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. 2000 Jun;37(6):428–433. doi: 10.1136/jmg.37.6.428

Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome

L Potocki 1, D Glaze 1, D Tan 1, S Park 1, C Kashork 1, L Shaffer 1, R Reiter 1, J Lupski 1
PMCID: PMC1734604  PMID: 10851253

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 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.
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 haploinsufficient 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.


Keywords: melatonin; circadian rhythms; Smith-Magenis syndrome; COPS3

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Selected References

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  1. Aldhous M. E., Arendt J. Radioimmunoassay for 6-sulphatoxymelatonin in urine using an iodinated tracer. Ann Clin Biochem. 1988 May;25(Pt 3):298–303. doi: 10.1177/000456328802500319. [DOI] [PubMed] [Google Scholar]
  2. Arendt J., Bojkowski C., Franey C., Wright J., Marks V. Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab. 1985 Jun;60(6):1166–1173. doi: 10.1210/jcem-60-6-1166. [DOI] [PubMed] [Google Scholar]
  3. Arendt J., Middleton B., Stone B., Skene D. Complex effects of melatonin: evidence for photoperiodic responses in humans? Sleep. 1999 Aug 1;22(5):625–635. doi: 10.1093/sleep/22.5.625. [DOI] [PubMed] [Google Scholar]
  4. Brzezinski A. Melatonin in humans. N Engl J Med. 1997 Jan 16;336(3):186–195. doi: 10.1056/NEJM199701163360306. [DOI] [PubMed] [Google Scholar]
  5. Chamovitz D. A., Wei N., Osterlund M. T., von Arnim A. G., Staub J. M., Matsui M., Deng X. W. The COP9 complex, a novel multisubunit nuclear regulator involved in light control of a plant developmental switch. Cell. 1996 Jul 12;86(1):115–121. doi: 10.1016/s0092-8674(00)80082-3. [DOI] [PubMed] [Google Scholar]
  6. Chen K. S., Gunaratne P. H., Hoheisel J. D., Young I. G., Miklos G. L., Greenberg F., Shaffer L. G., Campbell H. D., Lupski J. R. The human homologue of the Drosophila melanogaster flightless-I gene (flil) maps within the Smith-Magenis microdeletion critical region in 17p11.2. Am J Hum Genet. 1995 Jan;56(1):175–182. [PMC free article] [PubMed] [Google Scholar]
  7. Chen K. S., Manian P., Koeuth T., Potocki L., Zhao Q., Chinault A. C., Lee C. C., Lupski J. R. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat Genet. 1997 Oct;17(2):154–163. doi: 10.1038/ng1097-154. [DOI] [PubMed] [Google Scholar]
  8. Dawson D., van den Heuvel C. J. Integrating the actions of melatonin on human physiology. Ann Med. 1998 Feb;30(1):95–102. doi: 10.3109/07853899808999390. [DOI] [PubMed] [Google Scholar]
  9. Greenberg F., Guzzetta V., Montes de Oca-Luna R., Magenis R. E., Smith A. C., Richter S. F., Kondo I., Dobyns W. B., Patel P. I., Lupski J. R. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am J Hum Genet. 1991 Dec;49(6):1207–1218. [PMC free article] [PubMed] [Google Scholar]
  10. Greenberg F., Lewis R. A., Potocki L., Glaze D., Parke J., Killian J., Murphy M. A., Williamson D., Brown F., Dutton R. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2) Am J Med Genet. 1996 Mar 29;62(3):247–254. doi: 10.1002/(SICI)1096-8628(19960329)62:3<247::AID-AJMG9>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  11. Juyal R. C., Figuera L. E., Hauge X., Elsea S. H., Lupski J. R., Greenberg F., Baldini A., Patel P. I. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients. Am J Hum Genet. 1996 May;58(5):998–1007. [PMC free article] [PubMed] [Google Scholar]
