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3. Both rare and common genetic variants contribute to autism in the Faroe Islands

Author

Leblond, Claire S, Cliquet, Freddy, Carton, Coralie, Huguet, Guillaume, Mathieu, Alexandre, Kergrohen, Thomas, Buratti, Julien, Lemière, Nathalie, Cuisset, Laurence, Bienvenu, Thierry, Boland, Anne, Deleuze, Jean-François, Stora, Tormodur, Biskupstoe, Rannva, Halling, Jónrit, Andorsdóttir, Guðrið, Billstedt, Eva, Gillberg, Christopher, and Bourgeron, Thomas

Published
2019
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4. Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations

Author

Gouder, Laura, Vitrac, Aline, Goubran-Botros, Hany, Danckaert, Anne, Tinevez, Jean-Yves, André-Leroux, Gwenaëlle, Atanasova, Ekaterina, Lemière, Nathalie, Biton, Anne, Leblond, Claire S., Poulet, Aurélie, Boland, Anne, Deleuze, Jean-François, Benchoua, Alexandra, Delorme, Richard, Bourgeron, Thomas, and Cloëz-Tayarani, Isabelle

Published
2019
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5. LMT USV Toolbox, a Novel Methodological Approach to Place Mouse Ultrasonic Vocalizations in Their Behavioral Contexts—A Study in Female and Male C57BL/6J Mice and in Shank3 Mutant Females

Author

De Chaumont, Fabrice, Lemière, Nathalie, Coqueran, Sabrina, Bourgeron, Thomas, Ey, Elodie, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), This work was partially funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, the Cognacq-Jay Foundation, the Conny-Maeva Foundation, the ERANET-NEURON ALTRUISM program, the Agence Nationale de la Recherche through grant number ANR-10-LABX-62-IBEID, France-BioImaging infrastructure through grant number ANR-10-INBS-04 and the INCEPTION program through grant number ANR-16-CONV-0005, the Centre National de la Recherche Scientifique, the University Paris Diderot, the BioPsy Labex, and the Foundation for Medical Research (Equipe DEQ20130326488). This study also benefited from the financial support of GIS 'Autisme et Troubles du Neuro-Développement'., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
mouse model, [SDV.BA]Life Sciences [q-bio]/Animal biology, Cognitive Neuroscience, autism, Neurosciences. Biological psychiatry. Neuropsychiatry, Behavioral Neuroscience, Neuropsychology and Physiological Psychology, age, Shank3, sex, social behavior analysis, mouse, RC321-571, ultrasonic vocalization (USV)
Abstract

International audience; Ultrasonic vocalizations (USVs) are used as a phenotypic marker in mouse models of neuropsychiatric disorders. Nevertheless, current methodologies still require time-consuming manual input or sound recordings clean of any background noise. We developed a method to overcome these two restraints to boost knowledge on mouse USVs. The methods are freely available and the USV analysis runs online at https://usv.pasteur.cloud . As little is currently known about usage and structure of ultrasonic vocalizations during social interactions over the long-term and in unconstrained context, we investigated mouse spontaneous communication by coupling the analysis of USVs with automatic labeling of behaviors. We continuously recorded during 3 days undisturbed interactions of same-sex pairs of C57BL/6J sexually naive males and females at 5 weeks and 3 and 7 months of age. In same-sex interactions, we observed robust differences between males and females in the amount of USVs produced, in the acoustic structure and in the contexts of emission. The context-specific acoustic variations emerged with increasing age. The emission of USVs also reflected a high level of excitement during social interactions. We finally highlighted the importance of studying long-term spontaneous communication by investigating female mice lacking Shank3 , a synaptic protein associated with autism. While the previous short-time constrained investigations could not detect USV emission abnormalities, our analysis revealed robust differences in the usage and structure of the USVs emitted by mutant mice compared to wild-type female pairs.

