Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders.

• Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Psykiatri (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Psychiatry (hsv//eng)

Nyckelord

Acetylserotonin O-Methyltransferase

Genetics

Arylalkylamine N-Acetyltransferase

Genetics

Attention Deficit Disorder with Hyperactivity

Genetics

Female

Genetic Variation

Genetics

Humans

Male

Melatonin

Genetics

Nerve Tissue

Proteins

Genetics

Receptor

Melatonin

MT1

Genetics Receptors

G-Protein-Coupled

Genetics

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration of melatonin signaling has been reported in a broad range of diseases

but little is known about the genetic variability of this pathway in humans. Here

we sequenced all the genes of the melatonin pathway - AA-NAT

ASMT

MTNR1A

MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with Attention Deficit/Hyperactivity Disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD

but no significant enrichment compared with the general population. Among these variations

we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) — detected exclusively in patients with ADHD — for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.

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