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17 results on '"MESH: Chromosomes, Human, Pair 15"'

1. Terminal 6.9 Mb deletion of chromosome 15q, associated with a structurally abnormal X chromosome in a patient with congenital diaphragmatic hernia and heart defect

Author

Florence Demurger, Isabelle Bertorello, Marc-Antoine Belaud-Rotureau, Gwenaelle Le Bouar, Véronique David, Sylvie Jaillard, Christèle Dubourg, Patrice Poulain, Josette Lucas, Philippe Loget, Sylvie Odent, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Laboratoire de Génétique Moléculaire, Hôpital Pontchaillou, Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], Service de Génétique Clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-hôpital Sud, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, and De Villemeur, Hervé

Subjects
Heart Defects, Congenital, MESH: Chromosome Deletion, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, X-inactivation, MESH: Chromosomes, Human, X, 03 medical and health sciences, Chromosome 15, X Chromosome Inactivation, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetics, medicine, Humans, Diaphragmatic hernia, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), X chromosome, 030304 developmental biology, Chromosomal inversion, Hernia, Diaphragmatic, Chromosomes, Human, Pair 15, Chromosomes, Human, X, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: X Chromosome Inactivation, 030305 genetics & heredity, MESH: Infant, Newborn, Infant, Newborn, Congenital diaphragmatic hernia, Karyotype, General Medicine, MESH: Heart Defects, Congenital, MESH: Chromosome Inversion, medicine.disease, 3. Good health, MESH: Hernia, Diaphragmatic, Chromosome Inversion, Female, XIST, Chromosome Deletion, Hernias, Diaphragmatic, Congenital, MESH: Female, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; We report the case of a female patient exhibiting multiple congenital malformations including diaphragmatic hernia and heart defect. Cytogenetic studies (including karyotype, FISH and array-CGH) showed a de novo terminal deletion (6.9 Mb) on chromosome 15 in association with a recombinant X chromosome bearing a 9-Mb Xp duplication and a 46-Mb Xq deletion distal to XIST. The recombinant X chromosome was caused by a maternal inv(X)(p22.31q22.3). The X chromosome inactivation pattern was skewed in the patient suggesting a possible inactivation of the recombinant X chromosome. Considering these results, the phenotype was linked to the de novo terminal 15q deletion. These results strengthen the assumption that array-CGH should be applied to each fetus/newborn with multiple congenital malformations.

Published
2011

2. Search for copy number variants in chromosomes 15q11-q13 and 22q11.2 in obsessive compulsive disorder

Author

Wolfgang Maier, Michael Wagner, Daniel Moreno-De-Luca, Richard Delorme, Catalina Betancur, Aurélie Gennetier, Peter Falkai, Rainald Mössner, Stephan Ruhrmann, Hans J. Grabe, Marion Leboyer, Marie-Christine Mouren, Pauline Chaste, Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, Universität Greifswald - University of Greifswald, University of Cologne, Georg-August-University = Georg-August-Universität Göttingen, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), This research was supported by INSERM, Fondation de France, FondaMental Foundation, and the German Research Foundation (DFG)., Betancur, Catalina, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, and Georg-August-University [Göttingen]

Subjects
Male, Obsessive-Compulsive Disorder, Chromosomes, Human, Pair 22, Gene Dosage, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Gene Dosage, 0302 clinical medicine, Segmental Duplications, Genomic, DiGeorge syndrome, MESH: Child, Genetics(clinical), MESH: Syndrome, Copy-number variation, MESH: Chromosomes, Human, Pair 22, Child, Genetics (clinical), Sequence Deletion, Genetics, 0303 health sciences, MESH: Middle Aged, MESH: Genetic Predisposition to Disease, Syndrome, Middle Aged, MESH: Sequence Deletion, 3. Good health, MESH: Young Adult, Female, MESH: DNA Copy Number Variations, Chromosome Deletion, Prader-Willi Syndrome, Research Article, Adult, medicine.medical_specialty, lcsh:Internal medicine, lcsh:QH426-470, Adolescent, DNA Copy Number Variations, MESH: Chromosome Deletion, Biology, Gene dosage, behavioral disciplines and activities, 03 medical and health sciences, Young Adult, MESH: Segmental Duplications, Genomic, mental disorders, medicine, DiGeorge Syndrome, Humans, Genetic Predisposition to Disease, Multiplex ligation-dependent probe amplification, lcsh:RC31-1245, Gene, 030304 developmental biology, MESH: Adolescent, MESH: Obsessive-Compulsive Disorder, Chromosomes, Human, Pair 15, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: DiGeorge Syndrome, Cytogenetics, Chromosome, MESH: Adult, medicine.disease, Human genetics, MESH: Male, lcsh:Genetics, MESH: Prader-Willi Syndrome, MESH: Female, 030217 neurology & neurosurgery, MESH: Chromosomes, Human, Pair 15
Abstract

Background Obsessive-compulsive disorder (OCD) is a clinically and etiologically heterogeneous syndrome. The high frequency of obsessive-compulsive symptoms reported in subjects with the 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) or Prader-Willi syndrome (15q11-13 deletion of the paternally derived chromosome), suggests that gene dosage effects in these chromosomal regions could increase risk for OCD. Therefore, the aim of this study was to search for microrearrangements in these two regions in OCD patients. Methods We screened the 15q11-13 and 22q11.2 chromosomal regions for genomic imbalances in 236 patients with OCD using multiplex ligation-dependent probe amplification (MLPA). Results No deletions or duplications involving 15q11-13 or 22q11.2 were identified in our patients. Conclusions Our results suggest that deletions/duplications of chromosomes 15q11-13 and 22q11.2 are rare in OCD. Despite the negative findings in these two regions, the search for copy number variants in OCD using genome-wide array-based methods is a highly promising approach to identify genes of etiologic importance in the development of OCD.

Published
2010

3. Genotype-phenotype correlation in four 15q24 deleted patients identified by array-CGH

Author

Bruno Delobel, Emilie Landais, Tania Attié-Bitach, Martine Doco-Fenzy, Eléonore Blondeel, Marlène Rio, Joris Andrieux, Elsa Delaby, Christèle Dubourg, Sylvie Manouvrier-Hanu, Muriel Holder-Espinasse, Henri Copin, Hubert Journel, Sylvie Odent, Michèle Mathieu, Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Moléculaire et Hormonologie, Hôpital Pontchaillou, Service de Génétique Médicale [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 Pédiatrie-Génétique, CHU Amiens-Picardie-Hôpital nord, Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Laboratoire de Cytogénétique, Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), De Villemeur, Hervé, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], CHU Pontchaillou [Rennes], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Bretagne Atlantique-Hôpital Chubert, Université de Picardie Jules Verne ( UPJV ) -CHU Amiens-Picardie, Centre Hospitalier Universitaire de Reims ( CHU Reims ) -Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne ( URCA ) -Université de Reims Champagne-Ardenne ( URCA ), and Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille )

Subjects
Male, Pathology, MESH : Genotype, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH : Child, Preschool, MESH: Genotype, 0302 clinical medicine, MESH: Pregnancy, MESH : Child, Pregnancy, MESH: Child, Genotype, MESH : Female, Child, MESH : Comparative Genomic Hybridization, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Genetics, 0303 health sciences, Comparative Genomic Hybridization, MESH: Infant, Newborn, Long philtrum, MESH : Infant, Chromosome Breakage, Micropenis, MESH : Chromosomes, Human, Pair 15, MESH: Infant, 3. Good health, MESH : Phenotype, Phenotype, MESH: Chromosome Breakage, Child, Preschool, Female, Chromosome breakage, Chromosome Deletion, Haploinsufficiency, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, MESH : Male, MESH: Chromosome Deletion, 15q24 deletion, Biology, genotype-phenotype correlation, MESH : Infant, Newborn, MESH: Phenotype, Article, 03 medical and health sciences, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Humans, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, 030304 developmental biology, Chromosomes, Human, Pair 15, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Humans, MESH: Child, Preschool, Infant, Newborn, Infant, medicine.disease, MESH : Chromosome Deletion, Iris coloboma, MESH: Male, MESH: Comparative Genomic Hybridization, MESH : Pregnancy, Palpebral fissure, MESH : Chromosome Breakage, Hypospadias, array-CGH, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, 030217 neurology & neurosurgery, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; Microdeletion 15q24 is an emerging syndrome recently described, mainly due to increased use of array-CGH. Clinical features associate mild to moderate developmental delay, typical facial characteristics (high forehead and frontal hairline, broad eyebrows, downslanting palpebral features, long philtrum), hands (particularly proximal implanted thumbs) and genital anomalies (micropenis, hypospadias). We report here on four de novo cases having 2.5-6.1 Mb deletions involving 15q24: one 15q23q24.2 (Patient 1) and three 15q24.1q24.2 deletions (Patients 2-4). We correlate phenotype to genotype according to molecular boundaries of these deletions. Since bilateral iris coloboma and severe ano-rectal malformation were only present in Patient 1, we could link these anomalies to haploinsufficiency of 15q23 genes. Neither hypospadias nor micropenis were present in Patient 3 bearing the smallest deletion, therefore we could define 500 kb 15q24.1 region linked to these anomalies.

Published
2009

4. Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders

Author

Daniel Moreno-De-Luca, Gudrun Nygren, Eric LeGuern, Pauline Chaste, Marion Leboyer, Delphine Bouteiller, Catalina Betancur, Baya Benyahia, Svenny Kopp, Christel Depienne, Aurélie Gennetier, Alain Verloes, Alexis Brice, Lydie Burglen, Maria Råstam, Jean-Pierre Siffroi, Sandra Chantot-Bastaraud, Maria E. Johansson, Delphine Héron, Richard Delorme, Oriane Trouillard, Christopher Gillberg, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Unité fonctionnelle de génétique clinique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Albert Chenevier, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institute of Child Health [London], University College of London [London] (UCL), This research was supported by Fondation de France, INSERM, Fondation pour la Recherche Médicale, Fondation France Télécom, Cure Autism Now, Assistance Publique-Hôpitaux de Paris, and the Swedish Science Council., Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Betancur, Catalina, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Gene Dosage, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Gene Dosage, 0302 clinical medicine, MESH: DNA Methylation, MESH: Child, deletion, Child, Genetics, 0303 health sciences, chromosome 15, Uniparental disomy, 3. Good health, MLPA, duplication, Child, Preschool, Female, Prader-Willi Syndrome, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, MESH: Autistic Disorder, autism, Biology, Dup15q, MESH: Angelman Syndrome, 03 medical and health sciences, Chromosome 15, Angelman syndrome, MESH: Uniparental Disomy, Happy puppet syndrome, mental disorders, medicine, Humans, MESH: Chromosome Aberrations, Multiplex ligation-dependent probe amplification, Autistic Disorder, Biological Psychiatry, 030304 developmental biology, Chromosome Aberrations, MESH: Adolescent, Chromosomes, Human, Pair 15, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Child, Preschool, MESH: Adult, DNA Methylation, Uniparental Disomy, medicine.disease, MESH: Male, Developmental disorder, MESH: Gene Deletion, MESH: Prader-Willi Syndrome, MESH: Microsatellite Repeats, Genomic imprinting, MESH: Female, 030217 neurology & neurosurgery, Gene Deletion, Microsatellite Repeats, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; BACKGROUND: Maternally derived duplications of the 15q11-q13 region are the most frequently reported chromosomal aberrations in autism spectrum disorders (ASD). Prader-Willi and Angelman syndromes, caused by 15q11-q13 deletions or abnormal methylation of imprinted genes, are also associated with ASD. However, the prevalence of these disorders in ASD is unknown. The aim of this study was to assess the frequency of 15q11-q13 rearrangements in a large sample of patients ascertained for ASD. METHODS: A total of 522 patients belonging to 430 families were screened for deletions, duplications, and methylation abnormalities involving 15q11-q13 with multiplex ligation-dependent probe amplification (MLPA). RESULTS: We identified four patients with 15q11-q13 abnormalities: a supernumerary chromosome 15, a paternal interstitial duplication, and two subjects with Angelman syndrome, one with a maternal deletion and the other with a paternal uniparental disomy. CONCLUSIONS: Our results show that abnormalities of the 15q11-q13 region are a significant cause of ASD, accounting for approximately 1% of cases. Maternal interstitial 15q11-q13 duplications, previously reported to be present in 1% of patients with ASD, were not detected in our sample. Although paternal duplications of chromosome 15 remain phenotypically silent in the majority of patients, they can give rise to developmental delay and ASD in some subjects, suggesting that paternally expressed genes in this region can contribute to ASD, albeit with reduced penetrance compared with maternal duplications. These findings indicate that patients with ASD should be routinely screened for 15q genomic imbalances and methylation abnormalities and that MLPA is a reliable, rapid, and cost-effective method to perform this screening.