Published
2021
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6. Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders

Author

Chaste, Pauline, Clement, Nathalie, Botros, Hany Goubran, Guillaume, Jean-Luc, Konyukh, Marina, Pagan, Cécile, Scheid, Isabelle, Nygren, Gudrun, Anckarsäter, Henrik, Rastam, Maria, Ståhlberg, Ola, Gillberg, Carina I., Melke, Jonas, Delorme, Richard, Leblond, Claire, Toro, Roberto, Huguet, Guillaume, Fauchereau, Fabien, Durand, Christelle, Boudarene, Lydia, Serrano, Emilie, Lemière, Nathalie, Launay, Jean Marie, Leboyer, Marion, Jockers, Ralf, Gillberg, Christopher, and Bourgeron, Thomas

Published
2011
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7. Genetic and Functional ascertainment of the Melatonin Pathway in Patients with Attention Deficit and Hyperactivity Disorders

Author

Chaste, Pauline, Clement, Nathalie, Botros, Hany, Guillaume, Jean-Luc, Konyukh, Marina, Pagan, Cécile, Scheid, Isabelle, Nygren, Gudrun, Anckarsäter, Henrik, Råstam, Maria, Ståhlberg, Ola, Gillberg, I. Carina, Melke, Jonas, Delorme, Richard, Leblond, Claire, Toro, Roberto, Huguet, Guillaume, Fauchereau, Fabien, Durand, Christelle, Boudarene, Lydia, Serrano, Emilie, Lemière, Nathalie, Launay, Jean Marie, Leboyer, Marion, Jockers, Ralf, Gillberg, Christopher, Bourgeron, Thomas, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Göteborgs Universitet (GU), Lund University [Lund], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut fédératif de Recherche Lariboisière (IFR_139), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Fondation FondaMental [Créteil], This work was supported by the Institut Pasteur, Université Paris Diderot, INSERM, CNRS, FP6 ENI‐NET, Fondation FondaMental and Fondation pour la Recherche Médicale (‘Equipe FRM’, RJ)., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), and Toro, Roberto

Subjects
[SDV] Life Sciences [q-bio], ASMT, [SDV]Life Sciences [q-bio], AA-NAT, ADHD, receptors, melatonin, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], genes
Abstract

Sleep wake cycles are frequently disturbed in patients with Attention Deficit and Hyperactivity Disorders. We hypothesized that the origin of the sleep problems may be the consequence of an abnormal circadian clock setting regulated by the melatonin pathway. Here, we sequenced all the genes of the melatonin pathway AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 in 328 individuals from Sweden including 108 patients with ADHD and 220 from the general population. Non-synonymous mutations were identified in all genes at a similar frequency in patients with ADHD and in controls. Among the functional variations, a splice site mutation (IVS5+2T>C) in ASMT and one stop mutation (Y170X) in MTNR1A were only detected in patients with ADHD. Biochemical analyses indicated that these mutations abolish the activity of ASMT and MTNR1A. We also identified clusters of SNPs within MTNR1B showing significant difference in the allelic frequency between ADHD patients and control (maximum signal at rs10830961 P=0.0002). Taken together, these genetic and functional results shed light on one new compelling candidate pathway for susceptibility to circadian rhythms alterations that could help clinicians for providing better treatments of patients with ADHD and sleep problems.

Published
2018

8. Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations

Author

Gouder, Laura, Vitrac, Aline, Goubran-Botros, Hany, Danckaert, Anne, Tinevez, Jean-Yves, ANDRE-LEROUX, Gwenaelle, Atanasova, Ekatarina, Lemière, Nathalie, Leblond, Claire S, Poulet, Aurélie, Benchoua, Alexandra, Delorme, Richard, Bourgeron, Thomas, Cloëz-Tayarani, Isabelle, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS), Human Genetics and Cognitive Functions, Université Paris Diderot - Paris 7 (UPD7), Imagopole (CITECH), Institut Pasteur [Paris], Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de la Recherche Agronomique (INRA), CECS - I-STEM, Association française contre les myopathies (AFM-Téléthon), Department of Child and Adolescent Psychiatry, University Hospitals Leuven [Leuven], and auto-saisine

Subjects
nervous system, [SDV]Life Sciences [q-bio], mental disorders, behavioral disciplines and activities
Abstract

Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations

Published
2017

9. Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders

Author

Pagan, Cécile, primary, Goubran-Botros, Hany, additional, Delorme, Richard, additional, Benabou, Marion, additional, Lemière, Nathalie, additional, Murray, Kerren, additional, Amsellem, Frédérique, additional, Callebert, Jacques, additional, Chaste, Pauline, additional, Jamain, Stéphane, additional, Fauchereau, Fabien, additional, Huguet, Guillaume, additional, Maronde, Erik, additional, Leboyer, Marion, additional, Launay, Jean-Marie, additional, and Bourgeron, Thomas, additional

Published
2017
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10. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments

Author

Barsh, Gregory S., Leblond, Claire S., Nava, Caroline, Polge, Anne, Gauthier, Julie, Huguet, Guillaume, Lumbroso, Serge, Giuliano, Fabienne, Stordeur, Coline, Depienne, Christel, Mouzat, Kevin, Pinto, Dalila, Howe, Jennifer, Lemière, Nathalie, Durand, Christelle M., Guibert, Jessica, Ey, Elodie, Toro, Roberto, Peyre, Hugo, Mathieu, Alexandre, Amsellem, Frédérique, Rastam, Maria, Gillberg, I. Carina, Rappold, Gudrun A., Holt, Richard, Monaco, Anthony P., Maestrini, Elena, Galan, Pilar, Heron, Delphine, Jacquette, Aurélia, Afenjar, Alexandra, Rastetter, Agnès, Brice, Alexis, Devillard, Françoise, Assouline, Brigitte, Laffargue, Fanny, Lespinasse, James, Chiesa, Jean, Rivier, François, Bonneau, Dominique, Regnault, Beatrice, Zelenika, Diana, Delepine, Marc, Lathrop, Mark, Sanlaville, Damien, Schluth-Bolard, Caroline, Edery, Patrick, Perrin, Laurence, Tabet, Anne Claude, Schmeisser, Michael J., Boeckers, Tobias M., Coleman, Mary, Sato, Daisuke, Szatmari, Peter, Scherer, Stephen W., Rouleau, Guy A., Betancur, Catalina, Leboyer, Marion, Gillberg, Christopher, Delorme, Richard, and Bourgeron, Thomas

Subjects
mental disorders
Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.

Published
2014

11. Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway

Author

Botros, Hany Goubran, Legrand, Pierre, Pagan, Cecile, Bondet, Vincent, Weber, Patrick, Ben-Abdallah, Mariem, Lemière, Nathalie, Huguet, Guillaume, Bellalou, Jacques, Maronde, Erik, Beguin, Pierre, Haouz, Ahmed, Shepard, William, Bourgeron, Thomas, Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Goethe-University Frankfurt am Main, This work was supported by the Institut Pasteur, University Paris Diderot, CNRS, Fondation Orange, ANR (ANR-08-MNPS-037-01 – SynGen), Neuron-ERANET (EUHF-AUTISM), Fondation FondaMentale, Fondation Recherche Médicale, the ESRF and Synchrotrons (SOLEIL Proposal 20080516, ESRF at Grenoble)., ANR-08-MNPS-0037,SynGen-ASD-LD,Genes synaptiques de l'autisme et du retard mental(2008), ANR-10-NEUR-0003,EUHFAUTISM(2010), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Gènes, Synapses et Cognition, and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris]

Subjects
Acetylserotonin O-Methyltransferase, Models, Molecular, Genetic variants, crystal structure, [SDV]Life Sciences [q-bio], Molecular Sequence Data, MESH: Sequence Alignment, MESH: Amino Acid Sequence, Crystallography, X-Ray, O‐methyl transferase, [SCCO]Cognitive science, ASMT, Asian People, Gene Frequency, MESH: Polymorphism, Genetic, MESH: Gene Frequency, Humans, Amino Acid Sequence, MESH: Melatonin, Melatonin, MESH: Acetylserotonin O-Methyltransferase, MESH: Asian Continental Ancestry Group, MESH: Humans, MESH: Molecular Sequence Data, Polymorphism, Genetic, MESH: Crystallography, X-Ray, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Sequence Alignment, MESH: Models, Molecular
Abstract

International audience; Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C-terminal domain, which is typical of other SAM-dependent O-methyltransferases, and an N-terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3-dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans.

