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a Department
of Molecular and Human Genetics, Baylor College of Medicine and Texas
Children's Hospital, One Baylor Plaza, Room 609E, Houston, TX 77030, USA, b Department of
Pediatrics, Baylor College of Medicine and Texas Children's Hospital,
Houston, TX 77030, USA, c Department of Neurology, Baylor College of
Medicine and Texas Children's Hospital, Houston, TX 77030, USA, d Department
of Structural and Cellular Biology, University of Texas Health Science
Center, San Antonio, TX, USA
Correspondence to: Dr Lupski, jlupski{at}bcm.tmc.edu
Revised version received 13 March 2000;
Accepted for publication 21 March
2000
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 haploinsufficient 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. Haploinsufficiency 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.
METHODSUrinary 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.
RESULTSAll 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 haploinsufficient for
COPS3.
CONCLUSIONSOur 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.
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