Published
2009

5. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Author

Hamid Azzedine, Alessandro Filla, Merle Ruberg, Paula Coutinho, Filippo M. Santorelli, Enrico Bertini, Vítor Tedim Cruz, Elodie Martin, N. Elleuch, D. Grid, Jacques Chomilier, Alessandra Tessa, Naima Bouslam, Perrine Charles, Alexandra Durr, Bertrand Fontaine, Eric LeGuern, Paola S. Denora, Christian Confavreux, Giovanni Stevanin, Anne Marie Ouvrard-Hernandez, Alexis Brice, Meriem Tazir, José Leal Loureiro, Alexander Lossos, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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), Unit of Molecular Medicine, IRCCS, UnIGENe, Universidade do Porto, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Department of Neurology, Hadassah Hebrew University Medical Center [Jerusalem], Departamento de Neurologia, Hospital S. Sebastiao, Department of neurology, Hopital Habib Bourguiba - Habib Bourguiba Hospital [Sfax], Hopital Neurologique, Ministère de la santé, Service de Neurologie A-Hopital Neurologique Pierre Wertheimer, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Généthon, Service de Neurologie, Hopital Mustapha, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurological Sciences, Università degli studi di Napoli Federico II, ANR-05-MRAR-0001,Cav3pathies,Approches physiopathologique et moléculaire de la signalisation calcique dans les caveolinopathies musculaires(2005), Université Mohammed V, 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), Hôpital neurologique, Hospices Civils de Lyon (HCL), Neurologie Expérimentale et Thérapeutique, IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Mustapha, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Computer Science and Engineering, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade do Porto = University of Porto, Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), University of Naples Federico II = Università degli studi di Napoli Federico II, 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), Stevanin, G, Santorelli, Fm, Azzedine, H, Coutinho, P, Chomilier, J, Denora, P, Martin, E, OUVRARD HERNANDEZ, Am, Tessa, A, Bouslam, N, Lossos, A, Charles, P, Loureiro, Jl, Elleuch, N, Confavreux, C, Cruz, Vt, Ruberg, M, Leguern, E, Grid, D, Tazir, M, Fontaine, B, Filla, Alessandro, Bertini, E, Durr, A, Brice, A., Université Mohammed V de Rabat [Agdal] (UM5), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Genetic Linkage, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, MESH: Rats, Sprague-Dawley, MESH: Base Sequence, Corpus callosum, Corpus Callosum, Rats, Sprague-Dawley, MESH: Genotype, 0302 clinical medicine, MESH: Child, Chlorocebus aethiops, Spastic, MESH: Proteins, MESH: Animals, Age of Onset, MESH: DNA Mutational Analysis, Child, ComputingMilieux_MISCELLANEOUS, Genetics, Cerebral Cortex, 0303 health sciences, MESH: Spastic Paraplegia, Hereditary, Pedigree, MESH: COS Cells, COS Cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Paraplegia, Adult, MESH: Mutation, Adolescent, Genotype, MESH: Rats, MESH: Pedigree, MESH: Age of Onset, Molecular Sequence Data, Locus (genetics), Biology, MESH: Corpus Callosum, Frameshift mutation, 03 medical and health sciences, Chromosome 15, Genetic linkage, medicine, Animals, Humans, 030304 developmental biology, MESH: Adolescent, Chromosomes, Human, Pair 15, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Spastic Paraplegia, Hereditary, Proteins, MESH: Adult, medicine.disease, MESH: Cercopithecus aethiops, MESH: Cerebral Cortex, Rats, nervous system diseases, MESH: Lod Score, Corticospinal tract, Mutation, Lod Score, MESH: Linkage (Genetics), 030217 neurology & neurosurgery, MESH: Chromosomes, Human, Pair 15
Abstract

Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial spastic paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP.

Published
2007

6. Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity

Author

Giovanni, Stevanin, Giorgia, Montagna, Hamid, Azzedine, Enza Maria Valente, Alexandra, Durr, Valentina, Scarano, Naima, Bouslam, Denise, Cassandrini, Denora, Paola S., Chiara, Criscuolo, Soraya, Belarbi, Antonio, Orlacchio, Philippe, Jonveaux, Gabriella, Silvestri, Anne Marie Ouvrad Hernandez, De Michele, G., Meriem, Tazir, Caterina, Mariotti, Knut, Brockmann, Alessandro, Malandrini, Van Der Knapp, M. S., Marcella, Neri, Hassan, Tonekaboni, Melone, Mariarosa A. B., Alessandra, Tessa, Teresa Dotti, M., Michela, Tosetti, Pauri, Flavia, Antonio, Federico, Casali, Carlo, Cruz, Vitor T., Loureiro, Jose L., Federico, Zara, Sylvie, Forlani, Enrico, Bertini, Paula, Coutinho, Alessandro, Filla, Alexis, Brice, Santorelli, Filippo M., Casali, C., Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unit of Molecular Medicine, IRCCS, Mendel Institute, Department of Neurological Sciences, University of Naples Federico II = Università degli studi di Napoli Federico II, Pediatric Neurology and Neuromuscular Diseases Unit, Università degli studi di Genova = University of Genoa (UniGe), Service de Neurologie, Hopital Mustapha, Department of Neurosciences, Università degli Studi di Roma Tor Vergata [Roma], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Department of Neuroscience, Catholic University, Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Besta Neurological Institute, Department of Pediatrics and Neuropediatrics, Georg-August-University = Georg-August-Universität Göttingen, Institute of Neurological Sciences, Department of Child Neurology, VU University Medical Center [Amsterdam], Medical Genetics, Università degli Studi di Ferrara = University of Ferrara (UniFE), Stella Maris, Department of Neurology and ORL, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Departamento de Neurologia, Hospital S. Sebastiao, ANR-05-MRAR-0001,Cav3pathies,Approches physiopathologique et moléculaire de la signalisation calcique dans les caveolinopathies musculaires(2005), Stevanin, G, Montagna, G, Azzedine, H, Valente, Em, Durr, A, Scarano, V, Bouslam, N, Cassandrini, D, Denora, P, Criscuolo, C, Belarbi, S, Orlacchio, A, Jonveaux, P, Silvestri, G, Hernandez, Am, DE MICHELE, G, Tazir, M, Mariotti, C, Brockmann, K, Malandrini, A, VAN DER KNAPP, M, Neri, M, Tonekaboni, H, Melone, Mariarosa Anna Beatrice, Tessa, A, Dotti, Mt, Tosetti, M, Pauri, F, Federico, A, Casali, C, Cruz, Vt, Loureiro, Jl, Zara, F, Forlani, S, Bertini, E, Coutinho, P, Filla, A, Brice, A, Santorelli, Fm, Pediatric surgery, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Napoli Federico II, Universita degli studi di Genova, Georg-August-University [Göttingen], Università degli Studi di Ferrara (UniFE), University of Naples Federico II, and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]

Subjects
Male, Candidate gene, Genetic Linkage, Corpus Callosum, Consanguinity, Autosomal recessive hereditary spastic, Genetic heterogeneity, 0302 clinical medicine, MESH: Child, Spastic Paraplegia, Autosomal recessive hereditary spastic paraplegia, Linkage, SPG11, Thin corpus callosum, Adolescent, Child, Child, Preschool, Chromosomes, Human, Pair 15, Female, Humans, Infant, Lod Score, Pedigree, Phenotype, Spastic Paraplegia, Hereditary, Genes, Recessive, Genetic Heterogeneity, Genetics, Genetics (clinical), Cellular and Molecular Neuroscience, 0303 health sciences, MESH: Spastic Paraplegia, Hereditary, MESH: Genetic Heterogeneity, MESH: Infant, autosomal recessive hereditary spastic paraplegia, genetic heterogeneity, linkage, spg11, thin corpus callosum, Hereditary, Settore MED/26 - Neurologia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human, Hereditary spastic paraplegia, MESH: Pedigree, Locus (genetics), Biology, MESH: Phenotype, MESH: Corpus Callosum, Chromosomes, 03 medical and health sciences, Gene mapping, Genetic linkage, medicine, Recessive, Preschool, MESH: Genes, Recessive, 030304 developmental biology, MESH: Adolescent, MESH: Consanguinity, Autosome, MESH: Humans, Thin corpus callosum, SPG11, Linkage, Haplotype, MESH: Child, Preschool, Pair 15, medicine.disease, MESH: Male, Genes, MESH: Lod Score, MESH: Linkage (Genetics), MESH: Female, 030217 neurology & neurosurgery, MESH: Chromosomes, Human, Pair 15
Abstract

