Abstract
Context: Smith-Magenis syndrome (SMS) is associated with sleep disturbances and disrupted melatonin production. Objectives: The study aimed to ascertain whether the sleep and melatonin production anomalies in SMS patients may be due to an alteration of the molecular mechanism of the circadian clock.
Subjects and Methods: Five SMS patients (3-17 yr old) and five healthy age-matched control subjects were involved in the study. Saliva and buccal scrub samples were collected every 4 h during a 24-h period.
Daily profiles of melatonin were determined in saliva using a direct double-antibody radioimmunoassay. Daily profiles of clock gene mRNA levels (Per1, Per2, and Rev-erb alpha) were determined in buccal scrub samples by RT-PCR.
Results: In controls, melatonin levels were elevated during the nighttime and very low during the daytime. Daily profiles of clock genes, Per1, Per2, and Rev-erb alpha, mRNA levels in buccal mucosa exhibited significant and mutually synchronized circadian variations (Per1 and Rev-erb alpha : P < 0.001; Per2: P < 0.05); the mRNA levels were elevated during the daytime and decreased during the nighttime.
In SMS patients, melatonin profiles were significantly altered compared with controls, being phase reversed, phase advanced, depressed, or abolished. Only Per1 and Rev-erb alpha mRNA profiles exhibited significant circadian rhythms (P < 0.05); the Per2 expression exhibited high variability, and the profile was out of phase with the other clock genes.
Conclusion: Our findings suggest that the anomalies in melatonin profiles of SMS patients might be due to a disturbance of the molecular circadian clockwork. (J Clin Endocrinol Metab 97: E312-E318, 2012)