunitaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'ophtalmologie, Service de Rhumatologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Département de Génétique Médicale, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-Hopital Necker-Enfants Malades, Service de Génétique, Hôtel Dieu, Service de génétique médicale, Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bichat, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1) - IFR3 - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université de Montpellier (UM), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB) - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon) - Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Ambroise Paré, Laboratoire de Génétique Moléculaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier) - Hôpital Arnaud de Villeneuve, Handicaps génétiques de l'enfant, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) - Hopital Necker-Enfants Malades, Université de Bordeaux (UB) - CHU Bordeaux [Bordeaux] - Groupe hospitalier Pellegrin, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bichat - Claude Bernard [Paris] - Université Paris Diderot - Paris 7 (UPD7), Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13) - Université Paris Diderot - Paris 7 (UPD7) - Université Sorbonne Paris Cité (USPC) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Institut Galilée, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Pharmacologie, toxicologie et signalisation cellulaire (U747), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'ophtalmologie [CHU Ambroise Paré], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), COLLOD-BEROUD, Gwenaëlle, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Proband, Marfan syndrome, Pathology, MESH : Receptors, Transforming Growth Factor beta, MESH : Polymorphism, Genetic, DNA Mutational Analysis, Receptor, Transforming Growth Factor-beta Type I, MESH : Genotype, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Gene mutation, MESH : Child, Preschool, Loeys–Dietz syndrome, MESH : Syndrome, MESH: Genotype, Aortic aneurysm, 0302 clinical medicine, MESH : Child, MESH: Child, Genotype, MESH: Syndrome, MESH : Female, MESH: DNA Mutational Analysis, Child, Genetics (clinical), TGFBR1, TAAD, 0303 health sciences, MESH: Middle Aged, MESH : Aortic Aneurysm, Thoracic, MESH: Infant, Newborn, MESH : Infant, Syndrome, Middle Aged, MESH : Adult, Phenotype, MESH: Infant, MESH: Amino Acid Substitution, 3. Good health, TGFBR2, genotype-phenotype, MESH : Phenotype, Child, Preschool, MESH: Aortic Aneurysm, Thoracic, Female, MESH: Receptors, Transforming Growth Factor beta, MESH : Mutation, Adult, MESH : Protein-Serine-Threonine Kinases, medicine.medical_specialty, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, MESH : Male, MESH : DNA Mutational Analysis, Protein Serine-Threonine Kinases, Biology, MESH: Phenotype, MESH : Infant, Newborn, MESH: Protein-Serine-Threonine Kinases, MESH: Marfan Syndrome, 03 medical and health sciences, MESH : Amino Acid Substitution, MESH : Adolescent, MESH: Polymorphism, Genetic, Genetics, medicine, Humans, Abnormalities, Multiple, MESH : Middle Aged, Gene, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, Loeys-Dietz Syndrome, Polymorphism, Genetic, MESH: Humans, MESH : Marfan Syndrome, Aortic Aneurysm, Thoracic, MESH : Abnormalities, Multiple, MESH: Child, Preschool, MESH : Humans, Infant, Newborn, Receptor, Transforming Growth Factor-beta Type II, Infant, MESH: Adult, medicine.disease, MESH: Male, Amino Acid Substitution, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Receptors, Transforming Growth Factor beta, MESH: Female
Abstract: International audience; TGFBR1 and TGFBR2 gene mutations have been associated with Marfan syndrome types 1 and 2, Loeys-Dietz syndrome and isolated familial thoracic aortic aneurysms or dissection. In order to investigate the molecular and clinical spectrum of TGFBR2 mutations we screened the gene in 457 probands suspected of being affected with Marfan syndrome or related disorders that had been referred to our laboratory for molecular diagnosis. We identified and report 23 mutations and 20 polymorphisms. Subsequently, we screened the TGFBR1 gene in the first 74 patients for whom no defect had been found, and identified 6 novel mutations and 12 polymorphisms. Mutation-carrying probands displayed at referral a large clinical spectrum ranging from the Loeys-Dietz syndrome and neonatal Marfan syndrome to isolated aortic aneurysm. Furthermore, a TGFBR1 gene mutation was found in a Shprintzen-Goldberg syndrome patient. Finally, we observed that the yield of mutation detection within the two genes was very low : 4.8% for classical MFS, 4.6% for incomplete MFS and 1% for TAAD in the TGFBR2 gene; 6.2%, 6.2% and 7% respectively in the TGFBR1 gene; in contrast to LDS, where the yield was exceptionally high (87.5%).
Published: 2008
Full Text: View/download PDF

