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152. Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis

Author

Mary, Laura, primary, Piton, Amélie, additional, Schaefer, Elise, additional, Mattioli, Francesca, additional, Nourisson, Elsa, additional, Feger, Claire, additional, Redin, Claire, additional, Barth, Magali, additional, El Chehadeh, Salima, additional, Colin, Estelle, additional, Coubes, Christine, additional, Faivre, Laurence, additional, Flori, Elisabeth, additional, Geneviève, David, additional, Capri, Yline, additional, Perrin, Laurence, additional, Fabre-Teste, Jennifer, additional, Timbolschi, Dana, additional, Verloes, Alain, additional, Olaso, Robert, additional, Boland, Anne, additional, Deleuze, Jean-François, additional, Mandel, Jean-Louis, additional, Gerard, Bénédicte, additional, and Giurgea, Irina, additional

Published
2018
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153. Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems

Author

V. Lombardo, Michael, primary, Auyeung, Bonnie, additional, Pramparo, Tiziano, additional, Quartier, Angélique, additional, Courraud, Jérémie, additional, J. Holt, Rosemary, additional, Waldman, Jack, additional, N. V. Ruigrok, Amber, additional, Mooney, Natasha, additional, Lai, Meng-Chuan, additional, Kundu, Prantik, additional, T. Bullmore, Edward, additional, Mandel, Jean-Louis, additional, Piton, Amélie, additional, and Baron-Cohen, Simon, additional

Published
2018
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154. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Author

Marsh, Ashley P.L., Heron, Delphine, Edwards, Timothy J., Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone A., Mcgillivray, George, Mcilroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura R., Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail A., Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah E.M., Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-bitach, Tania, Delatycki, Martin B., Mandel, Jean-louis, Amor, David J., Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Sherr, Elliott H., Leventer, Richard J., Richards, Linda J., Lockhart, Paul J., Depienne, Christel, Marsh, Ashley P.L., Heron, Delphine, Edwards, Timothy J., Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone A., Mcgillivray, George, Mcilroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura R., Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail A., Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah E.M., Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-bitach, Tania, Delatycki, Martin B., Mandel, Jean-louis, Amor, David J., Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Sherr, Elliott H., Leventer, Richard J., Richards, Linda J., Lockhart, Paul J., and Depienne, Christel

Abstract

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Published
2017

155. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance.

Author

Marsh, Ashley, Marsh, Ashley, Heron, Delphine, Edwards, Timothy, Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-Laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone, McGillivray, George, McIlroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura, Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail, Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah, Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-Bitach, Tania, Delatycki, Martin, Mandel, Jean-Louis, Amor, David, Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Leventer, Richard, Richards, Linda, Lockhart, Paul, Depienne, Christel, Sherr, Elliott, Marsh, Ashley, Marsh, Ashley, Heron, Delphine, Edwards, Timothy, Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-Laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone, McGillivray, George, McIlroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura, Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail, Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah, Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-Bitach, Tania, Delatycki, Martin, Mandel, Jean-Louis, Amor, David, Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Leventer, Richard, Richards, Linda, Lockhart, Paul, Depienne, Christel, and Sherr, Elliott

Abstract

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Published
2017

156. Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage

Author

Ferrer, Isidre, Kapfhammer, Josef P., Hindelang, Colette, Kemp, Stephan, Troffer-Charlier, Nathalie, Broccoli, Vania, Callyzot, Noëlle, Mooyer, Petra, Selhorst, Jacqueline, Vreken, Peter, Wanders, Ronald J.A., Mandel, Jean Louis, Pujol, Aurora, Ferrer, Isidre, Kapfhammer, Josef P., Hindelang, Colette, Kemp, Stephan, Troffer-Charlier, Nathalie, Broccoli, Vania, Callyzot, Noëlle, Mooyer, Petra, Selhorst, Jacqueline, Vreken, Peter, Wanders, Ronald J.A., Mandel, Jean Louis, and Pujol, Aurora

Abstract

ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy (X-ALD), a disease characterized by an accumulation of very-long-chain fatty acids (VLCFAs). Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD [Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum. Mol. Genet., 11, 499-505.]. In the present work, we have generated and characterized a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological feature in abcd2−/− mice is a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root ganglia cell degeneration, correlating with accumulation of VLCFAs in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the origin of the pathological cascade

Published
2017

157. Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis

Author

Vincent, Anne, Heitz, Dominique, Petei, Christine, Kretz, Christine, Oberle, Isabelle, and Mandel, Jean-Louis

