Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with Intellectual Disability

BMC Medical Genetics

Research Article

Hilde Van Esch¹  Arjan de Brouwer²  Marjolein H Willemsen²  Bregje W van Bon²  Hany Goubran Botros³  Sarah Moreno³  Richard Delorme³  Thomas Bourgeron⁴  Cecile Pagan⁵  Anne Dumaine⁶  Stéphane Jamain⁷  Marion Leboyer⁸  Frédéric Laumonnier⁹  Martine Raynaud^1,10  Andreas Tzschach^1,11  Vera Kalscheuer^1,11  Didier Lacombe^1,12  Sylvain Briault^1,13  Karine Poirier^1,14  Jamel Chelly^1,14  Jean-Marie Launay^1,15 

[1] Center for Human Genetics, University Hospitals Leuven, B-3000, Leuven, Belgium;Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France;CNRS URA 2182 "Genes, synapses et cognition", Institut Pasteur, Paris, France;Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France;CNRS URA 2182 "Genes, synapses et cognition", Institut Pasteur, Paris, France;University Denis Diderot Paris 7, Paris, France;Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France;CNRS URA 2182 "Genes, synapses et cognition", Institut Pasteur, Paris, France;University Paris Descartes, Paris, France;Inserm U 955, IMRB, Psychiatry Genetics, F-94000, Creteil, France;Inserm U 955, IMRB, Psychiatry Genetics, F-94000, Creteil, France;Foundation Fondamental, Creteil, France;Inserm U 955, IMRB, Psychiatry Genetics, F-94000, Creteil, France;Foundation Fondamental, Creteil, France;University Paris-East, Faculty of Medicine, UMR-S 955, F-94000, Creteil, France;AP-HP, Henri Mondor-Albert Chenevier Group, Department of Psychiatry, F-94000, Creteil, France;Inserm U930 "Imaging and Brain", Tours, France;University François-Rabelais, Tours, France;CNRS ERL3106, Tours, France;Inserm U930 "Imaging and Brain", Tours, France;University François-Rabelais, Tours, France;CNRS ERL3106, Tours, France;Centre Hospitalier Régional Universitaire, Service de Génétique, Tours, France;Max Planck Institute for Molecular Genetics, Department Ropers, Berlin, Germany;Service de Génétique Médicale, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France;UMR 6218, CNRS, IEM, équipe « génétique expérimentale et moléculaire », université d'Orléans, Orléans, France;Centre hospitalier régional d'Orléans, Orléans, France;University Paris Descartes, Paris, France;Institut Cochin, CNRS ULD, 8104, Paris, France;University Paris Descartes, Paris, France;Service de Biochimie, INSERM U942, Hopital Lariboisière, Assistance Publique-Hopitaux de Paris, Paris, France;

关键词: Autism Spectrum Disorder;    Autism Spectrum Disorder;    Melatonin;    Intellectual Disability;    Intellectual Disability;   

DOI  :  10.1186/1471-2350-12-17

 received in 2010-10-19, accepted in 2011-01-20,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundIntellectual disability (ID) is frequently associated with sleep disorders. Treatment with melatonin demonstrated efficacy, suggesting that, at least in a subgroup of patients, the endogenous melatonin level may not be sufficient to adequately set the sleep-wake cycles. Mutations in ASMT gene, coding the last enzyme of the melatonin pathway have been reported as a risk factor for autism spectrum disorders (ASD), which are often comorbid with ID. Thus the aim of the study was to ascertain the genetic variability of ASMT in a large cohort of patients with ID and controls.MethodsHere, we sequenced all exons of ASMT in a sample of 361 patients with ID and 440 controls. We then measured the ASMT activity in B lymphoblastoid cell lines (BLCL) of patients with ID carrying an ASMT variant and compared it to controls.ResultsWe could identify eleven variations modifying the protein sequence of ASMT (ID only: N13H, N17K, V171M, E288D; controls only: E61Q, D210G, K219R, P243L, C273S, R291Q; ID and controls: L298F) and two deleterious splice site mutations (IVS5+2T>C and IVS7+1G>T) only observed in patients with ID. We then ascertained ASMT activity in B lymphoblastoid cell lines from patients carrying the mutations and showed significantly lower enzyme activity in patients carrying mutations compared to controls (p = 0.004).ConclusionsWe could identify patients with deleterious ASMT mutations as well as decreased ASMT activity. However, this study does not support ASMT as a causative gene for ID since we observed no significant enrichment in the frequency of ASMT variants in ID compared to controls. Nevertheless, given the impact of sleep difficulties in patients with ID, melatonin supplementation might be of great benefit for a subgroup of patients with low melatonin synthesis.

【 授权许可】

Unknown   
© Pagan et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.