The role of melatonin 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. Individuals with autism spectrum disorders (ASD) have in several studies been found to display low melatonin levels but the underlying cause of this deficit is unknown. In a series of studies, we have investigated the possible role of melatonin-related genes iin autism spectrum disorders. First, the ASMT gene, encoding the last enzyme of melatonin synthesis, was screened for mutations and genotyped for common polymorphisms. These studies revealed both rare variants and common alleles associated with ASD. Several deleterious mutations were identified, including a splicing mutation present in two families with ASD but not in controls. Moreover, two polymorphisms located in the promoter were more frequent in ASD compared to controls (P=0.0008) and associated also with low level of ASMT transcripts (P=2x10^–10). In our next series of experiments, we have further explored the importance of genetic variation in melatonin-related genes for the development of autism. To this end, mutation screening of the ASMT gene, the three melatonin receptor genes (MTNR1A, MTNR1B and GPR50), and the enzyme converting serotonin to melatonin (AA-NAT), was performed in a cohort of 72 patients with autism. We could identify several rare variants in ASMT, including the previously reported splice-site mutation. Potentially damaging variants were also found in MTNR1A and MTNR1B. Taken together, our studies hence suggest that the ASMT-gene, and possibly also other melatonin-related genes indeed are true susceptibility genes for autism.