Published
2012

12. 11q24.2‐25 micro‐rearrangements in autism spectrum disorders: Relation to brain structures

Author

Maruani, Anna, primary, Huguet, Guillaume, additional, Beggiato, Anita, additional, ElMaleh, Monique, additional, Toro, Roberto, additional, Leblond, Claire S., additional, Mathieu, Alexandre, additional, Amsellem, Frederique, additional, Lemière, Nathalie, additional, Verloes, Alain, additional, Leboyer, Marion, additional, Gillberg, Christopher, additional, Bourgeron, Thomas, additional, and Delorme, Richard, additional

Published
2015
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13. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Author

Leblond, Claire S., primary, Nava, Caroline, additional, Polge, Anne, additional, Gauthier, Julie, additional, Huguet, Guillaume, additional, Lumbroso, Serge, additional, Giuliano, Fabienne, additional, Stordeur, Coline, additional, Depienne, Christel, additional, Mouzat, Kevin, additional, Pinto, Dalila, additional, Howe, Jennifer, additional, Lemière, Nathalie, additional, Durand, Christelle M., additional, Guibert, Jessica, additional, Ey, Elodie, additional, Toro, Roberto, additional, Peyre, Hugo, additional, Mathieu, Alexandre, additional, Amsellem, Frédérique, additional, Rastam, Maria, additional, Gillberg, I. Carina, additional, Rappold, Gudrun A., additional, Holt, Richard, additional, Monaco, Anthony P., additional, Maestrini, Elena, additional, Galan, Pilar, additional, Heron, Delphine, additional, Jacquette, Aurélia, additional, Afenjar, Alexandra, additional, Rastetter, Agnès, additional, Brice, Alexis, additional, Devillard, Françoise, additional, Assouline, Brigitte, additional, Laffargue, Fanny, additional, Lespinasse, James, additional, Chiesa, Jean, additional, Rivier, François, additional, Bonneau, Dominique, additional, Regnault, Beatrice, additional, Zelenika, Diana, additional, Delepine, Marc, additional, Lathrop, Mark, additional, Sanlaville, Damien, additional, Schluth-Bolard, Caroline, additional, Edery, Patrick, additional, Perrin, Laurence, additional, Tabet, Anne Claude, additional, Schmeisser, Michael J., additional, Boeckers, Tobias M., additional, Coleman, Mary, additional, Sato, Daisuke, additional, Szatmari, Peter, additional, Scherer, Stephen W., additional, Rouleau, Guy A., additional, Betancur, Catalina, additional, Leboyer, Marion, additional, Gillberg, Christopher, additional, Delorme, Richard, additional, and Bourgeron, Thomas, additional

Published
2014
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14. Heterogeneous Pattern of Selective Pressure for PRRT2 in Human Populations, but No Association with Autism Spectrum Disorders

Author

Huguet, Guillaume, primary, Nava, Caroline, additional, Lemière, Nathalie, additional, Patin, Etienne, additional, Laval, Guillaume, additional, Ey, Elodie, additional, Brice, Alexis, additional, Leboyer, Marion, additional, Szepetowski, Pierre, additional, Gillberg, Christopher, additional, Depienne, Christel, additional, Delorme, Richard, additional, and Bourgeron, Thomas, additional

Published
2014
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15. Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

