Human narcolepsy gene

Details Human narcolepsy gene Human narcolepsy gene

1999-10-25

2002-06-25

Wilson, Michael C. (Department: 1632)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023100, C435S320100, C435S325000

Reexamination Certificate

active

06410712

ABSTRACT:

BACKGROUND OF THE INVENTION
Narcolepsy, a disorder which affects approximately 1 in 2,000 individuals, is characterized by daytime sleepiness, sleep fragmentation, and symptoms of abnormal rapid eye movement (REM) sleep that include cataplexy (loss of muscle tone), sleep paralysis, and hypnagogic hallucinations (Aldrich, M. S.,
Neurology
42:34-43 (1992); Siegel, J. M.,
Cell
98:409-412 (1999)). In humans, susceptibility to narcolepsy has been associated with a specific human leukocyte antigen (HLA) alleles, including DQB1*0602 (Mignot, E.,
Neurology
50:S16-22 (1998); Kadotani, H. et al.,
Genome Res
. 8:427-434 (1998); Faraco, J. et al.,
J Hered.
90:129-132 (1999)); however, attempts to verify narcolepsy as an autoimmune disorder have failed (Mignot, E. et al.,
Adv. Neuroimmunol
. 5:23-37 (1995); Mignot, E.,
Curr. Opin. Pulm. Med
. 2:482-487 (1996)). In a canine model of narcolepsy, the disorder is transmitted as an autosomal recessive trait, canarc-1 (Foutz, A.S. et al.,
Sleep
1:413-421 91979); Baker, T. L. and Dement, W. C., Brain Mechanisms of Sleep (D. J. McGinty et al., eds., New York: Raven Press, pp. 199-233 (1985)). The possibility of linkage between canare-1 and the canine major histocompatibility complex has been excluded (Mignot, E. et al.,
Proc. Natl. Acad. Sci. USA
88:3475-3478 (1991)).
A mutation in the hypocretin (orexin) receptor 2 gene in canines has been identified in narcolepsy (Lin, L. et al.,
Cell
98:365-376 (1999)); Hypocrexins/orexins (orexin-A and -B) are neuropeptides associated with regulation of food consumption (de Lecea, L., et al.,
Proc. natl. Acad. Sci. USA
95:322-327 (1998); Sakurai, T. et al.,
Cell
92:573-585 (1998)) as well as other possible functions (Peyron, C. et al.,
J Neurosci
. 18:9996-10015 (1998)). Human cDNA of receptors for orexins have been cloned (Sakurai, T. et al.,
Cell
92:573-585 (1998)), however, full human genes for the orexin receptors have not yet been identified.
Diagnosis of narcolepsy is difficult, as it is necessary to distinguish narcolepsy from other conditions such as chronic fatigue syndrome or other sleep disorders (Ambrogetti, A. and Olson, L. C.,
Med. J Aust
. 160:426-429 (1994); Aldrich, M. S.,
Neurology
50:S2-7 (1998)). Methods of diagnosing narcolepsy based on specific criteria would facilitate identification of the disease, reduce the time and expense associated with diagnosis, and expedite commencement of treatment.
SUMMARY OF THE INVENTION
As described herein, a full gene for the human hypocretin (orexin) receptor 2 (HCRTR2) has been identified. The sequence of the HCRTR2 gene as described herein is shown in
FIG. 1
(SEQ ID NO: 1). Accordingly, this invention pertains to an isolated nucleic acid molecule containing the HCRTR2 gene. The invention also relates to DNA constructs comprising the nucleic acid molecules described herein operatively linked to a regulatory sequence, and to recombinant host cells, such as bacterial cells, fingal cells, plant cells, insect cells and mammalian cells, comprising the nucleic acid molecules described herein operatively linked to a regulatory sequence. The invention also pertains to methods of diagnosing narcolepsy in an individual. The methods include detecting the presence of a mutation in the HCRTR2 gene. The invention additionally pertains to pharmaceutical compositions comprising the HCRTR2 nucleic acids of the invention. The invention further pertains to methods of treating narcolepsy, by administering HCRTR2 nucleic acids of the invention or compositions comprising the HCRTR2 nucleic acids. The methods of the invention allow the accurate diagnosis of narcolepsy and reduce the need for time-consuming and expensive sleep laboratory assessments.


REFERENCES:
patent: 0875566 (1998-11-01), None
patent: WO 96/34877 (1996-11-01), None
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Orkin et al., in Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy, Dec. 7, 1995.*
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Peyron, Christelle, et al., “A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains”,Nature Medicine, vol. 6, No. 9, pp. 991-997 (Sep. 2000).
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Aldrich, Michael S. and Reynolds, Paul, R., “Narcolepsy and the Hypocretin Receptor 2 Gene”Neuron, 625-626 (1999).
Sakurai, T., et al., “Structure and Function of Human Prepro-orexin Gene,”J. of Biol. Chem. 274(25):1771-1776 (1999).
Lin, L., et al., “The Sleep Disorder Canine Narcolepsy is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene,”Cell 98:365-376 (1999).
Chemelli, R.M. et al., “Narcolepsy in orexin Knockout Mice: Molecular Genetics of Sleep Regulation,”Cell, 98:437-451 (1999).
Siegel, J.M., “Narcolepsy: A Key Role for Hypocretins (Orexins),”Cell 98:409-412 (1999).
Sakurai, T., et al., “Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior,”Cell 92:573-585 (1998).
De Lecea, L., et al., “The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity,”Proc. Natl. Acad. Sci USA 95:322-327.
Mignot, E., et al., “Narcolepsy and immunity,”Adv. in Neuroimmunology 5:23-37 (1995).
Mignot, E., “Genetic and familial aspects of narcolepsy,”Neuro, 50(Suppl 1) :S16-S22 (1998).
Faraco, J., et al., “Genetic Studies in Narcolepsy, a Disorder Affecting REM Sleep,”Amer. Genet. Assoc. 90:129-132 (1997).
Kadotani, H., et al., “Genetic Studies in the Sleep Disorder Narcolepsy,”Genome Res. 8427-434 (1998).
Mayer, G., et al., “Segregation of HLA genes in multicase narcolepsy families,”J. Sleep Res. 7:127-133 (1998).

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