Abnormal melatonin synthesis in autism spectrum disorders

Melke, Jonas; Botros, Hany Goubran; Chaste, Pauline; Betancur, Catalina; Nygren, Gudrun; Anckarsäter, Henrik; Råstam, Maria; Ståhlberg, Ola; Gillberg, I. Carina; Delorme, Richard; Chabane, Nadia; Mouren-Siméoni, M. C.; Fauchereau, Fabien; Durand, Christelle; Chevalier, Fabien Le; Drouot, Xavier; Collet, Corinne; Launay, J. M.; Leboyer, Marion; Gillberg, Christopher; Bourgeron, Thomas

doi:10.1038/sj.mp.4002016

Cited by 436 publications

(416 citation statements)

References 47 publications

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“…These were NOSTRIN (nitric oxide synthase trafficker), 16 GRIK2 (glutamate receptor, ionotropic, kainite 2), 17,18 RELN, 9 PRKCB1 (protein kinase C, beta), 19,20 SLC6A4 (solute carrier family 5 (neurotransmitter transporter, serotonin), member 4), 21,22 SHANK3 (SH3 and multiple ankyrin repeat domains 3) 2,23 and ASMT (acetylserotonin O-methyltransferase). 24 …”

Section: Introductionmentioning

confidence: 99%

Linkage and candidate gene studies of autism spectrum disorders in European populations

et al. 2010

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the EU Autism MOLGEN Consortium 8Over the past decade, research on the genetic variants underlying susceptibility to autism and autism spectrum disorders (ASDs) has focused on linkage and candidate gene studies. This research has implicated various chromosomal loci and genes. Candidate gene studies have proven to be particularly intractable, with many studies failing to replicate previously reported associations. In this paper, we investigate previously implicated genomic regions for a role in ASD susceptibility, using four cohorts of European ancestry. Initially, a 384 SNP Illumina GoldenGate array was used to examine linkage at six previously implicated loci. We identify linkage approaching genome-wide suggestive levels on chromosome 2 (rs2885116, MLOD¼1.89). Association analysis showed significant associations in MKL2 with ASD (rs756472, P¼4.31Â10 À5 ) and between SND1 and strict autism (rs1881084, P¼7.76Â10 À5 ) in the Finnish and Northern Dutch populations, respectively. Subsequently, we used a second 384 SNP Illumina GoldenGate array to examine the association in seven candidate genes, and evidence for association was found in RELN (rs362780, P¼0.00165). Further increasing the sample size strengthened the association with RELN (rs362780, P¼0.001) and produced a second significant result in GRIK2 (rs2518261, P¼0.008). Our results strengthen the case for a more detailed study of the role of RELN and GRIK2 in autism susceptibility, as well as identifying two new potential candidate genes, MKL2 and SND1.

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Section: Introductionmentioning

confidence: 99%

Linkage and candidate gene studies of autism spectrum disorders in European populations

et al. 2010

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“…Melatonin receptors are expressed not only in the pituitary pars tuberalis and SCN, which are crucial sites for photoperiodism and circadian rhythm, but also slightly in several hypothalamic nuclei, hippocampus, cerebral cortex, amygdala, and so on (25). Identification of the mouse Hiomt gene will provide "melatonin knockout" or "melatonin knockin" mice (e.g., melatonin-deficient MSM mice or melatonin-proficient B6J mice), which would tell us the uncharacterized functions involving melatonin such as neural development (39) and mood (40).…”

Section: Discussionmentioning

confidence: 99%

Genetic variation of melatonin productivity in laboratory mice under domestication

Kasahara

Abe²,

Mekada

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

171

161

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Melatonin is a pineal hormone produced at night; however, many strains of laboratory mice are deficient in melatonin. Strangely enough, the gene encoding HIOMT enzyme (also known as ASMT) that catalyzes the last step of melatonin synthesis is still unidentified in the house mouse (Mus musculus) despite the completion of the genome sequence. Here we report the identification of the mouse Hiomt gene, which was mapped to the pseudoautosomal region (PAR) of sex chromosomes. The gene was highly polymorphic, and nonsynonymous SNPs were found in melatonin-deficient strains. In C57BL/6 strain, there are two mutations, both of which markedly reduce protein expression. Mutability of the Hiomt likely due to a high recombination rate in the PAR could be the genomic basis for the high prevalence of melatonin deficiency. To understand the physiologic basis, we examined a wild-derived strain, MSM/Ms, which produced melatonin more under a short-day condition than a long-day condition, accompanied by increased Hiomt expression. We generated F2 intercrosses between MSM/ Ms and C57BL/6 strains and N2 backcrosses to investigate the role of melatonin productivity on the physiology of mice. Although there was no apparent effect of melatonin productivity on the circadian behaviors, testis development was significantly promoted in melatonin-deficient mice. Exogenous melatonin also had the antigonadal action in mice of a melatonin-deficient strain. These findings suggest a favorable impact of melatonin deficiency due to Hiomt mutations on domestic mice in breeding colonies.

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“…Autism has been associated with atypical sleep patterns and circadian rhythms [135]. Polymorphisms in ASMT (involved in melatonin synthesis), paralleled by reduced levels of circulating melatonin, have been reported in autism [136]. Interestingly, the eCB system also plays a role in regulating circadian rhythms [134], thus making it a putative target to examine using animal models of autism-related phenotypes.…”

Section: Suggested Roles Of the Ecb System In Autismmentioning

confidence: 99%

Endocannabinoid Signaling in Autism

et al. 2015

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Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the Bendocannabinoid (eCB) system^, a rather complex ensemble of lipid signals (Bendocannabinoids^), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.Key Words Autism spectrum disorder . endocannabinoid system . fragile X syndrome . metabolic regulation . reward system The Endocannabinoid SystemTwenty-five years after the cloning and expression of a complementary DNA that encoded a G protein-coupled receptor, named type-1 cannabinoid (CB 1 ) receptor [1], there is a good deal of information on the main components of the so-called Bendocannabinoid (eCB) system^, as well as on its role in controlling cannabinergic signaling in human health and disease [2][3][4]. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most active eCBs as yet identified, although this family of bioactive lipids includes other arachidonic acid (AA) derivatives with cannabimimetic properties (i.e., noladin ether, virodhamine, N-arachidonoyldopamine, to name but a few). The classical dogma that eCBs are synthesized and released Bon demand^upon (patho)physiological stimuli has been recently revisited on the basis of unexpected evidence for intracellular reservoirs and transporters of eCBs. These new entities have been shown to drive intracellular trafficking of eCBs, adding a new dimension to the regulation of their biological activity [5]. To date, several metabolic routes have B. Chakrabarti, A. Persico and N. Battista are equal first authors.

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Abnormal melatonin synthesis in autism spectrum disorders

Cited by 436 publications

References 47 publications

Linkage and candidate gene studies of autism spectrum disorders in European populations

Linkage and candidate gene studies of autism spectrum disorders in European populations

Genetic variation of melatonin productivity in laboratory mice under domestication

Endocannabinoid Signaling in Autism

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