Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome

Abstract

Background-Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/ mental retardation syndrome associated with a hemizygous deletion of chromosome 17, band p11.2. Characteristic features include neurobehavioural abnormalities such as aggressive and self-injurious behaviour and significant sleep disturbances. The majority of patients have a common deletion characterised at the molecular level. Physical mapping studies indicate that all patients with the common deletion are haploinsuYcient for subunit 3 of the COP9 signalosome (COPS3), which is conserved from plants to humans, and in the plant Arabidopis thaliana regulates gene transcription in response to light. HaploinsuYciency of this gene is hypothesised to be potentially involved in the sleep disturbances seen in these patients. Melatonin is a hormone secreted by the pineal gland. SMS patients are reported to have fewer sleep disturbances when given a night time dose of this sleep inducing hormone. Methods-Urinary excretion of 6-sulphatoxymelatonin (aMT6s), the major hepatic metabolite of melatonin, in 19 SMS patients were measured in conjunction with 24 hour sleep studies in 28 SMS patients. Five of the 28 patients did not have the common SMS deletion. To investigate a potential correlation of COPS3 haploinsufficiency and disturbed melatonin excretion, we performed fluorescence in situ hybridisation (FISH) using two BACs containing coding exons of COPS3. Results-All SMS patients show significant sleep disturbances when assessed by objective criteria. Abnormalities in the circadian rhythm of aMT6s were observed in all but one SMS patient. Interestingly this patient did not have the common deletion. All patients studied, including the one patient with a normal melatonin rhythm, were haploinsuYcient for COPS3. Conclusions-Our data indicate a disturbed circadian rhythm in melatonin and document the disturbed sleep pattern in Smith-Magenis syndrome. Our findings suggest that the abnormalities in the circadian rhythm of melatonin and altered sleep patterns could be secondary to aberrations in the production, secretion, distribution, or metabolism of melatonin; however, a direct role for COPS3 could not be established. (J Med Genet 2000;37:428-433)

Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]

“…19 All patients showed sleep disturbances when assessed by objective criteria using the Epworth Sleepiness Scale, total sleep time and sleep stage distribution (by polysomnography), and the Multiple Sleep Latency Test. 20 Variable features in SMS patients with del(17)(p11.2p11.2) included otolaryngological and ophthalmological abnormalities, hearing impairment, short stature, scoliosis, electroencephalogram (EEG) abnormalities, cardiac, and renal or urinary tract anomalies. Abnormalities in lipid profiles and metacarpal phalangeal profile are also variable but have been previously reported in this cohort.…”

“…1,2 The neurobehavioral features of SMS are perhaps the most distinctive characteristic of this microdeletion syndrome and include self-injurious, aggressive, and maladaptive behavior 3,19,27,28 and significant sleep disturbances. 3,20,29 We have previously described the clinical phenotype of SMS in 27 patients with del(17)(p11.2p11.2), 2 and herein have extensively characterized the clinical phenotype in another 31 SMS patients. Whereas common phenotypic features can be defined, a wide range of clinical variability exists among patients.…”

The COP9 signalosome regulates the Neurospora circadian clock by controlling the stability of the SCFFWD-1 complex

“…The clinical phenotype includes craniofacial abnormalities, developmental anomalies, development delay, mental retardation, and abnormal behavior. In addition, sleep disturbances (such as early sleep onset and early waking) and a phase shift of the circadian rhythms of melatonin were found in patients with this disease (Greenberg et al 1996;Smith et al 1998;Potocki et al 2000;De Leersnyder et al 2001), suggesting that they have an aberrant biological clock. The actual gene(s) causing these phenotypes are not known.…”

“…The Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome arising from a hemizygous deletion of human chromosome 17, band p11.2 (Greenberg et al 1996;Potocki et al 2000;De Leersnyder et al 2001). The deleted region spans 1.5-2.0 Mb of DNA, which contains ∼20 genes.…”

“…The actual gene(s) causing these phenotypes are not known. Interestingly, all patients with the common deletion are haploinsufficient for the CSN3 (COPS3) subunit of the human CSN, which was mapped to the distal portion of the SMS critical interval (Elsea et al 1999;Potocki et al 1999Potocki et al , 2000. The evolutionary conservation of CSN functions in eukaryotes and the Cold Spring Harbor Laboratory Press on May 11, 2018 -Published by genesdev.cshlp.org Downloaded from conservation of post-translational regulations of circadian clock between Neurospora and animals raises the possibility that a partial deficiency in CSN function might contribute to the circadian and sleep disturbance phenotypes in SMS patients.…”