16. The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum

Author: Thibault Moreau, Frédéric Sedel, D. Perennou, M.-H. Horellou, C. Tonneti, Alice Masurel-Paulet, Emmanuel Roze, C. Thauvin-Robinet, Stéphane Giraudier, G. Bruneteau, G. Couvreur, M. Giroud, D. Grabli, Laurence Faivre, H. Ogier de Baulny, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Motricité - Plasticité, Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] ( IBMM ), Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Pathology, DNA Mutational Analysis, MESH: Hydroxocobalamin, MESH: Brain Diseases, Metabolic, Inborn, Disease, MESH : Neurologic Examination, 0302 clinical medicine, Gene Duplication, Hydroxocobalamin, Child and adolescent psychiatry, Medicine, MESH: DNA Mutational Analysis, MESH : Amino Acid Metabolism, Inborn Errors, 0303 health sciences, MESH: Gene Duplication, Brain, MESH : Infusions, Intravenous, MESH: Follow-Up Studies, 3. Good health, Psychiatry and Mental health, Spinal Cord, Homocystinuria, MESH : Carrier Proteins, MESH: Homocystinuria, medicine.medical_specialty, MESH : Injections, Intramuscular, MESH : Gene Duplication, MESH: Methylmalonic Acid, MESH: Carrier Proteins, MESH : DNA Mutational Analysis, 03 medical and health sciences, MESH : Adolescent, MESH : Magnetic Resonance Imaging, Humans, MESH: Amino Acid Metabolism, Inborn Errors, MESH: Genes, Recessive, Chromosome Aberrations, MESH: Adolescent, MESH: Mutation, Missense, MESH: Humans, MESH : Humans, Brain Diseases, Metabolic, Inborn, MESH : Genes, Recessive, MESH: Adult, MESH : Follow-Up Studies, MMACHC, MESH : Brain, Surgery, MESH: Cerebral Ventricles, Neurology (clinical), Carrier Proteins, MESH: Female, 030217 neurology & neurosurgery, MESH : Mutation, Missense, Pediatrics, Compound heterozygosity, Cerebral Ventricles, MESH: Magnetic Resonance Imaging, MESH: Spinal Cord, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Missense mutation, MESH: Neurologic Examination, MESH : Female, Infusions, Intravenous, Neurologic Examination, medicine.diagnostic_test, Genetic Carrier Screening, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH : Adult, Magnetic Resonance Imaging, MESH: Injections, Intramuscular, MESH : Methylmalonic Acid, Female, MESH : Cerebral Ventricles, Oxidoreductases, Adult, Adolescent, MESH : Male, MESH : Chromosome Aberrations, Mutation, Missense, Genes, Recessive, MESH : Brain Diseases, Metabolic, Inborn, Injections, Intramuscular, MESH: Brain, MESH : Heterozygote Detection, Neuroimaging, MESH: Chromosome Aberrations, MESH: Infusions, Intravenous, Amino Acid Metabolism, Inborn Errors, 030304 developmental biology, MESH: Heterozygote Detection, MESH : Homocystinuria, MESH : Hydroxocobalamin, business.industry, Magnetic resonance imaging, MESH : Spinal Cord, MESH: Male, CBLC, business, Follow-Up Studies, Methylmalonic Acid
Abstract: International audience; BACKGROUND: Cobalamin C disease is the most common inborn error of cobalamin metabolism with an autosomal recessive mode of inheritance and mutations within the MMACHC gene. Clinical features, including systemic, haematological and neurological abnormalities, usually occur in the first year of life. Adolescent and adult onset presentations are rare. METHODS: We report on the clinical, molecular and imaging features in three patients aged 40, 42 and 42 years at the last follow-up. We examine these cases together with eight previously described cases to determine the clinical and molecular features of the disease in adults. RESULTS: Mean age at onset of clinical symptoms was 26 years; clinical features included predominant neurological disturbances and thromboembolic complications. White matter abnormalities on brain MRI were sometimes observed. Most patients (eight of nine patients investigated) were compound heterozygotes for the 271dupA mutation and a missense mutation. Intramuscular or intravenous hydroxycobalamin therapy stopped the progression of the disease and resulted in a better clinical outcome and favourable biological status in 7/9 treated cases, while the two untreated patients died quickly. CONCLUSIONS: As cobalamin C disease and related disorders of homocysteine metabolism are treatable conditions, homocysteinaemia should be included in the investigations of patients with progressive neurological deterioration, unexplained psychiatric disturbances or recurrent thromboembolic events.
Published: 2008
Full Text: View/download PDF

17. Analysis of the DND1 gene in men with sporadic and familial testicular germ cell tumors

Author: Gedske Daugaard, Sophie D. Fosså, Sergei Tjulandin, Walter P. Weber, Douglas F. Easton, Rachel Linger, Dominique Stoppa-Lyonnet, Peter Albers, David W. Hogg, Parry Guilford, Robert Huddart, Michael Friedlander, Peter A. Daly, Ketil Heimdal, Michael A.S. Jewett, Darshna Dudakia, Michael R. Stratton, Katherine L. Nathanson, Hans Stoll, Lajos Géczi, Mary L. McMaster, Catherine Bonaïti-Pellié, Stéphane Richard, Elizabeth A. Rapley, Lawrence H. Einhorn, Mark H. Greene, Victoria K. Cortessis, Edith Olah, Agnès Chompret, Axel Heidenreich, Radka Lohynska, Katherine M. Tucker, Kelly-Anne Phillips, D. Timothy Bishop, Larissa A. Korde, Ludmila Liubchenko, István Bodrogi, Section of Cancer Genetics, Institute of cancer research, Academic Radiotherapy Unit, Dept of Medical Oncology, Division of Medicine, University of New South Wales [Sydney] (UNSW)-Prince of Wales Hospital Randwick, Dept of Haematology and Medical Oncology, Peter MacCallum Cancer Center, Princess Margaret Hospital, University of Toronto, Dept of Radiotherapy and Oncology, University hospital of Prague, Dept of Oncology, Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Génétique oncologique (GO - UMR 8125), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Service d'urologie, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Centre de Recherches Biologiques, CERB, Génomes et cancer (GC (FRE2939)), Département de Pédiatrie, Institut Gustave Roussy (IGR), Epidémiologie des cancers, Institut National de la Santé et de la Recherche Médicale (INSERM), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de Génétique Oncologique, Institut Curie [Paris], Département de génétique, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-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), Epidémiologie génétique, Dept of Urological Oncology, Phillips university, Department of Urology, Klinikum Kassel GmbH, Department of Molecular Genetics and Department of Chemotherapy, National Institute of Oncology, Department of Medical Oncology, St James's hospital, Cancer Genetics Laboratory, University of Otago [Dunedin, Nouvelle-Zélande], Departments of Clinical Cancer Research and genetics, Rikshospitalet-Radiumhospitalet Trust, Laboratory of Clinical Genetics, Institute of Clinical Oncology, Medical Oncology, University Hospital Basel [Basel], Google Inc., Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Barts and The London Queen Mary's School of Medicine, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Department of Preventive Medicine, Keck School of Medicine [Los Angeles], University of Southern California (USC)-University of Southern California (USC), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Saint James's University Hospital, University of New South Wales [Sydney] ( UNSW ) -Prince of Wales Hospital Randwick, Peter MacCallum Cancer Centre, University of Toronto-Princess Margaret Hospital, Génétique oncologique ( GO - UMR 8125 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Génomes et cancer ( GC (FRE2939) ), Institut Gustave Roussy ( IGR ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique épidémiologique et structures des populations humaines ( Inserm U535 ), Epidémiologie, sciences sociales, santé publique ( IFR 69 ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -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 ), University of Otago, Institut de Physique et Chimie des Matériaux de Strasbourg ( IPCMS ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Abramson Family Cancer Research Institute-University of Pennsylvania School of Medicine, University of Cambridge [UK] ( CAM ), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Institut Curie, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-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)
Subjects: Male, MESH: Neoplasm Proteins, Cancer Research, DNA Mutational Analysis, medicine.disease_cause, Polymerase Chain Reaction, law.invention, 0302 clinical medicine, law, Polymorphism (computer science), Family history, MESH: DNA Mutational Analysis, MESH : Polymerase Chain Reaction, Polymerase chain reaction, MESH: Testicular Neoplasms, Genetics, 0303 health sciences, Mutation, MESH: Genetic Predisposition to Disease, Neoplasms, Germ Cell and Embryonal, Neoplasm Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Neoplasms, Germ Cell and Embryonal, MESH : Mutation, Germ cell, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], MESH: Mutation, MESH : Male, MESH : DNA Mutational Analysis, Biology, MESH : Family Health, Article, 03 medical and health sciences, MESH : Neoplasm Proteins, MESH : Neoplasms, Germ Cell and Embryonal, Testicular Neoplasms, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, MESH : Testicular Neoplasms, [ SDV.OT ] Life Sciences [q-bio]/Other [q-bio.OT], Gene, 030304 developmental biology, Family Health, MESH: Humans, MESH : Humans, Cancer, MESH: Polymerase Chain Reaction, medicine.disease, MESH: Male, MESH: Family Health, MESH : Genetic Predisposition to Disease
Abstract: A base substitution in the mouse Dnd1 gene resulting in a truncated Dnd protein has been shown to be responsible for germ cell loss and the development of testicular germ cell tumors (TGCT) in the 129 strain of mice. We investigated the human orthologue of this gene in 263 patients (165 with a family history of TGCT and 98 without) and found a rare heterozygous variant, p. Glu86Ala, in a single case. This variant was not present in control chromosomes (0/4,132). Analysis of the variant in an additional 842 index TGCT cases (269 with a family history of TGCT and 573 without) did not reveal any additional instances. The variant, p. Glu86Ala, is within a known functional domain of DND1 and is highly conserved through evolution. Although the variant may be a rare polymorphism, a change at such a highly conserved residue is characteristic of a disease-causing variant. Whether it is disease-causing or not, mutations in DND1 make, at most, a very small contribution to TGCT susceptibility in adults and adolescents.
Published: 2008
Full Text: View/download PDF

18. Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy

Author: Sylvie Odent, Jamel Chelly, Christophe Philippe, Thierry Bienvenu, Haydeé Rosas-Vargas, L. Lazaro, B. Girard, C. Gitiaux, Nadia Bahi-Buisson, Juliette Nectoux, Philippe Jonveaux, M. A. N'Guyen Morel, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique médicale, hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Sud, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-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 Paris Descartes - Paris 5 (UPD5), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: MESH : RNA, Messenger, MESH: Sequence Homology, Amino Acid, Mutant, CDKL5, MESH: Brain Diseases, Metabolic, Inborn, MESH: Amino Acid Sequence, MESH : Child, Preschool, MESH: Base Sequence, medicine.disease_cause, MESH: Magnetic Resonance Imaging, 0302 clinical medicine, Missense mutation, MESH : Female, MESH: Animals, MESH: DNA Mutational Analysis, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), Genetics, 0303 health sciences, Mutation, MESH : Cell Nucleus, MESH: X Chromosome Inactivation, MESH : Amino Acid Sequence, MESH : Infant, Phenotype, MESH: Amino Acid Substitution, MESH: Infant, Hypotonia, MESH : Sequence Homology, Amino Acid, 3. Good health, MESH: COS Cells, MESH : Phenotype, MESH : X Chromosome Inactivation, medicine.symptom, MESH : Transfection, MESH : COS Cells, MESH : Protein-Serine-Threonine Kinases, MESH: Cell Nucleus, Encephalopathy, MESH : Brain Diseases, Metabolic, Inborn, MESH : DNA Mutational Analysis, Biology, MESH: Phenotype, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, MESH : Amino Acid Substitution, MESH: Plasmids, MESH : Magnetic Resonance Imaging, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, MESH: Electroencephalography, medicine, Atypical Rett syndrome, MESH : Electroencephalography, 030304 developmental biology, MESH: RNA, Messenger, MESH: Mutation, Missense, MESH: Humans, MESH: Transfection, MESH : Humans, MESH: Child, Preschool, medicine.disease, MESH: Cercopithecus aethiops, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH : Plasmids, MESH : Base Sequence, MESH : Animals, MESH : Cercopithecus aethiops, MESH: Female, 030217 neurology & neurosurgery, MESH : Mutation, Missense, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been shown to cause infantile spasms as well as Rett syndrome-like phenotype. To date, fewer than 20 different mutations have been reported. So far, no clear genotype-phenotype correlation has been established. We screened the entire coding region of CDKL5 in 151 affected girls with a clinically heterogeneous phenotype ranging from encephalopathy with epilepsy to atypical Rett syndrome by denaturing high liquid performance chromatography and direct sequencing, and we identified three novel missense mutations located in catalytic domain (p.Ala40Val, p.Arg65Gln, p.Leu220Pro). Segregation analysis showed that p.Arg65Gln was inherited from the healthy father, which rules out the involvement of CDKL5 in the aetiology of the phenotype in this patient. However, the de novo occurrence was shown for p.Ala40Val and p.Leu220Pro. The p.Ala40Val mutation was observed in two unrelated patients and represented the first recurrent mutation in the CDKL5 gene. For the two de novo mutations, we analysed the cellular localisation of the wild-type and CDKL5 mutants by transfection experiments. We showed that the two CDKL5 mutations cause mislocalisation of the mutant CDKL5 proteins in the cytoplasm. Interestingly these missense mutations that result in a mislocalisation of the CDKL5 protein are associated with severe developmental delay which was apparent within the first months of life characterised by early and generalised hypotonia, and autistic features, and as well as early infantile spasms.
Published: 2008
Full Text: View/download PDF