Subjects
Fragile X syndrome -- Genetic aspects, Human chromosome abnormalities -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The fragile-X syndrome is an inherited form of mental retardation. With an incidence of 1 in 1,500 males, it occurs more frequently than any other form of inherited mental retardation. The location of the gene(s) involved in the disease is next to a fragile site (where the chromosome is easily broken by experimental procedures) on the X chromosome, known as q27.3. Fragile-X syndrome has an unusual pattern of inheritance for a trait linked to the X-chromosome. It can be passed by normal men to their daughters who become asymptomatic carriers of the disease and whose children, of either sex, can exhibit the genetic defect. Theories have been proposed to account for the abnormal inheritance of the mutation, including genetic rearrangements and reactivation of an inactive X chromosome. Using a process known as pulse-field gel electrophoresis, which allows analysis of large pieces of DNA, abnormalities have been seen in the gene sequence near the fragile-X locus in patients with fragile-X syndrome, and not in normal controls, nor in males who were carriers but did not show symptoms of the disease. These abnormalities showed an increase in methylation of that portion of the chromosome that was not due to rearrangement of a large portion of the chromosome, indicating inactivity in that part of the chromosome. The presence of these genetic alterations can perhaps be used in the genetic analysis to diagnose fragile-X syndrome. (Consumer Summary produced by Reliance Medical Information, Inc.)

Published
1991

159. Fragile X syndrome

Author

Hagerman, Randi J., primary, Berry-Kravis, Elizabeth, additional, Hazlett, Heather Cody, additional, Bailey, Donald B., additional, Moine, Herve, additional, Kooy, R. Frank, additional, Tassone, Flora, additional, Gantois, Ilse, additional, Sonenberg, Nahum, additional, Mandel, Jean Louis, additional, and Hagerman, Paul J., additional

Published
2017
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160. Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Author

Quartier, Angélique, primary, Poquet, Hélène, additional, Gilbert-Dussardier, Brigitte, additional, Rossi, Massimiliano, additional, Casteleyn, Anne-Sophie, additional, Portes, Vincent des, additional, Feger, Claire, additional, Nourisson, Elsa, additional, Kuentz, Paul, additional, Redin, Claire, additional, Thevenon, Julien, additional, Mosca-Boidron, Anne-Laure, additional, Callier, Patrick, additional, Muller, Jean, additional, Lesca, Gaetan, additional, Huet, Frédéric, additional, Geoffroy, Véronique, additional, El Chehadeh, Salima, additional, Jung, Matthieu, additional, Trojak, Benoit, additional, Le Gras, Stéphanie, additional, Lehalle, Daphné, additional, Jost, Bernard, additional, Maury, Stéphanie, additional, Masurel, Alice, additional, Edery, Patrick, additional, Thauvin-Robinet, Christel, additional, Gérard, Bénédicte, additional, Mandel, Jean-Louis, additional, Faivre, Laurence, additional, and Piton, Amélie, additional

Published
2017
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161. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Author

Mattioli, Francesca, primary, Schaefer, Elise, additional, Magee, Alex, additional, Mark, Paul, additional, Mancini, Grazia M., additional, Dieterich, Klaus, additional, Von Allmen, Gretchen, additional, Alders, Marielle, additional, Coutton, Charles, additional, van Slegtenhorst, Marjon, additional, Vieville, Gaëlle, additional, Engelen, Mark, additional, Cobben, Jan Maarten, additional, Juusola, Jane, additional, Pujol, Aurora, additional, Mandel, Jean-Louis, additional, and Piton, Amélie, additional

Published
2017
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162. Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

Author

Friez, Michael J, Willems, Marjolaine, Gunel, Murat, Thevenon, Julien, Aylsworth, Arthur S, Mandel, Jean-Louis, Gan, Grace, Gleeson, Joseph G, Stevenson, Roger E, Jones, Julie R, Isidor, Bertrand, Rivière, Jean-Baptiste, and Francannet, Christine

Abstract

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

Published
2015
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163. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus

Author

Stoetzel, Corinne, Laurier, Virginie, Davis, Erica E, Muller, Jean, Rix, Suzanne, Badano, José L, Leitch, Carmen C, Salem, Nabiha, Chouery, Eliane, Corbani, Sandra, Jalk, Nadine, Vicaire, Serge, Sarda, Pierre, Hamel, Christian, Lacombe, Didier, Holder, Muriel, Odent, Sylvie, Holder, Susan, Brooks, Alice S, Elcioglu, Nursel H, Da Silva, Eduardo, Rossillion, Béatrice, Sigaudy, Sabine, de Ravel, Thomy J L, Lewis, Richard Alan, Leheup, Bruno, Verloes, Alain, Amati-Bonneau, Patrizia, Mégarbané, André, Poch, Olivier, Bonneau, Dominique, Beales, Philip L, Mandel, Jean-Louis, Katsanis, Nicholas, Dollfus, Hélène, 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), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), Clinical Genetics, Clinical sciences, Medical Genetics, and Institute for European Studies

Subjects
BBS2, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, BBS1, BBS7, Locus (genetics), Biology, 03 medical and health sciences, 0302 clinical medicine, Bardet–Biedl syndrome, MESH: Bardet-Biedl Syndrome, Genetics, medicine, Humans, MESH: Proteins, Bardet-Biedl Syndrome, MESH: Cohort Studies, 030304 developmental biology, 0303 health sciences, MESH: Humans, Proteins, Oligogenic Inheritance, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Ciliopathy, Proteins/genetics, Cohort studies, BBS12, mutation, Bardet-Biedl Syndrome/genetics, 030217 neurology & neurosurgery
Abstract

International audience; Bardet-Biedl syndrome (BBS) is a genetically heterogeneous ciliopathy. Although nine BBS genes have been cloned, they explain only 40-50% of the total mutational load. Here we report a major new BBS locus, BBS10, that encodes a previously unknown, rapidly evolving vertebrate-specific chaperonin-like protein. We found BBS10 to be mutated in about 20% of an unselected cohort of families of various ethnic origins, including some families with mutations in other BBS genes, consistent with oligogenic inheritance. In zebrafish, mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants.