  12. Park J. P., Moeschler J. B., Davies W. S., Patel P. I., Mohandas T. K. Smith-Magenis syndrome resulting from a de novo direct insertion of proximal 17q into 17p11.2. Am J Med Genet. 1998 Apr 28;77(1):23–27. [PubMed] [Google Scholar]
  13. Pentao L., Wise C. A., Chinault A. C., Patel P. I., Lupski J. R. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nat Genet. 1992 Dec;2(4):292–300. doi: 10.1038/ng1292-292. [DOI] [PubMed] [Google Scholar]
  14. Potocki L., Chen K. S., Lupski J. R. Subunit 3 of the COP9 signal transduction complex is conserved from plants to humans and maps within the smith-magenis syndrome critical region in 17p11.2. Genomics. 1999 Apr 1;57(1):180–182. doi: 10.1006/geno.1998.5748. [DOI] [PubMed] [Google Scholar]
  15. Reiter R. J., Barlow-Walden L., Poeggeler B., Heiden S. M., Clayton R. J. Twenty-four hour urinary excretion of 6-hydroxymelatonin sulfate in Down syndrome subjects. J Pineal Res. 1996 Jan;20(1):45–50. doi: 10.1111/j.1600-079x.1996.tb00238.x. [DOI] [PubMed] [Google Scholar]
  16. Reiter R. J. Melatonin and human reproduction. Ann Med. 1998 Feb;30(1):103–108. doi: 10.3109/07853899808999391. [DOI] [PubMed] [Google Scholar]
  17. Reiter R. J. Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol. 1998 Oct;56(3):359–384. doi: 10.1016/s0301-0082(98)00052-5. [DOI] [PubMed] [Google Scholar]
  18. Reiter R. J. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev. 1991 May;12(2):151–180. doi: 10.1210/edrv-12-2-151. [DOI] [PubMed] [Google Scholar]
  19. Reiter R. J. The melatonin rhythm: both a clock and a calendar. Experientia. 1993 Aug 15;49(8):654–664. doi: 10.1007/BF01923947. [DOI] [PubMed] [Google Scholar]
  20. Roa B. B., Greenberg F., Gunaratne P., Sauer C. M., Lubinsky M. S., Kozma C., Meck J. M., Magenis R. E., Shaffer L. G., Lupski J. R. Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie-Tooth type-1 neuropathy. Hum Genet. 1996 May;97(5):642–649. [PubMed] [Google Scholar]
  21. Schmickel R. D. Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr. 1986 Aug;109(2):231–241. doi: 10.1016/s0022-3476(86)80377-8. [DOI] [PubMed] [Google Scholar]
  22. Shaffer L. G., Kennedy G. M., Spikes A. S., Lupski J. R. Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. Am J Med Genet. 1997 Mar 31;69(3):325–331. [PubMed] [Google Scholar]
  23. Smith A. C., Dykens E., Greenberg F. Sleep disturbance in Smith-Magenis syndrome (del 17 p11.2). Am J Med Genet. 1998 Mar 28;81(2):186–191. [PubMed] [Google Scholar]
  24. Vakkuri O., Leppäluoto J., Vuolteenaho O. Development and validation of a melatonin radioimmunoassay using radioiodinated melatonin as tracer. Acta Endocrinol (Copenh) 1984 Jun;106(2):152–157. doi: 10.1530/acta.0.1060152. [DOI] [PubMed] [Google Scholar]
  25. Wei N., Tsuge T., Serino G., Dohmae N., Takio K., Matsui M., Deng X. W. The COP9 complex is conserved between plants and mammals and is related to the 26S proteasome regulatory complex. 1998 Jul 30-Aug 13Curr Biol. 8(16):919–922. doi: 10.1016/s0960-9822(07)00372-7. [DOI] [PubMed] [Google Scholar]
  26. Zhao Q., Chen K. S., Bejjani B. A., Lupski J. R. Cloning, genomic structure, and expression of mouse ring finger protein gene Znf179. Genomics. 1998 May 1;49(3):394–400. doi: 10.1006/geno.1998.5285. [DOI] [PubMed] [Google Scholar]
  27. Zhao Z., Lee C. C., Jiralerspong S., Juyal R. C., Lu F., Baldini A., Greenberg F., Caskey C. T., Patel P. I. The gene for a human microfibril-associated glycoprotein is commonly deleted in Smith-Magenis syndrome patients. Hum Mol Genet. 1995 Apr;4(4):589–597. doi: 10.1093/hmg/4.4.589. [DOI] [PubMed] [Google Scholar]

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