Abnormal melatonin synthesis in autism spectrum disorders.

Jonas Melke (1) , Hany Goubran-Botros (1) , Pauline Chaste (1) , Catalina Betancur (2) , Gudrun Nygren (3) , Henrik Anckarsäter (3, 4) , Maria Rastam (3) , Ola Ståhlberg (3) , I. Carina Gillberg (3) , Richard Delorme (1) , Nadia Chabane (5) , Marie-Christine Mouren-Simeoni (5) , Fabien Fauchereau (1) , Christelle M. Durand (1) , Fabien Chevalier (1) , Xavier Drouot (6) , Corinne Collet (7) , Jean-Marie Launay (7) , Marion Leboyer (2, 8) , Christopher Gillberg (3, 9) , Thomas Bourgeron (1, 10)

1 Génétique Humaine et Fonctions Cognitives
2 Neurobiologie et Psychiatrie
3 Department of Child and Adolescent Psychiatry
4 Institute of Clinical Sciences
5 Service de psychopathologie de l'enfant et de l'adolescent
6 Service de physiologie, explorations fonctionnelles [Mondor]
7 Service de Biochimie
8 Service de psychiatrie
9 Saint George's Hospital Medical School
10 UPD7 - Université Paris Diderot - Paris 7

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.Molecular Psychiatry (2008) 13, 90-98; doi:10.1038/sj.mp.4002016; published online 15 May 2007.

Mots clés: autism; melatonin; circadian rhythm; sleep; HIOMT; ASMT

Domaines: Génétique

Jonas Melke, Hany Goubran-Botros, Pauline Chaste, Catalina Betancur, Gudrun Nygren, et al.. Abnormal melatonin synthesis in autism spectrum disorders.. Molecular Psychiatry, 2008, 13 (1), pp.90-8. ⟨10.1038/sj.mp.4002016⟩. ⟨inserm-00166901⟩