Published
2006
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165. A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P

Author

Schenck, Annette, Bardoni, Barbara, Moro, Annamaria, Bagni, Claudia, and Mandel, Jean-Louis

Subjects
Proteins -- Physiological aspects, Mental retardation -- Physiological aspects, Fragile X syndrome -- Physiological aspects, Science and technology
Abstract

The absence of the fragile X mental retardation protein (FMRP), encoded by the FMR1 gene, is responsible for pathologic manifestations in the Fragile X Syndrome, the most frequent cause of inherited mental retardation. FMRP is an RNA-binding protein associated with polysomes as part of a messenger ribonucleoprotein (mRNP) complex. Although its function is poorly understood, various observations suggest a role in local protein translation at neuronal dendrites and in dendritic spine maturation. We present here the identification of CYFIP1/2 (Cytoplasmic FMRP Interacting Proteins) as FMRP interactors. CYFIP1/2 share 88% amino acid sequence identity and represent the two members in humans of a highly conserved protein family. Remarkably, whereas CYFIP2 also interacts with the FMRP-related proteins FXR1P/2P, CYFIP1 interacts exclusively with FMRP. FMRP-CYFIP interaction involves the domain of FMRP also mediating homo- and heteromerization, thus suggesting a competition between interaction among the FXR proteins and interaction with CYFIP. CYFIP1/2 are proteins of unknown function, but CYFIP1 has recently been shown to interact with the small GTPase Rac1, which is implicated in development and maintenance of neuronal structures. Consistent with FMRP and Rac1 localization in dendritic fine structures, CYFIP1/2 are present in synaptosomal extracts.

Published
2001

166. Mutations in theERCC2(XPD) gene associated with severe fetal ichthyosis and dysmorphic features

Author

Miguet, Marguerite, primary, Thevenon, Julien, additional, Laugel, Vincent, additional, Lefebvre, Mathilde, additional, Bourchany, Aurélie, additional, Rivière, Jean-Baptiste, additional, Duffourd, Yannis, additional, Schaefer, Elise, additional, Antal, Maria Cristina, additional, Abida, Rosalie, additional, Weingertner, Anne-Sophie, additional, Kremer, Valérie, additional, Vabres, Pierre, additional, Morice-Picard, Fanny, additional, Gonzales, Marie, additional, Lipsker, Dan, additional, Fraitag, Sylvie, additional, Mandel, Jean-Louis, additional, Chelly, Jamel, additional, Dollfus, Hélène, additional, Faivre, Laurence, additional, Thauvin-Robinet, Christel, additional, Calmels, Nadège, additional, and El Chehadeh, Salima, additional

Published
2016
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168. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome

Author

Masurel‐Paulet, Alice, primary, Piton, Amélie, additional, Chancenotte, Sophie, additional, Redin, Claire, additional, Thauvin‐Robinet, Christel, additional, Henrenger, Yvan, additional, Minot, Delphine, additional, Creppy, Audrey, additional, Ruffier‐Bourdet, Marie, additional, Thevenon, Julien, additional, Kuentz, Paul, additional, Lehalle, Daphné, additional, Curie, Aurore, additional, Blanchard, Gaelle, additional, Ghosn, Ezzat, additional, Bonnet, Marlene, additional, Archimbaud‐Devilliers, Mélanie, additional, Huet, Frédéric, additional, Perret, Odile, additional, Philip, Nicole, additional, Mandel, Jean‐Louis, additional, and Faivre, Laurence, additional

Published
2016
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170. Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing

Author

Calmels, Nadège, primary, Greff, Géraldine, additional, Obringer, Cathy, additional, Kempf, Nadine, additional, Gasnier, Claire, additional, Tarabeux, Julien, additional, Miguet, Marguerite, additional, Baujat, Geneviève, additional, Bessis, Didier, additional, Bretones, Patricia, additional, Cavau, Anne, additional, Digeon, Béatrice, additional, Doco-Fenzy, Martine, additional, Doray, Bérénice, additional, Feillet, François, additional, Gardeazabal, Jesus, additional, Gener, Blanca, additional, Julia, Sophie, additional, Llano-Rivas, Isabel, additional, Mazur, Artur, additional, Michot, Caroline, additional, Renaldo-Robin, Florence, additional, Rossi, Massimiliano, additional, Sabouraud, Pascal, additional, Keren, Boris, additional, Depienne, Christel, additional, Muller, Jean, additional, Mandel, Jean-Louis, additional, and Laugel, Vincent, additional

Published
2016
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172. Cerberus, an Access Control Scheme for Enforcing Least Privilege in Patient Cohort Study Platforms.

