title: Identification of pathway-biased and deleterious melatonin receptor mutants in autism spectrum disorders and in the general population.
abstract: 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.
authors.affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chaste
authors.forename: Nathalie
authors.initials: N
authors.lastname: Clement
authors.forename: Oriane
authors.initials: O
authors.lastname: Mercati
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Guillaume
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.forename: Hany Goubran
authors.initials: HG
authors.lastname: Botros
authors.forename: Cécile
authors.initials: C
authors.lastname: Pagan
authors.forename: Samuel
authors.initials: S
authors.lastname: Périvier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Scheid
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nygren
authors.forename: Henrik
authors.initials: H
authors.lastname: Anckarsäter
authors.forename: Maria
authors.initials: M
authors.lastname: Rastam
authors.forename: Ola
authors.initials: O
authors.lastname: Ståhlberg
authors.forename: Carina
authors.initials: C
authors.lastname: Gillberg
authors.forename: Emilie
authors.initials: E
authors.lastname: Serrano
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lemière
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Launay
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Mouren-Simeoni
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.forename: Christopher
authors.initials: C
authors.lastname: Gillberg
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeron
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D044122:Receptor, Melatonin, MT1 / Q000235:genetics; D044123:Receptor, Melatonin, MT2 / Q000235:genetics; D044094:Receptors, Melatonin / Q000235:genetics*
chemical_list: D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D044094:Receptors, Melatonin; D000242:Cyclic AMP; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3