19. New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation

Author: Michel Fardeau, Akiko Yanagisawa, C. Bouchet, Jean-Marie Cuisset, F. Leturcq, Pascale Guicheney, Susana Quijano-Roy, Norma B. Romero, P. Van den Bergh, Nathalie Seta, Louis Viollet, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Biochimie Métabolique et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie, Université Catholique de Louvain = Catholic University of Louvain (UCL), Maladies Neuromusculaires de l'Enfant, Hôpital Roger Salengro [Lille], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Guicheney, Pascale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université Catholique de Louvain ( UCL ), Hôpital Roger Salengro, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], CHU Pitié-Salpêtrière [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP Hôpital Raymond Poincaré [Garches]
Subjects: Male, Microcephaly, Pathology, DNA Mutational Analysis, MESH : Muscle Weakness, MESH: Mannosyltransferases, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Genetic Markers, MESH: Founder Effect, Compound heterozygosity, medicine.disease_cause, Mannosyltransferases, Muscular Dystrophies, MESH : Muscular Dystrophies, 0302 clinical medicine, MESH: Genetic Screening, Gene Frequency, MESH : Child, MESH : Microcephaly, MESH: Child, MESH: Mental Retardation, MESH : Genetic Markers, Medicine, MESH : Female, MESH : Gene Frequency, MESH : Atrophy, Muscular dystrophy, MESH: DNA Mutational Analysis, Child, Dystroglycans, MESH : Muscle, Skeletal, Genetics, 0303 health sciences, Mutation, MESH: Muscle, Skeletal, Muscle Weakness, MESH : Mannosyltransferases, MESH: Genetic Predisposition to Disease, Brain, MESH: Muscle Weakness, MESH : Adult, MESH: Dystroglycans, Founder Effect, 3. Good health, Congenital muscular dystrophy, Female, MESH : Mutation, medicine.symptom, Adult, Genetic Markers, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH : Male, MESH : Founder Effect, MESH : Dystroglycans, MESH : DNA Mutational Analysis, MESH: Atrophy, MESH: Microcephaly, 03 medical and health sciences, MESH: Brain, Intellectual Disability, MESH : Adolescent, MESH: Gene Frequency, Humans, Genetic Predisposition to Disease, Genetic Testing, MESH : Mental Retardation, Muscle, Skeletal, MESH : Haplotypes, Gene, 030304 developmental biology, MESH : Genetic Screening, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, MESH : Humans, Haplotype, fungi, Muscle weakness, MESH: Adult, MESH: Haplotypes, medicine.disease, MESH: Muscular Dystrophies, MESH: Male, Haplotypes, MESH : Brain, MESH : Genetic Predisposition to Disease, Neurology (clinical), Atrophy, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance, often associated with CNS and ocular involvement. They are characterized by the abnormal glycosylation of alpha-dystroglycan, and caused by mutations in at least six genes encoding enzymes: FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE. POMT2 mutations have recently been identified in Walker-Warburg syndrome and in a milder muscle-eye-brain disease-like form. METHODS: We studied mentally retarded patients with CMD, analyzed POMT2 by sequencing the coding regions, and also performed a haplotype analysis in all patients and their family members carrying the new POMT2 mutation. RESULTS: We report three novel POMT2 mutations. One of these, p.Tyr666Cys, was homozygous in two unrelated patients and in a compound heterozygous state in others. All patients showed severe diffuse muscle weakness, microcephaly, severe mental retardation, and marked lordoscoliosis with hyperextended head. Elevated CK levels, cerebral cortical atrophy, and cerebellar vermis hypoplasia were constant findings. Mild cardiac abnormalities, focal white matter abnormalities, or partial corpus callosum hypoplasia were detected in single cases. Eye involvement was absent or mild. By genotype analysis, we defined a distinct 170kb haplotype encompassing POMT2 and shared by all the subjects harboring the mutation p.Tyr666Cys. CONCLUSIONS: Our results broaden the clinical spectrum associated with POMT2 mutations, which should be considered in patients with CMD associated with microcephaly, and severe mental retardation with or without ocular involvement.
Published: 2007
Full Text: View/download PDF

20. Parallel evolution of adaptive mutations in Plasmodium falciparum mitochondrial DNA during atovaquone-proguanil treatment

Author: Lise Musset, Jérôme Clain, Jacques Le Bras, EA 209 - Transports membranaires et chimiorésistances (LABORATOIRE DE PARASITOLOGIE-MYCOLOGIE), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5), Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), Centre National de Référence du Paludisme, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) - AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: MESH : Molecular Sequence Data, MESH : Cytochromes b, DNA Mutational Analysis, Drug Resistance, MESH: Base Sequence, MESH: Parasitic Sensitivity Tests, MESH : Malaria, Falciparum, Parasitic Sensitivity Tests, MESH : Biological Evolution, MESH : DNA, Mitochondrial, MESH : Proguanil, Genotype, MESH : Plasmodium falciparum, MESH : Parasitic Sensitivity Tests, MESH: Animals, Malaria, Falciparum, MESH: DNA Mutational Analysis, MESH: Plasmodium falciparum, Genetics, 0303 health sciences, biology, Cytochrome b, MESH: Malaria, Falciparum, Cytochromes b, MESH: Proguanil, MESH: Cytochromes b, Biological Evolution, 3. Good health, Proguanil, MESH: Drug Resistance, MESH : Atovaquone, MESH : Mutation, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, medicine.drug, Mitochondrial DNA, MESH: Mutation, Molecular Sequence Data, Plasmodium falciparum, MESH: Atovaquone, MESH: Biological Evolution, MESH : DNA Mutational Analysis, DNA, Mitochondrial, MESH: Sequence Homology, Nucleic Acid, Antimalarials, 03 medical and health sciences, Sequence Homology, Nucleic Acid, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, MESH : Sequence Homology, Nucleic Acid, Allele, Molecular Biology, Gene, Atovaquone, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, MESH : Drug Resistance, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, 030306 microbiology, MESH : Humans, Haplotype, MESH: DNA, Mitochondrial, biology.organism_classification, Atovaquone/proguanil, MESH: Antimalarials, Mutation, MESH : Antimalarials, MESH : Base Sequence, MESH : Animals
Abstract: International audience; Here we provide direct evidence that two adaptive nucleotide changes in the same codon (268) of the cytochrome b gene (pfcytb) each occurred repeatedly in independent Plasmodium falciparum lineages exposed to the antimalarial drug atovaquone-proguanil (AP). We analyzed the history of 7 AP resistance alleles from clinical isolates by sequencing the mitochondrial (mt) genome that encodes the pfcytb gene and found that a distinct mt haplotype was associated with each AP resistance allele. By comparing mt sequences and microsatellite genotypes of the isolates both before treatment initiation and at the day of failure for each uncured patient, we observed that the AP resistance alleles occurred and spread within the patients. These data demonstrate that identical AP resistance alleles have multiple independent origins and provide an example of parallel evolution driven by drug treatment selection in P. falciparum.
Published: 2007
Full Text: View/download PDF

