Abnormal melatonin synthesis in autism spectrum disorders

• Published in: Molecular psychiatry Vol. 13; no. 1; pp. 90 - 98
• Main Authors: Melke, J, Goubran Botros, H, Chaste, P, Betancur, C, Nygren, G, Anckarsäter, H, Rastam, M, Ståhlberg, O, Gillberg, I C, Delorme, R, Chabane, N, Mouren-Simeoni, M-C, Fauchereau, F, Durand, C M, Chevalier, F, Drouot, X, Collet, C, Launay, J-M, Leboyer, M, Gillberg, C, Bourgeron, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2008; Nature Publishing Group; Nature Publishing Group Specialist Journals
• Subjects: Acetylserotonin O-Methyltransferase; Acetylserotonin O-Methyltransferase - genetics; Acetylserotonin O-Methyltransferase - metabolism; Adolescent; Adult; ASMT; Autism; Autistic Disorder; Autistic Disorder - enzymology; Autistic Disorder - genetics; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Biosynthesis; Case-Control Studies; Child; Child clinical studies; circadian rhythm; Circadian rhythms; Clinical Medicine; Developmental disorders; Enzymology; Female; Genetic; Genetic aspects; Genetics; Health aspects; HIOMT; Humans; Infantile autism; Klinisk medicin; Life Sciences; Male; Matched-Pair Analysis; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Melatonin; Melatonin - biosynthesis; Melatonin - metabolism; Metabolism; Middle Aged; Neurosciences; original-article; Pedigree; Pharmacotherapy; Polymorphism; Polymorphism, Genetic; Promoter Regions; Promoter Regions, Genetic - genetics; Properties; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psykiatri; Reference Values; Risk factors; sleep; France; sleep; melatonin; HIOMT; autism; circadian rhythm; ASMT; Autism; Melatonin; Sleep; Biological rhythm; Developmental disorder; Sleep wake cycle; Circadian rhythm; Pineal hormone
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4002016

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 × 10
−10
). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (
P
=2 × 10
−12
) and melatonin level (
P
=3 × 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.