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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 × 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.

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References

  1. Axelrod J . The pineal gland: a neurochemical transducer. Science 1974; 184: 1341–1348.

    Article  CAS  Google Scholar 

  2. Brzezinski A . Melatonin in humans. N Engl J Med 1997; 336: 186–195.

    Article  CAS  Google Scholar 

  3. Arendt J . Melatonin, circadian rhythms, and sleep. N Engl J Med 2000; 343: 1114–1116.

    Article  CAS  Google Scholar 

  4. Saper CB, Scammell TE, Lu J . Hypothalamic regulation of sleep and circadian rhythms. Nature 2005; 437: 1257–1263.

    Article  CAS  Google Scholar 

  5. Simonneaux V, Ribelayga C . Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters. Pharmacol Rev 2003; 55: 325–395.

    Article  CAS  Google Scholar 

  6. Hallam KT, Olver JS, Chambers V, Begg DP, McGrath C, Norman TR . The heritability of melatonin secretion and sensitivity to bright nocturnal light in twins. Psychoneuroendocrinology 2006; 31: 867–875.

    Article  CAS  Google Scholar 

  7. Liu C, Weaver DR, Jin X, Shearman LP, Pieschl RL, Gribkoff VK et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 1997; 19: 91–102.

    Article  CAS  Google Scholar 

  8. Wan Q, Man HY, Liu F, Braunton J, Niznik HB, Pang SF et al. Differential modulation of GABAA receptor function by Mel1a and Mel1b receptors. Nat Neurosci 1999; 2: 401–403.

    Article  CAS  Google Scholar 

  9. El-Sherif Y, Tesoriero J, Hogan MV, Wieraszko A . Melatonin regulates neuronal plasticity in the hippocampus. J Neurosci Res 2003; 72: 454–460.

    Article  CAS  Google Scholar 

  10. von Gall C, Garabette ML, Kell CA, Frenzel S, Dehghani F, Schumm-Draeger PM et al. Rhythmic gene expression in pituitary depends on heterologous sensitization by the neurohormone melatonin. Nat Neurosci 2002; 5: 234–238.

    Article  CAS  Google Scholar 

  11. Jansen R, Metzdorf R, van der Roest M, Fusani L, ter Maat A, Gahr M . Melatonin affects the temporal organization of the song of the zebra finch. FASEB J 2005; 19: 848–850.

    Article  CAS  Google Scholar 

  12. Smith AC, Dykens E, Greenberg F . Behavioral phenotype of Smith-Magenis syndrome (del 17p11.2). Am J Med Genet 1998; 81: 179–185.

    Article  CAS  Google Scholar 

  13. Nir I, Meir D, Zilber N, Knobler H, Hadjez J, Lerner Y . Brief report: circadian melatonin, thyroid-stimulating hormone, prolactin, and cortisol levels in serum of young adults with autism. J Autism Dev Disord 1995; 25: 641–654.

    Article  CAS  Google Scholar 

  14. Kulman G, Lissoni P, Rovelli F, Roselli MG, Brivio F, Sequeri P . Evidence of pineal endocrine hypofunction in autistic children. Neuroendocrinol Lett 2000; 21: 31–34.

    PubMed  Google Scholar 

  15. Tordjman S, Anderson GM, Pichard N, Charbuy H, Touitou Y . Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder. Biol Psychiatry 2005; 57: 134–138.

    Article  CAS  Google Scholar 

  16. (APA) APA. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. APA: Washington, DC, 1994.

  17. Baird G, Simonoff E, Pickles A, Chandler S, Loucas T, Meldrum D et al. Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 2006; 368: 210–215.

    Article  Google Scholar 

  18. Chakrabarti S, Fombonne E . Pervasive developmental disorders in preschool children: confirmation of high prevalence. Am J Psychiatry 2005; 162: 1133–1141.

    Article  Google Scholar 

  19. Veenstra-VanderWeele J, Cook EH . Molecular genetics of autism spectrum disorder. Mol Psychiatry 2004; 9: 819–832.

    Article  CAS  Google Scholar 

  20. Persico AM, Bourgeron T . Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 2006; 29: 349–358.

    Article  CAS  Google Scholar 

  21. Vorstman JA, Staal WG, van Daalen E, van Engeland H, Hochstenbach PF, Franke L . Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry 2006; 11: 1, 18–28.

    Article  CAS  Google Scholar 

  22. Thomas NS, Sharp AJ, Browne CE, Skuse D, Hardie C, Dennis NR . Xp deletions associated with autism in three females. Hum Genet 1999; 104: 43–48.

    Article  CAS  Google Scholar 

  23. Yi H, Donohue SJ, Klein DC, McBride OW . Localization of the hydroxyindole-O-methyltransferase gene to the pseudoautosomal region: implications for mapping of psychiatric disorders. Hum Mol Genet 1993; 2: 127–131.

    Article  Google Scholar 

  24. Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ . Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters. J Biol Chem 1994; 269: 31969–31977.

    CAS  PubMed  Google Scholar 

  25. Lord C, Rutter M, Le Couteur A . Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994; 24: 659–685.

    Article  CAS  Google Scholar 

  26. Wing L, Leekam SR, Libby SJ, Gould J, Larcombe M . The diagnostic interview for social and communication disorders: background, inter-rater reliability and clinical use. J Child Psychol Psychiatry 2002; 43: 307–325.

