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Abnormal melatonin synthesis in autism spectrum disorders

Melke, Jonas; Goubran-Botros, Hany; Chaste, Pauline; Betancur, Catalina; Nygren, Guddrun; Anckarsäter, Henrik LU ; Råstam, Maria LU ; Ståhlberg, Ola; Gillberg, I Carina and D3elorme, Richard, et al. (2008) In Molecular Psychiatry 13(1). p.90-98
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 was 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... (More)
Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level was 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. (Less)
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Contribution to journal
publication status
published
subject
keywords
melatonin, autism, circadian rhythm, sleep, HIOMT, ASMT
in
Molecular Psychiatry
volume
13
issue
1
pages
90 - 98
publisher
Nature Publishing Group
external identifiers
  • wos:000251727800008
  • scopus:37249005751
ISSN
1359-4184
DOI
10.1038/sj.mp.4002016
language
English
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yes
id
df4fa54f-dc00-4f3c-9198-c9c20bf79e5d (old id 1440323)
date added to LUP
2009-07-31 15:25:07
date last changed
2017-11-19 03:36:19
@article{df4fa54f-dc00-4f3c-9198-c9c20bf79e5d,
  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 was 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.},
  author       = {Melke, Jonas and Goubran-Botros, Hany and Chaste, Pauline and Betancur, Catalina and Nygren, Guddrun and Anckarsäter, Henrik and Råstam, Maria and Ståhlberg, Ola and Gillberg, I Carina and D3elorme, Richard and Chabane, Nadia and Mouren-Simeoni, Marie-Christine and Fauchereau, Fabien and Durand, Christelle M and Chevalier, Fabien and Drouot, Xavier and Collet, Corinne and Launay, Jean-Marie and Leboyer, Marion and Gilblerg, Crhstopher and Bourgeron, Thomas and and, The Paris Study},
  issn         = {1359-4184},
  keyword      = {melatonin,autism,circadian rhythm,sleep,HIOMT,ASMT},
  language     = {eng},
  number       = {1},
  pages        = {90--98},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Psychiatry},
  title        = {Abnormal melatonin synthesis in autism spectrum disorders},
  url          = {http://dx.doi.org/10.1038/sj.mp.4002016},
  volume       = {13},
  year         = {2008},
}