21. Tumor genomic profiling and TP53 germline mutation analysis of first-degree relative familial gliomas

Author: Blandine Boisselier, Catherine Carpentier, Sophie Paris, Florence Laigle-Donadey, Khê Hoang-Xuan, Jean-Yves Delattre, Yannick Marie, Karima Mokhtari, Olivier Delattre, Emmanuelle Crinière, Michèle Kujas, Stéphane Liva, Ahmed Idbaih, Marc Sanson, Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Bioinformatique (CURIE-BIOINFO), Institut Curie [Paris], Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de Bioinformatique ( CURIE-BIOINFO ), INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Idbaih, Ahmed, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Male, Cancer Research, MESH : Germ-Line Mutation, DNA Mutational Analysis, MESH : Aged, MESH: Genes, p53, [SDV.GEN] Life Sciences [q-bio]/Genetics, Allelic Imbalance, MESH: Base Sequence, Germline, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Glioma, 0302 clinical medicine, MESH: Germ-Line Mutation, MESH : Female, MESH: DNA Mutational Analysis, Genetics, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Brain Neoplasms, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, Glioma, MESH : Adult, Middle Aged, 3. Good health, Pedigree, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Adult, MESH: Pedigree, MESH : Male, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, Biology, MESH : Genes, p53, Polymorphism, Single Nucleotide, 03 medical and health sciences, MESH: Gene Expression Profiling, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, MESH : Middle Aged, Family, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Allele, MESH : Brain Neoplasms, Molecular Biology, MESH : Allelic Imbalance, neoplasms, MESH: Family, Germ-Line Mutation, 030304 developmental biology, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Base Sequence, MESH : Gene Expression Profiling, Gene Expression Profiling, MESH : Humans, MESH: Allelic Imbalance, Chromosome, MESH: Adult, medicine.disease, Genes, p53, MESH: Male, Gene expression profiling, MESH : Glioma, MESH : Pedigree, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Base Sequence, MESH : Family, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, Comparative genomic hybridization
Abstract: International audience; About 5% of gliomas occur in a familial context, which suggests a genetic origin, but the predisposing molecular factors remain unknown in most cases. A series of nine familial gliomas were characterized with 1-megabase resolution BAC array-based comparative genomic hybridization (aCGH) together with germline sequence analysis of TP53. This series was compared with a literature series of familial gliomas and a personal series of sporadic gliomas, analyzed by chromosome CGH and aCGH, respectively. No significant difference was noted between the three populations in terms of clinical characteristics, pathologic features, and the most frequent chromosomal alterations, including loss of 1p, 10p, 10q, 13q, and 19q, and gain of 7p, 7q, 16p, 18q, 19p, 19q, 20p, and 22q. However, a genomic region located in 6q was more frequently gained in our series of familial as compared to sporadic gliomas (P=0.028). A germline TP53 mutation was observed in 1/9 cases, which suggests Li-Fraumeni syndrome. Interestingly, the Pro allele in the codon 72 of TP53 was observed in 5/9 tumors. Although familial and sporadic gliomas share very similar cytogenetic quantitative patterns, aCGH is a promising technique for the detection of small genomic differences of potential significance.
Published: 2007
Full Text: View/download PDF

22. Joint association of polymorphism of the FGFR4 gene and mutation TP53 gene with bladder cancer prognosis

Author: Victor E. Reuter, Carlos Cordon-Cardo, Arie S. Belldegrun, Zuo-Feng Zhang, Yonghui Yang, Guido Dalbagni, Ming-Lan Lu, Lin Cai, Wei Cao, Allan J. Pantuck, Jianyu Rao, Hervé Wallerand, Robert A. Figlin, Service d'urologie, andrologie et transplantation rénale, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Department of Materials Science and Engineering, University of Florida [Gainesville], Département de pharmacochimie moléculaire ( DPM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre National de la Recherche Scientifique ( CNRS ), State Key Joint Laboratory of Environmental Simulation and Pollution Control, School of Environmental Science and Engineering, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Department of Materials Science and Engineering [Gainesville] (UF|MSE), University of Florida [Gainesville] (UF), Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Sun Yat-Sen University [Guangzhou] (SYSU)-Sun Yat-Sen University [Guangzhou] (SYSU)
Subjects: p53, Male, Cancer Research, Fibroblast Growth Factor, DNA Mutational Analysis, MESH: Genes, p53, MESH : Aged, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, single nucleotide polymorphism, Clinical Studies, Genotype, 2.1 Biological and endogenous factors, MESH : Female, MESH: DNA Mutational Analysis, Cancer, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH : Prognosis, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, fibroblast growth factor receptor 4, TP53 mutation, Single Nucleotide, Middle Aged, Prognosis, MESH : Survival Rate, 3. Good health, MESH: Urinary Bladder Neoplasms, Survival Rate, Oncology, MESH : Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, MESH: Survival Analysis, Public Health and Health Services, bladder cancer, Female, MESH : Mutation, Type 4, Receptor, Urologic Diseases, MESH: Receptor, Fibroblast Growth Factor, Type 4, MESH: Mutation, Tumor suppressor gene, MESH: Survival Rate, MESH : Male, Oncology and Carcinogenesis, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, Biology, MESH : Receptor, Fibroblast Growth Factor, Type 4, Polymorphism, Single Nucleotide, MESH : Genes, p53, MESH: Prognosis, 03 medical and health sciences, Growth factor receptor, Clinical Research, Genetics, medicine, Humans, Receptor, Fibroblast Growth Factor, Type 4, MESH : Middle Aged, Oncology & Carcinogenesis, Polymorphism, Survival rate, Survival analysis, Aged, 030304 developmental biology, Bladder cancer, MESH: Humans, MESH : Humans, Fibroblast growth factor receptor 4, Genes, p53, medicine.disease, Survival Analysis, MESH: Male, Genes, Urinary Bladder Neoplasms, Mutation, Cancer research, MESH : Survival Analysis, MESH: Female
Abstract: International audience; The impact of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism on bladder cancer is unknown. We found no clear correlations between the FGFR4 genotype and risk of bladder cancer or pathological parameters. Neither the polymorphism nor TP53 mutation status was an independent predictor of prognosis, but they might act jointly on the disease-specific survival of patients.
Published: 2006
Full Text: View/download PDF