We studied 20 Mediterranean families (40 patients) with autosomal recessive hereditary spastic paraplegia and thin corpus callosum (ARHSP-TCC, MIM 604360) to characterize their clinical and genetic features. In six families (17 patients) of Algerian Italian, Moroccan, and Portuguese ancestry, we found data consistent with linkage to the SPG11 locus on chromosome 15q13-15, whereas, in four families (nine patients of Italian, French, and Portuguese ancestry) linkage to the SPG11 locus could firmly be excluded, reinforcing the notion that ARHSP-TCC is genetically heterogeneous. Patients from linked and unlinked families could not be distinguished on the basis of clinical features alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal chromosomal interval, but analysis of two genes (MAP1A and SEMA6D) in this region did not identify causative mutations. Our findings suggest that ARHSP-TCC is the most frequent form of ARHSP in Mediterranean countries and that it is particularly frequent in Italy.

Published
2006

7. Physical and transcript map of the autosomal dominant colobomatous microphthalmia locus on chromosome 15q12-q15 and refinement to a 4.4 Mb region

Author

Muriel Bozon, Jean-Christophe Zech, Jacqueline Godet, Laurent Duret, Patrick Edery, Laetitia Michon, Laurette Morlé, Henry Plauchu, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Bioinformatique, phylogénie et génomique évolutive (BPGE), Département PEGASE [LBBE] (PEGASE), 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), Laboratoire de métallurgie physique (LMP), Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, Service de Génétique, Hôtel Dieu, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Laviron, Nathalie, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Université de Poitiers-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Candidate gene, Transcription, Genetic, Genetic Linkage, Cell Cycle Proteins, Microphthalmia, Connexins, Trinucleotide Repeats, Microphthalmos, Colobomatous microphthalmia, Genetics (clinical), Genes, Dominant, Genetics, Expressed Sequence Tags, 0303 health sciences, 030305 genetics & heredity, Physical Chromosome Mapping, Phenotype, Pedigree, MESH: Repressor Proteins, Microsatellite, Intercellular Signaling Peptides and Proteins, Female, MESH: Kruppel-Like Transcription Factors, MESH: Computational Biology, MESH: Trinucleotide Repeats, MESH: Pedigree, MESH: Microphthalmos, Kruppel-Like Transcription Factors, Locus (genetics), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Physical Chromosome Mapping, MESH: Expressed Sequence Tags, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH: Polymorphism, Genetic, medicine, Humans, MESH: Intercellular Signaling Peptides and Proteins, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, 030304 developmental biology, Chromosomes, Human, Pair 15, Polymorphism, Genetic, MESH: Humans, MESH: Transcription, Genetic, Computational Biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, MESH: Connexins, Repressor Proteins, Genetic marker, MESH: Genes, Dominant, MESH: Linkage (Genetics), MESH: Female, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; Congenital microphthalmia is a developmental disorder characterized by shortened axial length of the eye. We have previously mapped the gene responsible for autosomal dominant colobomatous microphthalmia in a 5-generation family to chromosome 15q12-q15. Here, we set up a physical and transcript map of the 13.8 cM critical region, flanked by loci D15S1002 and D15S1040. Physical mapping and genetic linkage analysis using 20 novel polymorphic markers allowed the refinement of the disease locus to two intervals in close vicinity, namely a centromeric interval, bounded by microsatellite DNA markers m3-m17, and a telomeric interval, m76-m24, encompassing respectively 1.9 and 2.5 Mb. Moreover, we excluded three candidate genes, CKTSF1B1, KLF13 and CX36. Finally, although a phenomenon of anticipation was suggested by phenotypic and pedigree data, no abnormal expansion of three trinucleotide repeats mapping to the refine interval was found in affected individuals.

Published
2004

8. Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p

Author

Philippe Froguel, Kazuo Hara, Kazuki Yasuda, Shuichi Otabe, Cécile Lecoeur, Takashi Kadowaki, Kazuyuki Tobe, Céline Populaire, Philippe Boutin, Emmanuelle Durand, Terumasa Okada, Christian Dina, Yasumichi Mori, Vincent Vatin, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé - Centre National de la Recherche Scientifique (CNRS), Science et Ingénierie des Matériaux et Procédés (SIMaP), Université Joseph Fourier - Grenoble 1 (UJF) - Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP) - Institut National Polytechnique de Grenoble (INPG) - Centre National de la Recherche Scientifique (CNRS) - Université Grenoble Alpes (UGA), Physique, Aucune, Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Université de Bordeaux (UB) - Centre National de la Recherche Scientifique (CNRS), Développement artériel, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Mercator Océan, Société Civile CNRS Ifremer IRD Météo-France SHOM, Itoh laboratory, Division of Materials Physics, Osaka University [Osaka] - School of Engineering Science, Section of Genomic Medicine, Imperial College London, Genome Centre, Imperial College London - Hammersmith campus, Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université de Bordeaux (UB), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Osaka University [Osaka]-School of Engineering Science, Imperial College London-Hammersmith campus, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)

Subjects
MESH : Chromosomes, Human, Pair 20, MESH : Transcription Factors, Genetic Linkage, MESH: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Endocrinology, Diabetes and Metabolism, Chromosomes, Human, Pair 20, MESH : Japan, Type 2 diabetes, MESH: Genetic Markers, MESH : Chromosomes, Human, Pair 3, Genome, MESH : Chromosomes, Human, Pair 1, MESH : Chromosomes, Human, Pair 7, 0302 clinical medicine, Japan, MESH : Diabetes Mellitus, Type 2, MESH: Chromosomes, Human, Pair 20, MESH : Genetic Markers, Age of Onset, MESH: Japan, Genetics, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH: Nuclear Family, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, MESH: Genetic Predisposition to Disease, Chromosome Mapping, MESH: Transcription Factors, Middle Aged, MESH : Adult, MESH : Chromosomes, Human, Pair 15, 3. Good health, MESH : Age of Onset, DNA-Binding Proteins, Hepatocyte Nuclear Factor 4, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 3, MESH: Hepatocyte Nuclear Factor 4, MESH : DNA-Binding Proteins, MESH : Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Chromosomes, Human, Pair 7, MESH: Diabetes Mellitus, Type 2, Adult, Genetic Markers, MESH : Genome, Human, MESH: Chromosomes, Human, Pair 7, MESH: Chromosomes, Human, Pair 1, MESH: Age of Onset, Population, MESH: Chromosomes, Human, Pair 3, 030209 endocrinology & metabolism, Susceptibility gene, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phosphoproteins, Nuclear Family, 03 medical and health sciences, MESH : Hepatocyte Nuclear Factor 4, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, MESH : Middle Aged, education, Gene, MESH: Genome, Human, 030304 developmental biology, Linkage (software), Chromosomes, Human, Pair 15, MESH: Humans, Genome, Human, MESH : Humans, Chromosome, MESH: Adult, medicine.disease, Phosphoproteins, Sib pairs, Diabetes Mellitus, Type 2, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH : Genetic Predisposition to Disease, MESH : Nuclear Family, MESH : Phosphoproteins, MESH: Chromosome Mapping, MESH: Linkage (Genetics), MESH: DNA-Binding Proteins, MESH : Linkage (Genetics), MESH : Chromosome Mapping, Transcription Factors, MESH: Chromosomes, Human, Pair 15
Abstract

