Abnormal melatonin synthesis in autism spectrum disorders.

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Melatonin, a key circadian rhythm regulator, is deficient in individuals with autism spectrum disorders (ASD).
• The precise cause of melatonin deficit in ASD remained unclear.
• The ASMT gene, crucial for melatonin synthesis, is located on a region prone to deletion in some ASD individuals.

Purpose of the Study:

• To investigate the role of the ASMT gene in melatonin deficiency in ASD.
• To identify genetic variations in ASMT and their association with ASD.
• To assess ASMT activity and melatonin levels in individuals with ASD.

Main Methods:

• Sequencing of ASMT exons and promoters in ASD patients (n=250) and controls (n=255).
• Comparison of allelic frequencies and identification of genetic variations.
• Biochemical analyses of ASMT activity and melatonin levels in blood samples and cell lines.

Main Results:

• Identified non-conservative ASMT variations, including a splicing mutation in ASD families.
• Found specific ASMT promoter polymorphisms (rs4446909, rs5989681) more frequent in ASD.
• Observed significantly decreased ASMT transcripts, ASMT activity, and melatonin levels in individuals with ASD.

Conclusions:

• Reduced ASMT activity leading to low melatonin levels is a risk factor for ASD.
• ASMT is implicated as a susceptibility gene for autism spectrum disorders.
• Melatonin plays a critical role in human cognition and behavior, with implications for ASD pathogenesis.