Author

Parrend, Pierre, Mazzucotelli, Timothée, Colin, Florent, Collet, Pierre, and Mandel, Jean-Louis

Subjects
GENETICS of autism, COMPUTER software, LONGITUDINAL method, MEDICAL research, PEOPLE with intellectual disabilities, ACCESS to information
Abstract

Cohort Study Platforms (CSP) are emerging as a key tool for collecting patient information, providing new research data, and supporting family and patient associations. However they pose new ethics and regulatory challenges since they cross the gap between patients and medical practitioners. One of the critical issues for CSP is to enforce a strict control on access privileges whilst allowing the users to take advantage of the breadth of the available data. We propose Cerberus, a new access control scheme spanning the whole life-cycle of access right management: design, implementation, deployment and maintenance, operations. Cerberus enables switching from a dual world, where CSP data can be accessed either from the users who entered it or fully de-identified, to an access-when-required world, where patients, practitioners and researchers can access focused medical data through explicit authorisation by the data owner. Efficient access control requires application-specific access rights, as well as the ability to restrict these rights when they are not used. Cerberus is implemented and evaluated in the context of the GENIDA project, an international CSP for Genetically determined Intellectual Disabilities and Autism Spectrum Disorders. As a result of this study, the software is made available for the community, and validated specifications for CSPs are given. [ABSTRACT FROM AUTHOR]

Published
2018
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173. MG-112 Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

Author

Bronicki, Lucas, primary, Redin, Claire, additional, Drunat, Severine, additional, Piton, Amélie, additional, Lyons, Michael, additional, Passemard, Sandrine, additional, Baumann, Clarisse, additional, Faivre, Laurence, additional, Thevenon, Julien, additional, Rivière, Jean-Baptiste, additional, Isidor, Bertrand, additional, Gan, Grace, additional, Francannet, Christine, additional, Gunel, Murat, additional, Jones, Julie, additional, Gleeson, Joseph, additional, Willems, Marjolaine, additional, Mandel, Jean-Louis, additional, Stevenson, Roger E, additional, Friez, Michael, additional, and Aylsworth, Arthur S, additional

Published
2015
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176. Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

Author

Bronicki, Lucas M, primary, Redin, Claire, additional, Drunat, Severine, additional, Piton, Amélie, additional, Lyons, Michael, additional, Passemard, Sandrine, additional, Baumann, Clarisse, additional, Faivre, Laurence, additional, Thevenon, Julien, additional, Rivière, Jean-Baptiste, additional, Isidor, Bertrand, additional, Gan, Grace, additional, Francannet, Christine, additional, Willems, Marjolaine, additional, Gunel, Murat, additional, Jones, Julie R, additional, Gleeson, Joseph G, additional, Mandel, Jean-Louis, additional, Stevenson, Roger E, additional, Friez, Michael J, additional, and Aylsworth, Arthur S, additional

Published
2015
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177. Cells lacking the fragile X mental retardation protein (FMRP) have normal RISC activity but exhibit altered stress granule assembly

Author

Didiot, Marie-Cécile, Subramanian, Murugan, Flatter, Eric, Mandel, Jean-Louis, Moine, Hervé, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), and This project benefited from grants from National Institutes of Health (R01 HD40612-01), from Agence Nationale de la Recheche, and from the Fondation pour la Recherche Médicale and the Fondation Jerôme Lejeune to H.M.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, MESH: Humans, MESH: Eukaryotic Initiation Factor-2, MESH: RNA Interference, MESH: Cytoplasmic Granules, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Protein Isoforms, MESH: RNA-Induced Silencing Complex, MESH: Fragile X Mental Retardation Protein, nervous system diseases, MESH: Pregnancy, MESH: Protein Biosynthesis, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Stress, Physiological, MESH: Mice, MESH: Female, MESH: Point Mutation, MESH: RNA, Messenger
Abstract

International audience; The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in the mRNA metabolism. The absence of FMRP in neurons leads to alterations of the synaptic plasticity, probably as a result of translation regulation defects. The exact molecular mechanisms by which FMRP plays a role in translation regulation have remained elusive. The finding of an interaction between FMRP and the RNA interference silencing complex (RISC), a master of translation regulation, has suggested that both regulators could be functionally linked. We investigated here this link, and we show that FMRP exhibits little overlap both physically and functionally with the RISC machinery, excluding a direct impact of FMRP on RISC function. Our data indicate that FMRP and RISC are associated to distinct pools of mRNAs. FMRP, unlike RISC machinery, associates with the pool of mRNAs that eventually goes into stress granules upon cellular stress. Furthermore, we show that FMRP plays a positive role in this process as the lack of FMRP or a point mutant causing a severe fragile X alter stress granule formation. Our data support the proposal that FMRP plays a role in controlling the fate of mRNAs after translation arrest.