The genetic background that predisposes the Japanese population to type 2 diabetes is largely unknown. Therefore, we conducted a 10-cM genome-wide scan for type 2 diabetes traits in the 359 affected individuals from 159 families, yielding 224 affected sib-pairs of Japanese origin. Nonparametric multipoint linkage analyses performed in the whole population showed one suggestive linked region on 11p13-p12 (maximum logarithm of odds score [MLS] 3.08, near Pax6) and seven potentially linked regions (MLS >1.17) at 1p36-p32, 2q34, 3q26-q28, 6p23, 7p22-p21, 15q13-q21, and 20q12-q13 (near the gene for hepatocyte nuclear factor-4α [HNF-4α]). Subset analyses according to maximal BMI and early age at diagnosis added suggestive evidence of linkage with type 2 diabetes at 7p22-p21 (MLS 3.51), 15q13-q21 (MLS 3.91), and 20q12-q13 (MLS 2.32). These results support previous indication for linkage found on chromosome 3q, 15q, and 20q in other populations and identifies two new potential loci on 7p and 11p that may confer genetic risk for type 2 diabetes in the Japanese population.

Published
2002

9. An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript

Author

Carlos Cardoso, Claire Rougeulle, Michel Fontes, Laurence Colleaux, Marc Lalande, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U491 (U491), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Biology, MESH: Base Sequence, Polymerase Chain Reaction, MESH: Angelman Syndrome, law.invention, Ligases, Genomic Imprinting, 03 medical and health sciences, 0302 clinical medicine, law, Genetics, UBE3A, Humans, RNA, Antisense, Base sequence, RNA, Messenger, MESH: RNA, Antisense, Polymerase chain reaction, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, MESH: RNA, Messenger, Chromosomes, Human, Pair 15, 0303 health sciences, MESH: Humans, Base Sequence, RNA, MESH: Polymerase Chain Reaction, MESH: Ubiquitin-Protein Ligases, Antisense RNA, MESH: Genomic Imprinting, MESH: Ligases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Prader-Willi Syndrome, Female, Angelman Syndrome, Genomic imprinting, Prader-Willi Syndrome, MESH: Female, 030217 neurology & neurosurgery, MESH: Chromosomes, Human, Pair 15
Abstract

International audience

Published
1998

10. Interaction of SP100 with HP1 proteins: A link between the promyelocytic leukemia-associated nuclear bodies and the chromatin compartment

Author

Catherine Transy, Delphine Sitterlin, Jacob-S. Seeler, Agnès Marchio, Anne Dejean, Cheriet Rauline, Samia, Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by fellowships from La Fondation pour la Recherche Médicale (to J-S.S.), le Ministère de la Recherche et de la Technologie (to D.S.), and by grants from the European Community and La Ligue Nationale Contre le Cancer., and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Chromosomal Proteins, Non-Histone, [SDV]Life Sciences [q-bio], Plasma protein binding, MESH: Amino Acid Sequence, Autoantigens, Leukemia, Promyelocytic, Acute, MESH: HMGB1 Protein, Nuclear protein, HMGB1 Protein, 0303 health sciences, Multidisciplinary, biology, 030302 biochemistry & molecular biology, High Mobility Group Proteins, Nuclear Proteins, Antigens, Nuclear, Biological Sciences, Chromatin, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, MESH: Autoantigens, MESH: Repressor Proteins, embryonic structures, MESH: Biomarkers, Tumor, Protein Binding, Acute promyelocytic leukemia, MESH: Cell Nucleus, endocrine system, Protein family, Molecular Sequence Data, MESH: Carrier Proteins, Transfection, MESH: Chromatin, 03 medical and health sciences, Promyelocytic leukemia protein, MESH: Chromosomal Proteins, Non-Histone, medicine, Biomarkers, Tumor, Humans, MESH: Protein Binding, Amino Acid Sequence, MESH: Antigens, Nuclear, 030304 developmental biology, Cell Nucleus, Chromosomes, Human, Pair 15, MESH: Humans, MESH: Molecular Sequence Data, MESH: Transfection, medicine.disease, MESH: High Mobility Group Proteins, Molecular biology, Repressor Proteins, Cell nucleus, Chromobox Protein Homolog 5, MESH: HeLa Cells, biology.protein, Heterochromatin protein 1, Carrier Proteins, MESH: Chromosomes, Human, Pair 17, MESH: Nuclear Proteins, MESH: Leukemia, Promyelocytic, Acute, Chromosomes, Human, Pair 17, HeLa Cells, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; The PML/SP100 nuclear bodies (NBs) were first described as discrete subnuclear structures containing the SP100 protein. Subsequently, they were shown to contain the PML protein which is part of the oncogenic PML-RARalpha hybrid produced by the t(15;17) chromosomal translocation characteristic of acute promyelocytic leukemia. Yet, the physiological role of these nuclear bodies remains unknown. Here, we show that SP100 binds to members of the heterochromatin protein 1 (HP1) families of non-histone chromosomal proteins. Further, we demonstrate that a naturally occurring splice variant of SP100, here called SP100-HMG, is a member of the high mobility group-1 (HMG-1) protein family and may thus possess DNA-binding potential. Both HP1 and SP100-HMG concentrate in the PML/SP100 NBs, and overexpression of SP100 leads to enhanced accumulation of endogenous HP1 in these structures. When bound to a promoter, SP100, SP100-HMG and HP1 behave as transcriptional repressors in transfected mammalian cells. These observations present molecular evidence for an association between the PML/SP100 NBs and the chromatin nuclear compartment. They support a model in which the NBs may play a role in certain aspects of chromatin dynamics.

