PMID: identifiant
de la référence Pubmed : |
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 (22566635)  |
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| titre : |
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A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. |
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| auteur(s) : |
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Patrícia Celestino-Soper1, Sara Violante2, 3, Emily Crawford4, Rui Luo5, Anath Lionel6, Elsa Delaby7, Guiqing Cai8, Bekim Sadikovic1, Kwanghyuk Lee1, Charlene Lo1, Kun Gao5, Richard Person1, Timothy Moss1, Jennifer German1, Ni Huang9, Marwan Shinawi1, 10, Diane Treadwell-Deering10, 11, Peter Szatmari12, Wendy Roberts13, Bridget Fernandez14, Richard Schroer15, Roger Stevenson15, Joseph Buxbaum8, Catalina Betancur7, Stephen Scherer6, 13, Stephan Sanders16, Daniel Geschwind5, James Sutcliffe4, Matthew Hurles9, Ronald Wanders3, Chad Shaw1, Suzanne Leal1, Edwin Cook17, Robin Goin-Kochel1, 10, 18, Frédéric Vaz3, Arthur Beaudet ( ) 1, 10, 18 |
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| laboratoire : |
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| 1 : |
Department of Molecular and Human Genetics |
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| Baylor College of Medicine |
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| Houston, TX 77030 |
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| États-Unis |
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| 2 : |
Metabolism and Genetics Group |
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| Research Institute for Medicines and Pharmaceutical Sciences – Universidade de Lisboa |
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| iMed.UL, Faculdade de Farmácia, 1649-003 Lisbon |
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| Portugal |
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| 3 : |
Laboratory Genetic Metabolic Disease |
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| Academic Medical Center – University of Amsterdam |
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| Departments of Clinical Chemistry and Pediatrics, 1105 AZ, Amsterdam |
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| Pays-Bas |
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| 4 : |
Department of Molecular Physiology and Biophysics |
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| Centers for Human Genetics Research and Molecular Neuroscience – Vanderbilt University |
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| Nashville, Tennessee 37232 |
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| États-Unis |
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| 5 : |
Department of Human Genetics |
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| University of California, Los Angeles – Semel Institute |
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| David Geffen School of Medicine, CA 90095 |
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| États-Unis |
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| 6 : |
The Centre for Applied Genomics and Program in Genetics and Genomic Biology |
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| The Hospital for Sick Children |
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| Toronto, Ontario, M5G 1L7 |
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| Canada |
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| 7 : |
Physiopathologie des Maladies du Système Nerveux Central |
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| INSERM : U952 – Université Pierre et Marie Curie [UPMC] - Paris VI – CNRS : UMR7224 |
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| Bât. B, 4ème étage, case courrier 37 9 quai Saint Bernard 75252 Paris Cedex 05 |
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| France |
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| 8 : |
Seaver Autism Research Center |
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| Mount Sinai School of Medicine |
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| New York |
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| États-Unis |
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| 9 : |
Department of Neurology |
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| Johns Hopkins University |
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| 733 North Broadway Baltimore, MD 21205-2196 |
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| États-Unis |
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| 10 : |
Texas Children's Hospital |
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| Texas Children's Hospital |
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| Houston, TX 77030 |
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| États-Unis |
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| 11 : |
Department of psychiatry |
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| Baylor College of Medicine |
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| Houston, TX 77030 |
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| États-Unis |
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| 12 : |
Department of Psychiatry and Behavioural Neurosciences |
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| McMaster University |
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| The Offord Centre for Child Studies, McMaster Children's Hospital, Hamilton, ON, L8S 4L8 |
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| Canada |
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| 13 : |
Autism Research Unit |
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| The Hospital for Sick Children and Bloorview Kids Rehabilitation – University of Toronto |
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| Toronto, Ontario, M5G 1Z8 |
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| Canada |
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| 14 : |
Disciplines of Genetics and Medicine |
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| Memorial University of Newfoundland |
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| St. John's Newfoundland |
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| Canada |
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| 15 : |
Greenwood Genetic Center |
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| Greenwood Genetic Center |
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| Greenwood, SC 29646 |
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| États-Unis |
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| 16 : |
Departments of Psychiatry and Genetics |
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| Yale University School of Medicine |
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| Program on Neurogenetics, Child Study Center , New Haven, CT 06520 |
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| États-Unis |
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| 17 : |
Department of Psychiatry |
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| Institute for Juvenile Research – University of Illinois at Chicago |
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| Chicago, Illinois |
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| États-Unis |
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| 18 : |
Department of pediatrics |
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| Baylor College of Medicine |
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| Houston, TX 77030 |
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| États-Unis |
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| résumé : |
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We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism. |
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| domaine : |
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Sciences du Vivant/Génétique
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langue du texte
intégral : |
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Anglais |
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| ISSN : |
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0027-8424 |
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| type de publication : |
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Articles dans des revues avec comité de lecture |
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| DOI : |
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10.1073/pnas.1120210109 |
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| journal : |
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Proceedings- National Academy of Sciences Usa |
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| Audience : |
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internationale |
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| date de publication : |
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22/05/2012 |
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date de publication
électronique : |
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07/05/2012 |
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| volume : |
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109 |
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| numéro : |
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21 |
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| page, identifiant, ... : |
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7974-81 |
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| Descripteur(s) MeSH : |
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Autistic Disorder – Carnitine – Chromosomes – Human – X – Cognition – Exons – Gene Deletion – Genes – X-Linked – Humans – Male – Metabolism – Inborn Errors – Mixed Function Oxygenases – Penetrance – Risk Factors – Siblings |
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| contrat, financement : |
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The AGRE is a program of Autism Speaks and is supported, in part, by Grant 1U24MH081810 from the National Institute of Mental Health (to Clara M. Lajonchere). Part of this work was supported by Grant SFARI 124827 from the Simons Foundation (to the investigators of the SSC Genetic Consortium) and Grant HD-37283 (to A.L.B) and Grant P30HD-0240640 from the National Institutes of Health. Part of this work was financially supported by the Fundação para a Ciência e Tecnologia, Lisbon, Portugal, by Grant SFRH/BD/38074/2007 (to. S.V.). Part of this work was supported by National Institutes of Health Grants R01 MH061009 and R01 NS049261 (to J.S.S.). Funding for part of this work was provided by the Wellcome Trust under Award 076113 and by Grant 077014/Z/05/Z. Funding for the Paris Autism Research International Sibpair study was provided, in part, by the Institut National de la Santé et de la Recherche Médicale, Fondation de France, Fondation Orange, Fondation pour la Recherche Médicale, Assistance Publique- Hôpitaux de Paris, and the Swedish Science Council. |
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