Published
2009
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178. Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes

Author

Schaefer, Elise, Durand, Myriam, Stoetzel, Corinne, Doray, Bérénice, Viville, Brigitte, Hellé, Sophie, Danse, Jean-Marc, Hamel, Christian, Bitoun, Pierre, Goldenberg, Alice, Finck, Sonia, Faivre, Laurence, Sigaudy, Sabine, Holder, Muriel, Vincent, Marie-Claire, Marion, Vincent, Bonneau, Dominique, Verloes, Alain, Nisand, Israël, Mandel, Jean-Louis, and Dollfus, Hélène

Published
2011
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179. [Mutations in amphiphysin 2 (BIN1) cause autosomal recessive centronuclear myopathy.]

Author

Toussaint, Anne, Nicot, Anne-Sophie, Mandel, Jean-Louis, Laporte, Jocelyn, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), ANR maladie rare, Association Française contre les Myopathies, INSERM, CNRS, Université Louis Pasteur, Collège de France, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique Humaine, and Laporte, Jocelyn

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, BIN1, dynamin, [SDV.GEN] Life Sciences [q-bio]/Genetics, membrane remodeling, membrane, amphiphysin, centronuclear myopathy, myopathie
Abstract

International audience; NOUVELLE : Mutations de l'amphiphysine 2 (BIN1) dans les myopathies centronucléaires récessives

Published
2007

180. [Bardet-Biedl syndrome: a unique family for a major gene (BBS10)]

Author

Dollfus, Hélène, Muller, Jean, Stoetzel, Corinne, Laurier, Virginie, Bonneau, Dominique, Mégarbané, André, Poch, Olivier, Mandel, Jean-Louis, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Chaperonins, MESH: Humans, MESH: Mutation, Chaperonins, MESH: Pedigree, Group II Chaperonins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Male, Pedigree, MESH: Bardet-Biedl Syndrome, Mutation, Humans, Family, Female, MESH: Family, MESH: Female, Bardet-Biedl Syndrome
Published
2006

184. Disease-causing variants in TCF4are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis

Author

Mary, Laura, Piton, Amélie, Schaefer, Elise, Mattioli, Francesca, Nourisson, Elsa, Feger, Claire, Redin, Claire, Barth, Magali, El Chehadeh, Salima, Colin, Estelle, Coubes, Christine, Faivre, Laurence, Flori, Elisabeth, Geneviève, David, Capri, Yline, Perrin, Laurence, Fabre-Teste, Jennifer, Timbolschi, Dana, Verloes, Alain, Olaso, Robert, Boland, Anne, Deleuze, Jean-François, Mandel, Jean-Louis, Gerard, Bénédicte, and Giurgea, Irina

Abstract

High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4(transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4mutation to 0.7%. So far, TCF4molecular abnormalities were known to cause a syndromic form of ID, Pitt–Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4(eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4mutations to nonspecific ID.

Published
2018
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185. The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation

Author

Mallaret, Martial, primary, Synofzik, Matthis, additional, Lee, Jaeho, additional, Sagum, Cari A., additional, Mahajnah, Muhammad, additional, Sharkia, Rajech, additional, Drouot, Nathalie, additional, Renaud, Mathilde, additional, Klein, Fabrice A. C., additional, Anheim, Mathieu, additional, Tranchant, Christine, additional, Mignot, Cyril, additional, Mandel, Jean-Louis, additional, Bedford, Mark, additional, Bauer, Peter, additional, Salih, Mustafa A., additional, Schüle, Rebecca, additional, Schöls, Ludger, additional, Aldaz, C. Marcelo, additional, and Koenig, Michel, additional

Published
2013
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186. 20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition

Author

Piton, Amélie, primary, Poquet, Hélène, additional, Redin, Claire, additional, Masurel, Alice, additional, Lauer, Julia, additional, Muller, Jean, additional, Thevenon, Julien, additional, Herenger, Yvan, additional, Chancenotte, Sophie, additional, Bonnet, Marlène, additional, Pinoit, Jean-Michel, additional, Huet, Frédéric, additional, Thauvin-Robinet, Christel, additional, Jaeger, Anne-Sophie, additional, Le Gras, Stéphanie, additional, Jost, Bernard, additional, Gérard, Bénédicte, additional, Peoc'h, Katell, additional, Launay, Jean-Marie, additional, Faivre, Laurence, additional, and Mandel, Jean-Louis, additional

Published
2013
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190. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome.