Published
1998

11. [Contribution of genetics to pathogenicity and diagnosis of Marfan syndrome]

Author

catherine boileau, Collod G, Bonnet D, Génétique, chromosome et cancer, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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], 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), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), 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, Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Necker - Enfants Malades [AP-HP], and COLLOD-BEROUD, Gwenaëlle

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Epidermal Growth Factor, MESH: Abnormalities, Multiple, MESH: Mutation, Fibrillin-2, MESH: Pedigree, Fibrillin-1, Molecular Sequence Data, [SDV.GEN] Life Sciences [q-bio]/Genetics, macromolecular substances, MESH: Amino Acid Sequence, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Fibrillins, Marfan Syndrome, MESH: Marfan Syndrome, MESH: Microfilament Proteins, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Child, Humans, Abnormalities, Multiple, Amino Acid Sequence, cardiovascular diseases, Child, Chromosomes, Human, Pair 15, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Molecular Sequence Data, MESH: Humans, Epidermal Growth Factor, integumentary system, Microfilament Proteins, MESH: Child, Preschool, MESH: Infant, Newborn, Infant, Newborn, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Infant, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Pedigree, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Mutation, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; The anatomical substrate of Marfan's syndrome is a degeneration of elastic fibres and disorganization of the collagen. It is now known that these lesions are due to mutation of genes localised on chromosome 15. The first of them (FBN1) codes for the main constitutive protein of the elastic tissue: fibrillin 1, present mainly in structures which must resist load and stress (aortic adventitia, the suspending ligament of the lens, skin); the second (FBN2) codes for fibrillin 2: responsible for the orientation of the elastin and mainly present in cartilage, the aortic media, the bronchi, and all tissues rich in elastin. Mutations of FBN1 are very common and are associated not only with Marfan's syndrome but also fibrillinopathies: incomplete forms, neonatal forms, ectopic lens, isolated aneurysms of the thoracic aorta. The widespread distribution of fibrillin explains the pleiotropic nature of Marfan's syndrome and its clinical presentation. The variability of interfamilial expression is due to genetic heterogeneity (at least two genes) and alletic differences (different mutations of FBN1 from one family to another), also explaining mild forms due to quantitative reduction in normal fibrillin and severe forms by "negative dominance" where the fibrillin is structurally abnormal because of alteration of the polymerisation mechanism. The biologic diagnosis of fibrillopathy can be made by a protein test analysing fibrillin on a culture of the patient's fibroblast obtained by skin biopsy. At present, molecular diagnosis of the mutation within the FBN1 gene is not feasible as a routine procedure.

Published
1997

12. Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways

Author

Abderrahim Mahfoudi, Sophie Rambaud, Walter Wahli, Anne Dejean, Joop H. Jansen, Catherine Lavau, Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Animale, Université de Lausanne = University of Lausanne (UNIL), This work was supported by the European Economic Community (Biomedical and Biotechnology Programs), the Association pour la Recherche contre le Cancer, the Etat de Vaud, and the Swiss National Science Foundation. J.H.J. was supported by the Human Frontier Science Program Organization., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne (UNIL), and Cheriet Rauline, Samia

Subjects
MESH: Neoplasm Proteins, MESH: Signal Transduction, Oncogene Proteins, Fusion, Protein Conformation, Receptors, Retinoic Acid, MESH: Drosophila, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Translocation, Genetic, Mice, Estrogen-related receptor alpha, 0302 clinical medicine, MESH: Protein Conformation, Leukemia, Promyelocytic, Acute, MESH: Animals, G alpha subunit, 0303 health sciences, Multidisciplinary, MESH: DNA, Liver X receptor alpha, MESH: Transcription Factors, MESH: Translocation, Genetic, Neoplasm Proteins, Cell biology, [SDV] Life Sciences [q-bio], Biochemistry, 030220 oncology & carcinogenesis, embryonic structures, MESH: Retinoid X Receptors, Drosophila, Retinoid X receptor beta, Signal Transduction, Research Article, Transcriptional Activation, Retinoid X receptor, Biology, MESH: Receptors, Cytoplasmic and Nuclear, 03 medical and health sciences, Animals, Humans, neoplasms, MESH: Mice, 030304 developmental biology, MESH: Receptors, Retinoic Acid, Chromosomes, Human, Pair 15, Binding Sites, MESH: Humans, Retinoid X receptor alpha, organic chemicals, DNA, Retinoid X receptor gamma, biological factors, body regions, Retinoid X Receptors, MESH: Binding Sites, Retinoic acid receptor alpha, MESH: HeLa Cells, MESH: Transcriptional Activation, MESH: Chromosomes, Human, Pair 17, MESH: Leukemia, Promyelocytic, Acute, Chromosomes, Human, Pair 17, HeLa Cells, Transcription Factors, MESH: Chromosomes, Human, Pair 15, MESH: Oncogene Proteins, Fusion
Abstract

International audience; The t(15;17) chromosomal translocation, specific for acute promyelocytic leukemia (APL), fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene, resulting in expression of a PML-RAR alpha hybrid protein. In this report, we analyzed the nature of PML-RAR alpha-containing complexes in nuclear protein extracts of t(15;17)-positive cells. We show that endogenous PML-RAR alpha can bind to DNA as a homodimer, in contrast to RAR alpha that requires the retinoid X receptor (RXR) dimerization partner. In addition, these cells contain oligomeric complexes of PML-RAR alpha and endogenous RXR. Treatment with retinoic acid results in a decrease of PML-RAR alpha protein levels and, as a consequence, of DNA binding by the different complexes. Using responsive elements from various hormone signaling pathways, we show that PML-RAR alpha homodimers have altered DNA-binding characteristics when compared to RAR alpha-RXR alpha heterodimers. In transfected Drosophila SL-3 cells that are devoid of endogenous retinoid receptors PML-RAR alpha inhibits transactivation by RAR alpha-RXR alpha heterodimers in a dominant fashion. In addition, we show that both normal retinoid receptors and the PML-RAR alpha hybrid bind and activate the peroxisome proliferator-activated receptor responsive element from the Acyl-CoA oxidase gene, indicating that retinoids and peroxisome proliferator receptors may share common target genes. These properties of PML-RAR alpha may contribute to the transformed phenotype of APL cells.

Published
1995

13. Retinoic acid regulates aberrant nuclear localization of PML-RARα in acute promyelocytic leukemia cells

Author

Sophie Rambaud, Anne Dejean, Angus I. Lamond, Maria Carmo-Fonseca, Catherine Lavau, Teresa Carvalho, Karsten Weis, Joop H. Jansen, European Molecular Biology Laboratory [Heidelberg] (EMBL), Recombinaison et Expression Génétique, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), This work was supported by grants from the European Economic Community, the Association pour la Recherche contre le Cancer, la Fondation pour la Recherche Médicale, the Junta National de InvestigaGao Cientifica. K. W. was supported by the Boehringer lngelheim Fonda., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universidade de Lisboa (ULISBOA)

