bourgeron.qxp 24/6/08 04:43 Page 61
SHANK3 Mutations and 22q13 Chromosomal Rearrangements in Autism Spectrum Disorders
spines, weaker synaptic transmission, increased anxiety-related
behaviour and impaired contextual fear memory, but show enhanced
spatial learning.
33
Editor’s Recommendation
Conclusion Abnormal Melatonin Synthesis in Autism
We have shown that recent studies on the genetics and function of the Spectrum Disorders
proteins involved in the establishment of synapses provide a better view
of the susceptibility to ASD. The exact types of synaptic alterations Melke J, et al., Mol Psychiatry, 2008;13:90–98.
involved in the appearance of autistic traits in patients with SHANK3
mutations remain unclear, however. Furthermore, mutations within the
This study sequenced all ASMT exons and promoters in individuals
NLGN–NRXN–SHANK pathway differ greatly from one individual to
with autism spectrum disorders (ASDs) (n=250) and compared the
another, even if they carry identical or similar mutations, and the
allelic frequencies with controls (n=255). Non-conservative
heterogeneity in clinical symptoms may indicate that the NLGN–
variations of the ASMT gene were identified, including a splicing
NRXN–SHANK pathway is modulated by other genetic/epigenetic and/or
mutation present in two families with ASDs, but not in controls.
environmental factors. Among these factors, we have recently proposed
that abnormalities in circadian rhythms might greatly increase the risk as
Two polymorphisms located in the promoter (rs4446909 and
well as the severity of the disorder.
34
Therefore, one of the current
rs5989681) were more frequent in ASDs compared with controls
challenges for genetic counselling and therapies for ASD is to identify (p=0.0006) and were associated with a dramatic decrease in
the major pathways related to this condition and to understand how
ASMT transcripts in blood cell lines (p=2x10
-10
). Biochemical
these pathways could be modulated. ■
analyses performed on blood platelets and/or cultured cells
revealed a highly significant decrease in ASMT activity (p=2x10
-12
)
Acknowledgements
and melatonin level (p=3x10
-11
) in individuals with ASDs. Low
We would like to thank Roberto Toro for helpful discussions and
melatonin level, caused by a primary deficit in ASMT activity, may
comments on the manuscript. This work was supported by the Pasteur
Institute, INSERM, Assistance Publique-Hôpitaux de Paris, Fondation
therefore be a risk factor for ASDs. Results also suggest ASMT as
France Télécom, Cure Autism Now, Fondation de France, Fondation
a susceptibility gene for ASDs and underscore the role of
Biomédicale de la Mairie de Paris, Fondation pour la Recherche
melatonin in human cognition and behaviour. ■
Médicale, EUSynapse European Commission FP6, AUTISM MOLGEN
European Commission FP6 and ENI-NET European Commission FP6.
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