Circadian rhythm abnormalities of melatonin and haploinsufficiency of COPS3 in Srnith-Magenis Syndrome

Abstract

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation syndrome associated with a hemizygous deletion of chromosome band 17p 11.2. The majority of patients have the same sized deletion; however, patients with smaller and larger deletions have been described. Characteristic features of SMS include a significant sleep disturbance. Urinary excretion of 6-sulphatoxymelatonin (aMT6s)—the major hepatic metabolite of melatonin—in conjunction with 24-hour sleep studies in 28 SMS patients reveal an aberrant diurnal rhythm of aMT6s and abnormalities in quality and quantity of nocturnal and daytime sleep. These data demonstrate a disturbed circadian rhythm of melatonin and objectively document the disturbed sleep pattern in Smith-Magenis syndrome. Our findings suggest that these abnormalities may be secondary to aberrations in the production, secretion, distribution, or metabolism of melatonin. One candidate, the gene for subunit 3 (COPS3) of the COP9 signalosome is conserved from plants to humans. In plants COP9 transduces light signals into gene expression, and in humans COPS3 maps within the SMS common deletion interval. We are investigating the hypothesis that COPS3 haploinsufficiency may be responsible for the abnormal melatonin circadian rhythm in SMS.