Subjects
MESH: Neoplasm Proteins, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Retinoic acid, Fluorescent Antibody Technique, Receptors, Cytoplasmic and Nuclear, Nuclear dots, Promyelocytic Leukemia Protein, Translocation, Genetic, chemistry.chemical_compound, MESH: Cell Compartmentation, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, MESH: Promyelocytic Leukemia Protein, MESH: Autoantibodies, MESH: Fluorescent Antibody Technique, Protein PML, 0303 health sciences, biology, Nuclear Proteins, MESH: Transcription Factors, MESH: Translocation, Genetic, Neoplasm Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Retinoid X Receptors, Acute promyelocytic leukemia, MESH: Cell Nucleus, Tretinoin, MESH: Microscopy, Electron, Retinoid X receptor, MESH: Receptors, Cytoplasmic and Nuclear, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Promyelocytic leukemia protein, medicine, Humans, MESH: Tumor Suppressor Proteins, neoplasms, Autoantibodies, 030304 developmental biology, Cell Nucleus, MESH: Receptors, Retinoic Acid, Chromosomes, Human, Pair 15, MESH: Tretinoin, MESH: Humans, Tumor Suppressor Proteins, medicine.disease, Cell Compartmentation, MESH: Cell Line, Microscopy, Electron, Cell nucleus, Retinoic acid receptor, Retinoid X Receptors, chemistry, Cancer research, biology.protein, MESH: Chromosomes, Human, Pair 17, MESH: Nuclear Proteins, MESH: Leukemia, Promyelocytic, Acute, Chromosomes, Human, Pair 17, Transcription Factors, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) translocation that fuses the retinoic acid receptor alpha (RAR alpha) to a novel gene product, PML. The involvement of RAR alpha is particularly intriguing in view of the efficient therapeutic effect of retinoic acid (RA) in this disease. In this report, we show that PML is specifically localized within a discrete subnuclear compartment corresponding to nuclear bodies recognized by patient autoimmune sera. In APL cells, the PML-RAR alpha hybrid displays an abnormal localization and directs RXR and other nuclear antigens into aberrant structures that are tightly bound to chromatin. This suggests that the hybrid could exert a dominant negative effect by diverting a subset of proteins from their natural sites of action. Interestingly, treatment of APL cells with RA induces a complete relocalization of each of these proteins. We propose that the beneficial role of RA in promoting myeloid differentiation in APL might be related to its ability to restore a normal subnuclear organization.

Published
1994

14. A PML/retinoic acid receptor alpha fusion transcript is constantly detected by RNA-based polymerase chain reaction in acute promyelocytic leukemia

Author

Castaigne S, Balitrand N, de Thé H, Dejean A, Degos L, Christine CHOMIENNE, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Recombinaison et Expression Génétique, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Supported by grants from lilssociation de la Recherche contre le Cancer, La Ligue Nationale contre le Cancer, and a Contrat de Recherche Clinique, Cheriet Rauline, Samia, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]

Subjects
Transcription, Genetic, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Retinoic acid, MESH: Base Sequence, Biochemistry, Polymerase Chain Reaction, Translocation, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, RNA, Neoplasm, 0303 health sciences, MESH: DNA, RNA-Directed DNA Polymerase, Hematology, MESH: Translocation, Genetic, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Acute promyelocytic leukemia, Immunology, Molecular Sequence Data, Alpha (ethology), MESH: Carrier Proteins, T-15, Biology, 03 medical and health sciences, MESH: RNA-Directed DNA Polymerase, Complementary DNA, medicine, MESH: Blotting, Northern, Humans, 030304 developmental biology, MESH: Receptors, Retinoic Acid, Chromosomes, Human, Pair 15, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Transcription, Genetic, MESH: Polymerase Chain Reaction, Cell Biology, DNA, MESH: RNA, Neoplasm, medicine.disease, Blotting, Northern, Minimal residual disease, Molecular biology, Fusion transcript, chemistry, Retinoic acid receptor alpha, Carrier Proteins, MESH: Chromosomes, Human, Pair 17, MESH: Leukemia, Promyelocytic, Acute, MESH: Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 17
Abstract

The t(15;17) translocation is specifically observed in patients with promyelocytic leukemia (AML3). The chromosomal rearrangement juxtaposes the retinoic acid receptor alpha (RAR alpha) and PML genes, resulting in PML/RAR alpha fusion transcripts. Our previous studies have shown that a polymerase chain reaction (PCR) amplification product could be obtained from the cDNA of the NB4 promyelocytic cell line from which the chimaeric PML/RAR alpha was cloned. We report here that in all 14 AML3 patients tested, reverse transcriptase-PCR (RT-PCR) allows the detection of three specific fusion products. In eight patients, one amplification product was detected corresponding to the previously described abnormal fusion. Five patients displayed a different amplified fragment corresponding to a different fusion point. One other patient always showed a third different-sized product. The different types of fusion transcripts amplified were correlated to the size of the abnormal RAR alpha transcripts detected in these patients by Northern analysis, but did not prove determinant for either the phenotypic features or the retinoic acid responsiveness in AML3 cells in this group of patients. The consistent identification by RT-PCR of the fusion of the PML and RAR alpha genes in AML3 patients suggest that this method will provide a useful tool for the diagnosis and detection of minimal residual disease in these patients.

Published
1992

15. The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR

Author

Hugues de Thé, Catherine Lavau, Agnès Marchio, Christine Chomienne, Laurent Degos, Anne Dejean, Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants of the Fondation pour la Recherche MBdicale, the Ligue Nationale Francaise contre le Cancer, and the Association pour la Recherche contre la Cancer., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Cheriet Rauline, Samia

Subjects
MESH: Neoplasm Proteins, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Oligonucleotides, Chromosome Disorders, MESH: Amino Acid Sequence, Promyelocytic Leukemia Protein, MESH: Base Sequence, Polymerase Chain Reaction, Translocation, Genetic, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, MESH: Oligonucleotides, MESH: Promyelocytic Leukemia Protein, Cloning, Molecular, Zinc finger, Protein PML, 0303 health sciences, MESH: Chromosome Disorders, MESH: DNA, Nuclear Proteins, MESH: Transcription Factors, MESH: Translocation, Genetic, Neoplasm Proteins, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, embryonic structures, medicine.drug, Transcriptional Activation, Acute promyelocytic leukemia, Molecular Sequence Data, Tretinoin, MESH: Binding, Competitive, MESH: Carrier Proteins, Biology, Binding, Competitive, General Biochemistry, Genetics and Molecular Biology, Gene product, 03 medical and health sciences, Promyelocytic leukemia protein, medicine, Humans, MESH: Chromosome Aberrations, MESH: Tumor Suppressor Proteins, MESH: Cloning, Molecular, Amino Acid Sequence, RNA, Messenger, neoplasms, 030304 developmental biology, MESH: RNA, Messenger, Chromosome Aberrations, MESH: Receptors, Retinoic Acid, Chromosomes, Human, Pair 15, MESH: Tretinoin, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Tumor Suppressor Proteins, MESH: Polymerase Chain Reaction, DNA, medicine.disease, Molecular biology, Fusion protein, Retinoic acid receptor alpha, biology.protein, MESH: Transcriptional Activation, Carrier Proteins, MESH: Chromosomes, Human, Pair 17, MESH: Nuclear Proteins, MESH: Leukemia, Promyelocytic, Acute, Chromosomes, Human, Pair 17, Transcription Factors, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; We have previously shown that the t(15;17) translocation specifically associated with acute promyelocytic leukemia (APL) fuses the retinoic acid receptor alpha (RAR alpha) locus to an as yet unknown gene, initially called myl and now renamed PML. We report here that this gene product contains a novel zinc finger motif common to several DNA-binding proteins. The PML-RAR alpha mRNA encodes a predicted 106 kd chimeric protein containing most of the PML sequences fused to a large part of RAR alpha, including its DNA- and hormone-binding domains. In transient expression assays, the hybrid protein exhibits altered transactivating properties if compared with the wild-type RAR alpha progenitor. Identical PML-RAR alpha fusion points are found in several patients. These observations suggest that in APL, the t(15;17) translocation generates an RAR mutant that could contribute to leukemogenesis through interference with promyelocytic differentiation.