Author

Stoetzel, Corinne, Muller, Jean, Laurier, Virginie, Davis, Erica E., Zaghloul, Norann A., Vicaire, Serge, Jacquelin, Cecile, Plewniak, Frederic, Leitch, Carmen C., Sarda, Pierre, Hamel, Christian, de Ravel, Thomy J. L., Lewis, Richard Alan, Friederich, Evelyne, Thibault, Christelle, Danse, Jean-Marc, Verloes, Alain, Bonneau, Dominique, Katsanis, Nicholas, Poch, Olivier, Mandel, Jean-Louis, Dollfus, Helene, Stoetzel, Corinne, Muller, Jean, Laurier, Virginie, Davis, Erica E., Zaghloul, Norann A., Vicaire, Serge, Jacquelin, Cecile, Plewniak, Frederic, Leitch, Carmen C., Sarda, Pierre, Hamel, Christian, de Ravel, Thomy J. L., Lewis, Richard Alan, Friederich, Evelyne, Thibault, Christelle, Danse, Jean-Marc, Verloes, Alain, Bonneau, Dominique, Katsanis, Nicholas, Poch, Olivier, Mandel, Jean-Louis, and Dollfus, Helene

Abstract

Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive ciliopathy characterized by progressive retinal degeneration, obesity, cognitive impairment, polydactyly, and kidney anomalies. The disorder is genetically heterogeneous, with 11 BBS genes identified to date, which account for ~70% of affected families. We have combined single-nucleotide-polymorphism array homozygosity mapping with in silico analysis to identify a new BBS gene, BBS12. Patients from two Gypsy families were homozygous and haploidentical in a 6-Mb region of chromosome 4q27. FLJ35630 was selected as a candidate gene, because it was predicted to encode a protein with similarity to members of the type II chaperonin superfamily, which includes BBS6 and BBS10. We found pathogenic mutations in both Gypsy families, as well as in 14 other families of various ethnic backgrounds, indicating that BBS12 accounts for approximately 5% of all BBS cases. BBS12 is vertebrate specific and, together with BBS6 and BBS10, defines a novel branch of the type II chaperonin superfamily. These three genes are characterized by unusually rapid evolution and are likely to perform ciliary functions specific to vertebrates that are important in the pathophysiology of the syndrome, and together they account for about one-third of the total BBS mutational load. Consistent with this notion, suppression of each family member in zebrafish yielded gastrulation-movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all three members resulted in severely affected embryos, possibly hinting at partial functional redundancy within this protein family.

Published
2007
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191. Mutations in the ERCC2 (XPD) gene associated with severe fetal ichthyosis and dysmorphic features.

Author

Miguet, Marguerite, Thevenon, Julien, Laugel, Vincent, Lefebvre, Mathilde, Bourchany, Aurélie, Rivière, Jean‐Baptiste, Duffourd, Yannis, Schaefer, Elise, Antal, Maria Cristina, Abida, Rosalie, Weingertner, Anne‐Sophie, Kremer, Valérie, Vabres, Pierre, Morice‐Picard, Fanny, Gonzales, Marie, Lipsker, Dan, Fraitag, Sylvie, Mandel, Jean‐Louis, Chelly, Jamel, and Dollfus, Hélène

Abstract

What's Already Known About This Topic? Congenital ichthyosis is a condition that includes several distinct subtypes with significant genetic heterogeneity.Defects in the ERCC2 [xeroderma pigmentosum (XP) complementation group D] gene lead to one of several clinical diseases, including XP, trichothiodystrophy, cerebrooculofacioskeletal syndrome, XP/Cockayne syndrome, and XP/trichothiodystrophy.What Does This Study Add? This observation enlarges the phenotypic spectrum of ERCC2 (XP complementation group D) mutations to severe fetal cases and expands the molecular basis of congenital ichthyosis by reporting the prenatal expression of a very rare nucleotide excision repair‐related condition. [ABSTRACT FROM AUTHOR]

Published
2016
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192. Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons.

Author

Tabet, Ricardos, Moutin, Enora, Becker, Jérôme A. J., Heintz, Dimitri, Fouillen, Laetitia, Flatter, Eric, Krężel, Wojciech, Alunni, Violaine, Koebel, Pascale, Dembélé, Doulaye, Tassone, Flora, Bardoni, Barbara, Mandel, Jean-Louis, Vitale, Nicolas, Muller, Dominique, Le Merrer, Julie, and Moine, Hervé

Subjects
FRAGILE X syndrome, PROTEIN crosslinking, BRAIN proteins, POSTSYNAPTIC density protein, EXCITATORY amino acid agents, IMMUNOPRECIPITATION, PROTEIN synthesis
Abstract

Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine. [ABSTRACT FROM AUTHOR]

Published
2016
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193. Novel de novo mutations in ZBTB20 in Primrose syndrome with congenital hypothyroidism.

Author

Mattioli, Francesca, Piton, Amelie, Gérard, Bénédicte, Superti‐Furga, Andrea, Mandel, Jean‐Louis, and Unger, Sheila

Abstract

The cardinal features of Primrose syndrome (MIM 259050) are dysmorphic facial features, macrocephaly, and intellectual disability, as well as large body size, height and weight, and calcified pinnae. A variety of neurological signs and symptoms have been reported including hearing loss, autism, behavioral abormalities, hypotonia, cerebral calcifications, and hypoplasia of the corpus callosum. Recently, heterozygous de novo missense mutations in ZBTB20, coding for a zing finger protein, have been identified in Primrose syndrome patients. We report a boy with intellectual disability carrying two de novo missense mutations in the last exon of ZBTB20 (Ser616Phe and Gly741Arg; both previously unreported). One of them, Ser616Phe, affects an amino acid located in one of the C2H2 zing-fingers involved in DNA-binding and close to other missense mutations already described. Reverse phenotyping showed that this patient presents with classic features of Primrose syndrome (dysmorphic facies, macrocephaly, hearing loss, hypotonia, hypoplasia of the corpus callosum) and, in addition, congenital hypothyroidism. Review of the literature reveals another Primrose syndrome patient with hypothyroidism and thus, this may represent an under recognized component that should be investigated in other patients. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Published
2016
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194. A 530kb YAC contig tightly linked to the Friedreich ataxia locus contains five CpG clusters and a new highly polymorphic microsatellite

