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Identification of pathway-biased and deleterious melatonin receptor mutants in autism spectrum disorders and in the general population.

Journal article
Authors Pauline Chaste
Nathalie Clement
Oriane Mercati
Jean-Luc Guillaume
Richard Delorme
Hany Goubran Botros
Cécile Pagan
Samuel Périvier
Isabelle Scheid
Gudrun Nygren
Henrik Anckarsäter
Maria Råstam
Ola Ståhlberg
I Carina Gillberg
Emilie Serrano
Nathalie Lemière
Jean Marie Launay
Marie Christine Mouren-Simeoni
Marion Leboyer
Christopher Gillberg
Ralf Jockers
Thomas Bourgeron
Published in PloS One
Volume 5
Issue 7
Pages e11495
ISSN 1932-6203
Publication year 2010
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages e11495
Language en
Keywords Adult, Animals, COS Cells, Cell Line, Cercopithecus aethiops, Child, Child Development Disorders, Pervasive, Genetics, Cyclic AMP, Metabolism, Female, Humans, Male, Microscopy, Fluorescence, Mitogen-Activated Protein Kinase 1, Metabolism, Mitogen-Activated Protein Kinase 3, Metabolism, Mutation, Genetics, Receptor, Melatonin, MT1, Genetics, Receptor, Melatonin, MT2, Genetics, Receptors, Melatonin, Genetics
Subject categories Child and adolescent psychiatry


Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration of the melatonin pathway has been reported in circadian disorders, diabetes and autism spectrum disorders (ASD). However, very little is known about the genetic variability of melatonin receptors in humans. Here, we sequenced the melatonin receptor MTNR1A and MTNR1B, genes coding for MT1 and MT2 receptors, respectively, in a large panel of 941 individuals including 295 patients with ASD, 362 controls and 284 individuals from different ethnic backgrounds. We also sequenced GPR50, coding for the orphan melatonin-related receptor GPR50 in patients and controls. We identified six non-synonymous mutations for MTNR1A and ten for MTNR1B. The majority of these variations altered receptor function. Particularly interesting mutants are MT1-I49N, which is devoid of any melatonin binding and cell surface expression, and MT1-G166E and MT1-I212T, which showed severely impaired cell surface expression. Of note, several mutants possessed pathway-selective signaling properties, some preferentially inhibiting the adenylyl cyclase pathway, others preferentially activating the MAPK pathway. The prevalence of these deleterious mutations in cases and controls indicates that they do not represent major risk factor for ASD (MTNR1A case 3.6% vs controls 4.4%; MTNR1B case 4.7% vs 3% controls). Concerning GPR50, we detected a significant association between ASD and two variations, Delta502-505 and T532A, in affected males, but it did not hold up after Bonferonni correction for multiple testing. Our results represent the first functional ascertainment of melatonin receptors in humans and constitute a basis for future structure-function studies and for interpreting genetic data on the melatonin pathway in patients.

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