Published
1991

16. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor α gene to a novel transcribed locus

Author

Hugues de Thé, Christine Chomienne, Michel Lanotte, Laurent Degos, Anne Dejean, Recombinaison et expression génétique, Institut Pasteur [Paris] (IP)-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), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique cellulaire et moléculaire des leucémies, This work was supported by grants from the Fondation pour Ia Recherche Médicale. the Commission of the European Communities, the Ligue Nationale Française contre le Cancer, and the Association pour Ia Recherche contre le Cancer., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Cheriet Rauline, Samia

Subjects
Transcription, Genetic, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Restriction Mapping, Retinoic acid, Chromosomal translocation, MESH: Base Sequence, Polymerase Chain Reaction, Translocation, Genetic, MESH: Nucleic Acid Hybridization, chemistry.chemical_compound, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, Gene expression, MESH: Restriction Mapping, Gene Rearrangement, 0303 health sciences, Multidisciplinary, biology, Nucleic Acid Hybridization, Exons, MESH: Translocation, Genetic, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, MESH: DNA Probes, DNA Probes, MESH: Gene Rearrangement, Molecular Sequence Data, Locus (genetics), MESH: Carrier Proteins, 03 medical and health sciences, Promyelocytic leukemia protein, medicine, Humans, RNA, Messenger, neoplasms, 030304 developmental biology, MESH: RNA, Messenger, MESH: Receptors, Retinoic Acid, Chromosomes, Human, Pair 15, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Transcription, Genetic, MESH: Polymerase Chain Reaction, Gene rearrangement, medicine.disease, Molecular biology, Retinoic acid syndrome, Retinoic acid receptor, chemistry, biology.protein, Carrier Proteins, MESH: Exons, MESH: Chromosomes, Human, Pair 17, MESH: Leukemia, Promyelocytic, Acute, Chromosomes, Human, Pair 17, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; Retinoic acid is a vitamin A derivative with striking effects on development and cell differentiation. Several nuclear retinoic acid receptors (RARs), acting as ligand-inducible transcription factors, have been characterized and indirect evidence suggests that they have distinct roles. One of the most intriguing properties of retinoic acid is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. Because the RAR alpha gene maps to chromosome 17q21 (ref. 14), close to the t(15;17) (q21-q11-22) translocation specifically associated with APL, we analysed RAR alpha gene structure and expression in APL cells. We report here that, in one APL-derived cell line, the RAR alpha gene has been translocated to a locus, myl, on chromosome 15, resulting in the synthesis of a myl/RAR alpha fusion messenger RNA. Using two probes located on either side of the cloned breakpoint, we have found genomic rearrangements of one or other locus in six patients out of eight, demonstrating that the RAR alpha and/or myl genes are frequently rearranged in APL and the breakpoints are clustered. These findings strongly implicate retinoic acid receptor alpha in leukaemogenesis.

Published
1990

17. Genome-wide Linkage Analyses of Quantitative and Categorical Autism Subphenotypes

Author

Andrew Paterson, Guiomar Oliveira, Ellen Wijsman, Guiomar Gonçalves Oliveira, Astrid Vicente, Catalina Betancur, Joseph Buxbaum, Sean Ennis, Anthony Monaco, Stephen W. Scherer, Andrew Green, Marion LEBOYER, Xiao-Qing Liu, Vanessa Bal, Annette Estes, Andrew Pickles, The Hospital for sick children [Toronto] (SickKids), University of Toronto, McMaster University [Hamilton, Ontario], Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), The Autism Genome Project Consortium, Liu XQ, Paterson AD, Szatmari P, Autism Genome Project Consortium [.., Maestrini E, ], Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Betancur, Catalina

Subjects
Male, Genetic Linkage, Autism, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Genetic Markers, genetic heterogeneity, Genetic heterogeneity, 0302 clinical medicine, MESH: Child, Child, Language, Genetics, 0303 health sciences, Intelligence quotient, MESH: Interpersonal Relations, Archival Report, Phenotype, Female, Psychology, Linkage analysis, Genetic Markers, MESH: Autistic Disorder, MESH: Genetic Linkage, Locus (genetics), Quantitative trait locus, MESH: Phenotype, behavioral disciplines and activities, 03 medical and health sciences, Genetic linkage, mental disorders, medicine, Humans, Interpersonal Relations, linkage analysis, Autistic Disorder, Biological Psychiatry, 030304 developmental biology, Chromosomes, Human, Pair 15, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Verbal Behavior, language, Verbal Behavior, Chromosomes, Human, Pair 11, medicine.disease, MESH: Male, Developmental disorder, schizophrenia, IQ, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: Genome-Wide Association Study, Schizophrenia, MESH: Chromosomes, Human, Pair 11, MESH: Female, 030217 neurology & neurosurgery, Genome-Wide Association Study, MESH: Chromosomes, Human, Pair 15
Abstract

International audience; Background: The search for susceptibility genes in autism and autism spectrum disorders (ASD) has been hindered by the possible small effects of individual genes and by genetic (locus) heterogeneity. To overcome these obstacles, one method is to use autism-related subphenotypes instead of the categorical diagnosis of autism since they may be more directly related to the underlying susceptibility loci. Another strategy is to analyze subsets of families that meet certain clinical criteria to reduce genetic heterogeneity.Methods: In this study, using 976 multiplex families from the Autism Genome Project consortium, we performed genome-wide linkage analyses on two quantitative subphenotypes, the total scores of the reciprocal social interaction domain and the restricted, repetitive, and stereotyped patterns of behavior domain from the Autism Diagnostic Interview-Revised. We also selected subsets of ASD families based on four binary subphenotypes, delayed onset of first words, delayed onset of first phrases, verbal status, and IQ > or = 70.Results: When the ASD families with IQ > or = 70 were used, a logarithm of odds (LOD) score of 4.01 was obtained on chromosome 15q13.3-q14, which was previously linked to schizophrenia. We also obtained a LOD score of 3.40 on chromosome 11p15.4-p15.3 using the ASD families with delayed onset of first phrases. No significant evidence for linkage was obtained for the two quantitative traits.Conclusions: This study demonstrates that selection of informative subphenotypes to define a homogeneous set of ASD families could be very important in detecting the susceptibility loci in autism.

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