Author

LGME-CNRS, U.184-INSERM, Institut de Chimie Biologique, Facult?? de M??decine, Universit?? Louis Pasteur, 11, Rue Humann, F-67085, Strasbourg Cedex, France; Department of Ophthalmology, University of Michigan, W.K. Kellogg Eye Center, 1000 Wall Street, 48105, Ann Arbor, MI, USA, Centre d'Etudes du Polymorphisme Humain, 27, Rue Juliette Dodu, F-75010, Paris, France, LGME-CNRS, U.184-INSERM, Institut de Chimie Biologique, Facult?? de M??decine, Universit?? Louis Pasteur, 11, Rue Humann, F-67085, Strasbourg Cedex, France, Department of Genetics and Center for Genetics in Medicine, Washington University School of Medicine, Box 8031, 63110, St. Louis, MO, USA, Ann Arbor, Koenig, Michel, Mandel, Jean-Louis, Schlessinger, David, Abderrahim, Hadi, Duclos, Franck, Brownstein, Bernard H., Paslier, Denis, Sirugo, Giorgio, Cohen, Daniel, Fujita, Ricardo, LGME-CNRS, U.184-INSERM, Institut de Chimie Biologique, Facult?? de M??decine, Universit?? Louis Pasteur, 11, Rue Humann, F-67085, Strasbourg Cedex, France; Department of Ophthalmology, University of Michigan, W.K. Kellogg Eye Center, 1000 Wall Street, 48105, Ann Arbor, MI, USA, Centre d'Etudes du Polymorphisme Humain, 27, Rue Juliette Dodu, F-75010, Paris, France, LGME-CNRS, U.184-INSERM, Institut de Chimie Biologique, Facult?? de M??decine, Universit?? Louis Pasteur, 11, Rue Humann, F-67085, Strasbourg Cedex, France, Department of Genetics and Center for Genetics in Medicine, Washington University School of Medicine, Box 8031, 63110, St. Louis, MO, USA, Ann Arbor, Koenig, Michel, Mandel, Jean-Louis, Schlessinger, David, Abderrahim, Hadi, Duclos, Franck, Brownstein, Bernard H., Paslier, Denis, Sirugo, Giorgio, Cohen, Daniel, and Fujita, Ricardo

Abstract

Friedreich ataxia (FA) is a severe autosomal recessive neurodegenerative disease. The defective gene has been previously assigned to chromosome 9q13-q21 by demonstration of tight linkage to the two independent loci D9S15 and D9S5. Linkage data indicate that FRDA is at less than 1 c M from both markers. Previous physical mapping has shown that probes defining D9S15 (MCT112) and D9S5 (26P) are less than 260kb apart and are surrounded by at least six CpG clusters within 450 kb, which might indicate the presence of???candidate??? genes for FA. We isolated and characterized a 530 kb YAC (yeast artificial chromosome) contig that contains five of the CpG clusters. The YACs were used to search for new polymorphic markers needed to map FRDA precisely with respect to the cloned segment. In particular, we found a (CA) n microsatellite polymorphism, GS4, that detects 13 alleles with a PIC value of 0.83 and allows the definition of haplotypes extending over 310kb when used in combination with polymorphic markers at D9S5 and D9S15.

Published
2006

195. Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome

Author

Koutsopoulos, Olga S, primary, Kretz, Christine, additional, Weller, Claudia M, additional, Roux, Aurelien, additional, Mojzisova, Halina, additional, Böhm, Johann, additional, Koch, Catherine, additional, Toussaint, Anne, additional, Heckel, Emilie, additional, Stemkens, Daphne, additional, ter Horst, Simone A J, additional, Thibault, Christelle, additional, Koch, Muriel, additional, Mehdi, Syed Q, additional, Bijlsma, Emilia K, additional, Mandel, Jean-Louis, additional, Vermot, Julien, additional, and Laporte, Jocelyn, additional

Published
2012
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197. Next generation sequencing for molecular diagnosis of neuromuscular diseases

Author

Vasli, Nasim, primary, Böhm, Johann, additional, Le Gras, Stéphanie, additional, Muller, Jean, additional, Pizot, Cécile, additional, Jost, Bernard, additional, Echaniz-Laguna, Andoni, additional, Laugel, Vincent, additional, Tranchant, Christine, additional, Bernard, Rafaelle, additional, Plewniak, Frédéric, additional, Vicaire, Serge, additional, Levy, Nicolas, additional, Chelly, Jamel, additional, Mandel, Jean-Louis, additional, Biancalana, Valérie, additional, and Laporte, Jocelyn, additional