23. Partial defects in transcriptional activity of two novel DAX-1 mutations in childhood-onset adrenal hypoplasia congenita

Author: Paul Laissue, Silvia Copelli, Marc Fellous, Gabriel Barrio, César Bergadá, Sinan Karaboga, Jean Marie Wurtz, Reiner A. Veitia, Ignacio Bergadá, Enzo Lalli, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Departamento de Ciencias Biologicas, Universidad CAECE, Centro de Investigaciones Endocrinológicas (CEDIE), Hospital de Niños 'Ricardo Gutiérrez', Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-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 Paris Descartes - Paris 5 (UPD5), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur - Strasbourg I - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (UNS), and Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA) - Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Transcription, Genetic, MESH : Hela Cells, Receptors, Retinoic Acid, Endocrinology, Diabetes and Metabolism, MESH : Immunohistochemistry, DNA Mutational Analysis, Mutant, MESH : Child, Preschool, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Endocrinology, MESH: Structure-Activity Relationship, MESH : Child, MESH: Child, Adrenal Glands, MESH : Structure-Activity Relationship, MESH: Adrenal Glands, MESH: DNA Mutational Analysis, Child, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH : Infant, Transfection, Immunohistochemistry, Protein subcellular localization prediction, MESH: Infant, MESH : Receptors, Retinoic Acid, DNA-Binding Proteins, MESH: Repressor Proteins, Child, Preschool, MESH: Adrenal Insufficiency, MESH : DNA-Binding Proteins, MESH : Mutation, MESH : Repressor Proteins, MESH : Transfection, MESH : Protein Structure, Tertiary, medicine.medical_specialty, MESH: Mutation, MESH : Male, 030209 endocrinology & metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, Biology, MESH : Adrenal Glands, Structure-Activity Relationship, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, X-linked adrenal hypoplasia congenita, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epigenetics, Gene, 030304 developmental biology, MESH: Receptors, Retinoic Acid, MESH: Humans, DAX-1 Orphan Nuclear Receptor, MESH: Transcription, Genetic, MESH: Transfection, MESH : Humans, MESH: Child, Preschool, Infant, MESH : Transcription, Genetic, MESH: Immunohistochemistry, MESH : Adrenal Insufficiency, medicine.disease, MESH: Male, Protein Structure, Tertiary, Repressor Proteins, MESH: Hela Cells, Nuclear receptor, Mutation, DAX1, MESH: DNA-Binding Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Adrenal Insufficiency, HeLa Cells
Abstract: OBJECTIVE: Mutations in DAX-1, an X-linked gene encoding an orphan nuclear receptor, have been associated with adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Here we describe two novel DAX-1 mutations, Y214X and I361T, associated with childhood-onset primary adrenal failure. We aimed at analysing their effects on protein localization, transcriptional activity and propose a structural-function relationship. DESIGN: We have directly sequenced the DAX-1 gene from PCR-amplified DNA. The effect of the mutations on protein localization was assessed by immunocytochemistry in transfected cells. The impact of mutations on transcriptional activity was determined by transfection using a StAR promoter-luciferase reporter system. RESULTS: The mutation Y214X produces a protein lacking the C-terminal half of DAX-1. The other one, I361T, affects a highly conserved amino acid within the putative ligand-binding domain. The mutant Y214X displayed a wild-type subcellular localization while I361T was partially retained in the cytoplasm. Both mutants retained subtantial transcriptional repressive activity, compared to mutants producing early onset adrenal failure. Interestingly, I361T displayed similar in vitro transcriptional repressive activity to the mutant I439S previously described in a case of late-onset AHC. This shows that molecular alterations of DAX-1 leading to similar in vitro activities may result in very different ages of onset of adrenal failure, which suggests that additional genetic and epigenetic factors are important in determining the clinical course of AHC. CONCLUSIONS: Our results help the understanding of structure-function relationships in the DAX-1 molecule, suggesting that the N-terminal domain is relatively autonomous and add credence to presumed molecular interactions within ligand binding domain of the protein.
Published: 2006
Full Text: View/download PDF

24. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease

Author: Claire Soudais, Capucine Picard, Angela Rösen-Wolff, Guillaume Vogt, C. Rolinck-Werninghaus, Emmanuelle Jouanguy, Jacqueline Feinberg, Jean-Laurent Casanova, Klaus Magdorf, Jacinta Bustamante, Kun Yang, Ada Prochnicka-Chalufour, Claire Fieschi, Orchidée Filipe Santos, Peter D. Arkwright, Joachim Roesler, Jean-François Emile, Robert D. Schreiber, Ludovic de Beaucoudrey, Stéphanie Boisson-Dupuis, Ariane Chapgier, Armanda Casrouge, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), French Chinese laboratory of Genetics (FRENCH CHINESE LABORATORY OF GENETICS), Rujin ospital, Shanghai II University, Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], University of Manchester [Manchester], Department of Pathology and Immunology (DEPARTMENT OF PATHOLOGY AND IMMUNOLOGY), Washington University in Saint Louis (WUSTL), Department of Pediatric Pneumology and Immunology (DEPARTMENT OF PEDIATRIC PNEUMOLOGY AND IMMUNOLOGY), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Pediatrics (DEPARTMENT OF PEDIATRICS), University Clinic Carl Gustav Carus, Dresden, Service d'immuno-hématologie pédiatrique [CHU Necker], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Service d'anatomie pathologique, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), French Chinese laboratory of Genetics ( FRENCH CHINESE LABORATORY OF GENETICS ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Department of Pathology and Immunology ( DEPARTMENT OF PATHOLOGY AND IMMUNOLOGY ), Washington University Saint Louis Missouri, Department of Pediatric Pneumology and Immunology ( DEPARTMENT OF PEDIATRIC PNEUMOLOGY AND IMMUNOLOGY ), Charité, Humboldt University of Berlin, Department of Pediatrics ( DEPARTMENT OF PEDIATRICS ), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH : Mutant Proteins, Transcription, Genetic, DNA Mutational Analysis, Cell Cycle Proteins, 0302 clinical medicine, MESH : Cell Cycle Proteins, MESH : Child, MESH: Child, MESH : Interferon-Stimulated Gene Factor 3, gamma Subunit, STAT1, MESH: DNA Mutational Analysis, Child, Cells, Cultured, 0303 health sciences, MESH : Gene Expression Regulation, MESH : Infant, MESH : Interferon Type II, MESH : Protein Binding, MESH : Genes, Dominant, MESH: Infant, 3. Good health, Pedigree, STAT1 Transcription Factor, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Child, Preschool, MESH : DNA-Binding Proteins, MESH: Membrane Proteins, MESH: Models, Molecular, MESH: Cells, Cultured, MESH : Heterozygote, MESH: Pedigree, Immunology, Alpha interferon, MESH : DNA Mutational Analysis, GPI-Linked Proteins, Transfection, 03 medical and health sciences, Interferon-gamma, MESH: Cell Cycle Proteins, MESH : Adolescent, Genetics, MESH: Protein Binding, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, MESH: Genes, Recessive, Alleles, MESH: Adolescent, Mycobacterium Infections, MESH: Humans, MESH: STAT1 Tra, MESH : Immunity, Active, MESH : Humans, MESH: Child, Preschool, MESH : Genes, Recessive, Infant, MESH: Adult, Interferon-Stimulated Gene Factor 3, gamma Subunit, MESH : Membrane Proteins, MESH : Mycobacterium Infections, Mutation, MESH : Alleles, MESH: Genes, Dominant, MESH: Female, MESH: Immunity, Active, Models, Molecular, Cancer Research, MESH : Models, Biological, MESH : Child, Preschool, [ SDV.IMM.IA ] Life Sciences [q-bio]/Immunology/Adaptive immunology, Loss of heterozygosity, MESH: Mutant Proteins, Homo (Human), Interferon gamma, MESH : Female, Genetics (clinical), MESH: Heterozygote, Genes, Dominant, MESH : Adult, MESH: Gene Expression Regulation, DNA-Binding Proteins, Immunity, Active, Infectious Diseases, MESH : Interferon-alpha, MESH: Interferon-Stimulated Gene Factor 3, gamma Subunit, Female, MESH : Mutation, MESH: Interferon-alpha, medicine.drug, Protein Binding, Research Article, MESH : STAT1 Tra, Adult, Heterozygote, MESH: Mutation, lcsh:QH426-470, Adolescent, MESH : Models, Molecular, MESH: Interferon Type II, MESH : Male, Genetics/Genetics of Disease, Genes, Recessive, Biology, Models, Biological, Immunity, MESH : Cells, Cultured, medicine, Allele, MESH: Mycobacterium Infections, Gene, 030304 developmental biology, MESH: Alleles, MESH: Models, Biological, Interferon-alpha, Membrane Proteins, Heterozygote advantage, MESH: Male, lcsh:Genetics, Gene Expression Regulation, MESH : Pedigree, biology.protein, Mutant Proteins, MESH: DNA-Binding Proteins
Abstract: The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)–induced gamma-activating factor–mediated immunity and interferon alpha (IFNA)–induced interferon-stimulated genes factor 3–mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor–mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3–mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding., Synopsis Mendelian susceptibility to mycobacterial disease is a rare syndrome. It is defined by the occurrence of severe disease caused by low virulence mycobacteria in otherwise healthy individuals, in whom antiviral immune response is not affected. Eleven known genetic defects, affecting five genes, have been involved in this type of deficient response to infection, involving immune-mediator molecules IL12 and interferon gamma: IL12B, IL12RB1, IFNGR1, IFNGR2, and STAT1. The signal transducer and activator of transcription-1 (STAT1) amino acid change L706S was previously shown to cause disease by impairing STAT1 phosphorylation. Here, we report two new STAT1 mutations that impair STAT1 DNA-binding activity. We show, by functional analysis of the three STAT1 mutant alleles, that they are intrinsically deleterious for both interferon gamma–induced antimycobacterial immunity, which is mediated through gamma-activated factor and for interferon alpha–induced antiviral immunity, which is mediated through interferon-stimulated genes factor 3. Interestingly, the three alleles are dominant for interferon gamma–induced gamma-activated factor–mediated antimycobacterial immunity, but recessive for interferon alpha–induced interferon-stimulated genes factor 3–mediated antiviral immunity at the cellular and clinical levels. These two new STAT1 alleles, which affect the binding of STAT1 to DNA, define distinct novel genetic causes of Mendelian susceptibility to mycobacterial disease and provide further insight into the molecular mechanism of disease.
Published: 2006
Full Text: View/download PDF

