title: Abnormal melatonin synthesis in autism spectrum disorders.
abstract: Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 x 10(-12)) and melatonin level (P=3 x 10(-11)) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.
authors.affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Melke
authors.forename: H
authors.initials: H
authors.lastname: Goubran Botros
authors.forename: P
authors.initials: P
authors.lastname: Chaste
authors.forename: C
authors.initials: C
authors.lastname: Betancur
authors.forename: G
authors.initials: G
authors.lastname: Nygren
authors.forename: H
authors.initials: H
authors.lastname: Anckarsäter
authors.forename: M
authors.initials: M
authors.lastname: Rastam
authors.forename: O
authors.initials: O
authors.lastname: Ståhlberg
authors.forename: I C
authors.initials: IC
authors.lastname: Gillberg
authors.forename: R
authors.initials: R
authors.lastname: Delorme
authors.forename: N
authors.initials: N
authors.lastname: Chabane
authors.forename: M-C
authors.initials: MC
authors.lastname: Mouren-Simeoni
authors.forename: F
authors.initials: F
authors.lastname: Fauchereau
authors.forename: C M
authors.initials: CM
authors.lastname: Durand
authors.forename: F
authors.initials: F
authors.lastname: Chevalier
authors.forename: X
authors.initials: X
authors.lastname: Drouot
authors.forename: C
authors.initials: C
authors.lastname: Collet
authors.forename: J-M
authors.initials: JM
authors.lastname: Launay
authors.forename: M
authors.initials: M
authors.lastname: Leboyer
authors.forename: C
authors.initials: C
authors.lastname: Gillberg
authors.forename: T
authors.initials: T
authors.lastname: Bourgeron
mesh_terms: D000121:Acetylserotonin O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D008550:Melatonin / Q000096:biosynthesis* / Q000378:metabolism; D008875:Middle Aged; D010375:Pedigree; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012016:Reference Values
chemical_list: C523771:ASMT protein, human; D000121:Acetylserotonin O-Methyltransferase; D008550:Melatonin