Published
2012
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199. Ataxia with Vitamin E Deficiency: Refinement of Genetic Localization and Analysis of Linkage Disequilibrium by Using New Markers in 14 Families

Author

Doerflinger, Nathalie, Linder, Catherine, Ouahchi, Karim, Gyapay, Gabor, Weissenbach, Jean, Le Paslier, Denis, Rigault, Philippe, Belal, Samir, Hamida, Christiane Ben, Hentati, Faycal, Hamida, Mongi Ben, Pandolfo, Massimo, DiDonato, Stephano, Sokol, Ronald, Kayden, Herbert, Landrieu, Pierre, Durr, Alexandra, Brice, Alexis, Goutières, Françoise, Kohlschütter, Alfried, Sabouraud, Pascal, Benomar, Ali, Yahyaoui, Mohamed, Mandel, Jean-Louis, and Koenig, Michel

Subjects
Genetic Markers, Male, Recombination, Genetic, Base Sequence, Molecular Sequence Data, Genes, Recessive, Original Articles, DNA, Satellite, Linkage Disequilibrium, Pedigree, Africa, Northern, Humans, Ataxia, Female, Vitamin E Deficiency, Chromosomes, Artificial, Yeast, Chromosomes, Human, Pair 8, Repetitive Sequences, Nucleic Acid
Abstract

Ataxia with vitamin E deficiency (AVED) is an autosomal recessive disease characterized clinically by neurological symptoms with often striking resemblance to those of Friedreich ataxia. This disorder has been reported previously as familial isolated vitamin E deficiency. We have mapped recently the AVED locus to a 5-cM confidence interval on chromosome 8q by homozygosity mapping in six Mediterranean families. We have now analyzed six new and two previously described families and demonstrate genetic homogeneity despite important clinical variability and wide geographic origins. Analysis of nine new tightly linked microsatellite markers, including four characterized in this study, revealed a predominant but not unique mutation in northern African populations, where this condition is more frequent. Haplotype analysis but also classical recombinations allowed us to refine the AVED position to a 1-cM interval. A YAC contig over this interval was constructed from marker STSs and YAC fingerprint data, in order to facilitate the search of the AVED gene.

Published
1995

200. Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region

Author

Dahl, N, Hu, L, Chery, M, Fardeau, M, Gilgenkrantz, S, Nivelon-Chevallier, A, Sidaner-Noisette, I, Mugneret, F, Gouyon, J, Gal, A, Kioschis, Petra, d'Urso, M., Mandel, Jean-Louis, Laboratoire de Biologie structurale, Institut National de la Santé et de la Recherche Médicale (INSERM), and univOAK, Archive ouverte

Subjects
Adult, MESH: Muscles, congenital, hereditary, and neonatal diseases and abnormalities, X Chromosome, MESH: Pedigree, In Vitro Techniques, MESH: Chromosomes, Human, Muscular Diseases, Dosage Compensation, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Chromosomes, Human, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Sex Chromosome Aberrations, Sex Chromosome Aberrations, Sequence Deletion, MESH: In Vitro Techniques, MESH: X Chromosome, MESH: Humans, Muscles, MESH: Muscular Diseases, Chromosome Mapping, Infant, MESH: Adult, Original Articles, MESH: Sequence Deletion, MESH: Infant, MESH: Dosage Compensation, Genetic, Chromosome Banding, Pedigree, MESH: Karyotyping, Karyotyping, MESH: DNA Probes, MESH: Chromosome Banding, Female, MESH: Chromosome Mapping, DNA Probes, MESH: Female
Abstract

International audience; A young girl with a clinically moderate form of myotubular myopathy was found to carry a cytogenetically detectable deletion in Xq27-q28. The deletion had occurred de novo on the paternal X chromosome. It encompasses the fragile X (FRAXA) and Hunter syndrome (IDS) loci, and the DXS304 and DXS455 markers, in Xq27.3 and proximal Xq28. Other loci from the proximal half of Xq28 (DXS49, DXS256, DXS258, DXS305, and DXS497) were found intact. As the X-linked myotubular myopathy locus (MTM1) was previously mapped to Xq28 by linkage analysis, the present observation suggested that MTM1 is included in the deletion. However, a significant clinical phenotype is unexpected in a female MTM1 carrier. Analysis of inactive X-specific methylation at the androgen receptor gene showed that the deleted X chromosome was active in approximately 80% of leukocytes. Such unbalanced inactivation may account for the moderate MTM1 phenotype and for the mental retardation that later developed in the patient. This observation is discussed in relation to the hypothesis that a locus modulating X inactivation may lie in the region. Comparison of this deletion with that carried by a male patient with a severe Hunter syndrome phenotype but no myotubular myopathy, in light of recent linkage data on recombinant MTM1 families, led to a considerable refinement of the position of the MTM1 locus, to a region of approximately 600 kb, between DXS304 and DXS497.

Published
1995

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