25. Eight previously unidentified mutations found in the OA1 ocular albinism gene

Author: Josseline Kaplan, Elise Heon, Daniel F. Schorderet, Helene Mayeur, Alex V. Levin, Dominique Bonneau, Maurice Menasche, Marc Abitbol, Hélène Dollfus, Joanne Sutherland, Eedy Mezer, Dominique Marchant, Cécile Marsac, Didier Lacombe, Olivier Roche, Jean-Louis Dufier, Carolina Jaliffa, Francis L. Munier, Edith Said, Christelle Vêtu, EA no 2502 du ministère de la Recherche, de l'Enseignement Supérieur et la Technologie, Université Paris Descartes - Paris 5 (UPD5)-CERTO, Service d'ophtalmologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Jules Gonin Eye Hospital, Institut de Recherche en Ophtalmologie (IRO), Institut de Recherche en Ophtalmologie, Department of Ophthalmology and Vision Sciences, The Hospital for sick children [Toronto] (SickKids), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Department of Pediatrics and Medical Genetics, St. Luke's Hospital, Alberto Moscona Department of Ophthalmology, Rambam Health Care Campus, Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), We would like to thank Rétina France, Président Claude Foucher, Pr Jean- Louis Dufier, Dean Patrick Berche, Genespoir, Fondation pour la Recherche Médicale, Fondation de France, Lions Club de France, Fondation de L'Avenir, Association Française contre les Myopathies, ORPHANET, INSERM, CNRS, Ministère de la Recherche, de l'Enseignement Supérieur et de la Technologie, Faculté de Médecine René Descartes, Brandan's Eye Research Fund (AL) and Essilor for their support., Autard, Delphine, Université Paris Descartes - Paris 5 ( UPD5 ) -CERTO, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université d'Angers ( UA ) -CHU Angers, Institut de Recherche en Ophtalmologie ( IRO ), The Hospital for Sick Children, Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Handicaps génétiques de l'enfant ( Inserm U393 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH : Point Mutation, Male, MESH : Molecular Sequence Data, genetic structures, MESH: Membrane Glycoproteins, DNA Mutational Analysis, MESH : Membrane Glycoproteins, MESH: RNA Splice Sites, MESH: Amino Acid Sequence, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, MESH: Research Support, Non-U.S. Gov't, Exon, 0302 clinical medicine, MESH : Research Support, Non-U.S. Gov't, MESH: Eye Proteins, Gene duplication, MESH : Female, Genetics(clinical), MESH: DNA Mutational Analysis, Genetics (clinical), Sequence Deletion, Genetics, 0303 health sciences, Mutation, Membrane Glycoproteins, MESH : Amino Acid Sequence, Albinism, Ocular, Amino Acid Sequence, Eye Proteins, Female, Humans, Molecular Sequence Data, Pedigree, Point Mutation, RNA Splice Sites, MESH: Sequence Deletion, 3. Good health, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [ SDV.MHEP.OS ] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Ocular albinism type 1, MESH : Mutation, MESH : RNA Splice Sites, Research Article, Ocular albinism, lcsh:Internal medicine, MESH: Mutation, lcsh:QH426-470, MESH: Pedigree, MESH : Male, MESH : DNA Mutational Analysis, Biology, 03 medical and health sciences, MESH : Eye Proteins, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, lcsh:RC31-1245, Gene, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Albinism, Ocular, MESH: Point Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, MESH : Albinism, Ocular, Point mutation, MESH : Sequence Deletion, Alternative splicing, MESH : Humans, medicine.disease, Molecular biology, MESH: Male, eye diseases, lcsh:Genetics, MESH : Pedigree, 030221 ophthalmology & optometry, sense organs, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female
Abstract: Background Ocular albinism type 1 (OA1) is an X-linked ocular disorder characterized by a severe reduction in visual acuity, nystagmus, hypopigmentation of the retinal pigmented epithelium, foveal hypoplasia, macromelanosomes in pigmented skin and eye cells, and misrouting of the optical tracts. This disease is primarily caused by mutations in the OA1 gene. Methods The ophthalmologic phenotype of the patients and their family members was characterized. We screened for mutations in the OA1 gene by direct sequencing of the nine PCR-amplified exons, and for genomic deletions by PCR-amplification of large DNA fragments. Results We sequenced the nine exons of the OA1 gene in 72 individuals and found ten different mutations in seven unrelated families and three sporadic cases. The ten mutations include an amino acid substitution and a premature stop codon previously reported by our team, and eight previously unidentified mutations: three amino acid substitutions, a duplication, a deletion, an insertion and two splice-site mutations. The use of a novel Taq polymerase enabled us to amplify large genomic fragments covering the OA1 gene. and to detect very likely six distinct large deletions. Furthermore, we were able to confirm that there was no deletion in twenty one patients where no mutation had been found. Conclusion The identified mutations affect highly conserved amino acids, cause frameshifts or alternative splicing, thus affecting folding of the OA1 G protein coupled receptor, interactions of OA1 with its G protein and/or binding with its ligand.
Published: 2006
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources

Refine your results

25 results on '"MESH : DNA Mutational Analysis"'

1. A quality control program for mutation detection in KIT and PDGFRA in gastrointestinal stromal tumours

2. ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences

3. Focal adhesion kinase is involved in rabies virus infection through its interaction with viral phosphoprotein P

4. Mutational founder effect in recessive dystrophic epidermolysis bullosa families from Southern Tunisia

5. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

6. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia

7. Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes

8. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation

9. Zidovudine (AZT) has a bactericidal effect on enterobacteria and induces genetic modifications in resistant strains

10. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias

11. Immunoglobulin heavy chain V-D-J gene rearrangement and mutational status in Uruguayan patients with chronic lymphocytic leukemia

12. Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome

13. Comparative analysis of oncogenic properties and nuclear factor-kappaB activity of latent membrane protein 1 natural variants from Hodgkin's lymphoma's Reed-Sternberg cells and normal B-lymphocytes

14. The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations

15. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders

16. The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum

17. Analysis of the DND1 gene in men with sporadic and familial testicular germ cell tumors

18. Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy

19. New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation

20. Parallel evolution of adaptive mutations in Plasmodium falciparum mitochondrial DNA during atovaquone-proguanil treatment

21. Tumor genomic profiling and TP53 germline mutation analysis of first-degree relative familial gliomas

22. Joint association of polymorphism of the FGFR4 gene and mutation TP53 gene with bladder cancer prognosis

23. Partial defects in transcriptional activity of two novel DAX-1 mutations in childhood-onset adrenal hypoplasia congenita

24. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease

25. Eight previously unidentified mutations found in the OA1 ocular albinism gene

Catalog

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

25 results on '"MESH : DNA Mutational Analysis"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources