Alteration of the Circadian Clock in Children with Smith-Magenis Syndrome

Dec 14, 2011The Journal of clinical endocrinology and metabolism

Changes in the body’s daily rhythm in children with Smith-Magenis syndrome

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Abstract

Melatonin profiles in Smith-Magenis syndrome patients are significantly altered compared to healthy controls.

In healthy controls, melatonin levels peak at night and are low during the day.
Clock gene mRNA levels showed significant circadian variations in controls, with Per1 and Rev-erbα exhibiting strong synchronized patterns.
In SMS patients, melatonin profiles were phase reversed, phase advanced, depressed, or abolished compared to controls.
Only Per1 and Rev-erbα mRNA levels in SMS patients showed significant circadian rhythms, while Per2 expression was highly variable and out of phase.

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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-erbα) 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-erbα, mRNA levels in buccal mucosa exhibited significant and mutually synchronized circadian variations (Per1 and Rev-erbα: 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-erbα 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.

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Alteration of the Circadian Clock in Children with Smith-Magenis Syndrome

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