    Article  Google Scholar 

  27. Gillberg C, Rastam M, Wentz E . The Asperger Syndrome (and high-functioning autism) Diagnostic Interview (ASDI): a preliminary study of a new structured clinical interview. Autism 2001; 5: 57–66.

    Article  CAS  Google Scholar 

  28. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  29. Horvath S, Xu X, Laird NM . The family based association test method: strategies for studying general genotype--phenotype associations. Eur J Hum Genet 2001; 9: 301–306.

    Article  CAS  Google Scholar 

  30. Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM . Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 2004; 26: 61–69.

    Article  Google Scholar 

  31. Axelrod J, Wurtman RJ, Snyder SH . Control of hydroxyindole O-methyltransferase activity in the rat pineal gland by environmental lighting. J Biol Chem 1965; 240: 949–954.

    CAS  PubMed  Google Scholar 

  32. Finocchiaro LM, Nahmod VE, Launay JM . Melatonin biosynthesis and metabolism in peripheral blood mononuclear leucocytes. Biochem J 1991; 280: 727–731.

    Article  CAS  Google Scholar 

  33. Leboyer M, Philippe A, Bouvard M, Guilloud-Bataille M, Bondoux D, Tabuteau F et al. Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives. Biol Psychiatry 1999; 45: 158–163.

    Article  CAS  Google Scholar 

  34. Limoges E, Mottron L, Bolduc C, Berthiaume C, Godbout R . Atypical sleep architecture and the autism phenotype. Brain 2005; 128 (Part 5): 1049–1061.

    Article  Google Scholar 

  35. Wiggs L, Stores G . Sleep patterns and sleep disorders in children with autistic spectrum disorders: insights using parent report and actigraphy. Dev Med Child Neurol 2004; 46: 372–380.

    Article  Google Scholar 

  36. Richdale AL, Prior MR . The sleep/wake rhythm in children with autism. Eur Child Adolesc Psychiatry 1995; 4: 175–186.

    Article  CAS  Google Scholar 

  37. Hayashi E . Effect of melatonin on sleep-wake rhythm: the sleep diary of an autistic male. Psychiatry Clin Neurosci 2000; 54: 383–384.

    Article  CAS  Google Scholar 

  38. Segawa M . Epochs of development of the sleep–wake cycle reflect the modulation of the higher cortical function particular for each epoch. Sleep Biol Rhythms 2006; 4: 4–15.

    Article  Google Scholar 

  39. Wang LM, Suthana NA, Chaudhury D, Weaver DR, Colwell CS . Melatonin inhibits hippocampal long-term potentiation. Eur J Neurosci 2005; 22: 2231–2237.

    Article  Google Scholar 

  40. Larson J, Jessen RE, Uz T, Arslan AD, Kurtuncu M, Imbesi M et al. Impaired hippocampal long-term potentiation in melatonin MT(2) receptor-deficient mice. Neurosci Lett 2006; 393: 23–26.

    Article  CAS  Google Scholar 

  41. Belmonte MK, Bourgeron T . Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat Neurosci 2006; 9: 1221–1225.

    Article  CAS  Google Scholar 

  42. Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003; 34: 27–29.

    Article  CAS  Google Scholar 

  43. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 2006; 39: 25–27.

    Article  Google Scholar 

  44. Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007; 39: 319–328.

    Article  CAS  Google Scholar 

  45. Garstang J, Wallis M . Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child Care Health Dev 2006; 32: 585–589.

    Article  CAS  Google Scholar 

  46. Giannotti F, Cortesi F, Cerquiglini A, Bernabei P . An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord 2006; 36: 741–752.

    Article  CAS  Google Scholar 

  47. Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG . Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study. Eur J Pediatr 2003; 162: 554–555.

    Article  Google Scholar 

  48. Malow BA . Sleep disorders, epilepsy, and autism. Ment Retard Dev Disabil Res Rev 2004; 10: 122–125.

    Article  Google Scholar 

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Acknowledgements

We thank the patients and their families for participating in this study. We also thank the DNA and cell bank of INSERM U679 (IFR des Neurosciences, Hôpital Pitié-Salpêtrière); the Centre d'Investigations Cliniques, Hôpital Robert Debré for obtaining and processing the samples from the French families; C Bouchier and S Duthoy for the use of sequencing facilities at the Génopole Pasteur; A Hchikat, L Margarit and G Rouffet for technical assistance; and Luis Barietos, Jean-Pierre Hardelin, Ken McElreavey, Lluis Quintana-Murci and David Skuse for reading the manuscript and making helpful comments. This work was supported by the Pasteur Institute, INSERM, Assistance Publique-Hôpitaux de Paris, FP6 AUTISM MOLGEN, FP6 EUSynapse, Fondation France Télécom, Cure Autism Now, Fondation de France, Fondation biomédicale de la Mairie de Paris, Fondation pour la Recherche Médicale, Fondation NRJ and the Swedish Science Council.

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Correspondence to T Bourgeron.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Melke, J., Goubran Botros, H., Chaste, P. et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry 13, 90–98 (2008). https://doi.org/10.1038/sj.mp.4002016

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