Author

Leblond, Claire S., primary, Heinrich, Jutta, additional, Delorme, Richard, additional, Proepper, Christian, additional, Betancur, Catalina, additional, Huguet, Guillaume, additional, Konyukh, Marina, additional, Chaste, Pauline, additional, Ey, Elodie, additional, Rastam, Maria, additional, Anckarsäter, Henrik, additional, Nygren, Gudrun, additional, Gillberg, I. Carina, additional, Melke, Jonas, additional, Toro, Roberto, additional, Regnault, Beatrice, additional, Fauchereau, Fabien, additional, Mercati, Oriane, additional, Lemière, Nathalie, additional, Skuse, David, additional, Poot, Martin, additional, Holt, Richard, additional, Monaco, Anthony P., additional, Järvelä, Irma, additional, Kantojärvi, Katri, additional, Vanhala, Raija, additional, Curran, Sarah, additional, Collier, David A., additional, Bolton, Patrick, additional, Chiocchetti, Andreas, additional, Klauck, Sabine M., additional, Poustka, Fritz, additional, Freitag, Christine M., additional, Waltes, Regina, additional, Kopp, Marnie, additional, Duketis, Eftichia, additional, Bacchelli, Elena, additional, Minopoli, Fiorella, additional, Ruta, Liliana, additional, Battaglia, Agatino, additional, Mazzone, Luigi, additional, Maestrini, Elena, additional, Sequeira, Ana F., additional, Oliveira, Barbara, additional, Vicente, Astrid, additional, Oliveira, Guiomar, additional, Pinto, Dalila, additional, Scherer, Stephen W., additional, Zelenika, Diana, additional, Delepine, Marc, additional, Lathrop, Mark, additional, Bonneau, Dominique, additional, Guinchat, Vincent, additional, Devillard, Françoise, additional, Assouline, Brigitte, additional, Mouren, Marie-Christine, additional, Leboyer, Marion, additional, Gillberg, Christopher, additional, Boeckers, Tobias M., additional, and Bourgeron, Thomas, additional

Published
2012
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16. Variations of the Candidate SEZ6L2 Gene on Chromosome 16p11.2 in Patients with Autism Spectrum Disorders and in Human Populations

Author

Konyukh, Marina, primary, Delorme, Richard, additional, Chaste, Pauline, additional, Leblond, Claire, additional, Lemière, Nathalie, additional, Nygren, Gudrun, additional, Anckarsäter, Henrik, additional, Rastam, Maria, additional, Ståhlberg, Ola, additional, Amsellem, Frederique, additional, Gillberg, I. Carina, additional, Mouren-Simeoni, Marie Christine, additional, Herbrecht, Evelyn, additional, Fauchereau, Fabien, additional, Toro, Roberto, additional, Gillberg, Christopher, additional, Leboyer, Marion, additional, and Bourgeron, Thomas, additional

Published
2011
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17. Identification of Pathway-Biased and Deleterious Melatonin Receptor Mutants in Autism Spectrum Disorders and in the General Population

Author

Chaste, Pauline, primary, Clement, Nathalie, additional, Mercati, Oriane, additional, Guillaume, Jean-Luc, additional, Delorme, Richard, additional, Botros, Hany Goubran, additional, Pagan, Cécile, additional, Périvier, Samuel, additional, Scheid, Isabelle, additional, Nygren, Gudrun, additional, Anckarsäter, Henrik, additional, Rastam, Maria, additional, Ståhlberg, Ola, additional, Gillberg, Carina, additional, Serrano, Emilie, additional, Lemière, Nathalie, additional, Launay, Jean Marie, additional, Mouren-Simeoni, Marie Christine, additional, Leboyer, Marion, additional, Gillberg, Christopher, additional, Jockers, Ralf, additional, and Bourgeron, Thomas, additional

Published
2010
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18. Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway.

Author

Botros, Hany Goubran, Legrand, Pierre, Pagan, Cecile, Bondet, Vincent, Weber, Patrick, Ben‐Abdallah, Mariem, Lemière, Nathalie, Huguet, Guillaume, Bellalou, Jacques, Maronde, Erik, Beguin, Pierre, Haouz, Ahmed, Shepard, William, and Bourgeron, Thomas

Subjects
METHYLTRANSFERASES, ACETYL compounds, CRYSTAL structure, HUMAN genetic variation, ENZYMOLOGY, BIOSYNTHESIS
Abstract

Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C-terminal domain, which is typical of other SAM-dependent O-methyltransferases, and an N-terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3-dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans. [ABSTRACT FROM AUTHOR]

Published
2013
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