OMIA 000703-9615 : Narcolepsy in Canis lupus familiaris

In other species: domestic cat , horse , sheep

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 161400 , 602393

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1999

Species-specific symbol: canarc-1

Species-specific description: Narcolepsy is a sleep disorder characterized by shortened sleep latency and cataplexy. Genetic tests are available to detect the causative mutations in HCRTR2.

Inheritance: The disorder shows classic autosomal recessive inheritance (Foutz et al., 1979).

Mapping: By using RFLPs detectable via two comparative candidate genes, Mignon et al. (1991) were able to show that canine narcolepsy is not tightly linked to the canine MHC, but is tightly linked to the canine equivalent of the human switch region of the mu immunoglobulin heavy-chain gene (S_sub(mu)), which was later shown (by Lin et al., 1999) to be located on a section of chromosome CFA12 that is homologous to human chromosome HSA6.

Markers: Narcolepsy is tightly linked (0 cM) to the mu immunoglobulin heavy-chain gene.

Molecular basis: Armed with the mapping knowledge summarised in the Genetic mapping section above, Lin et al. (1999) performed a Herculean series of linkage and comparative physical mapping studies within a 1.8Mb region of chromosome CFA12, finally narrowed the chase down to one comparative positional candidate gene, namely HCRTR2, which "encodes a G protein–coupled receptor with high affinity for the hypocretin neuropeptides". They then reported that a "SINE insertion mutation [in the HCRTR2 gene] is the cause of narcolepsy in Dobermans". These same authors showed that the causative mutation in Labrador retrievers is a deletion of exon 6 due to a "G to A transition in the 5′ splice junction consensus sequence (position +5, exon 6–intron 6)". The work of Lin et al. (1999) was the subject of a commentary by Reilly (1999). The causative mutation in dachshunds is a G to A substitution at exon 1 of the HCRTR2 gene (Hungs et al., 2001).

Clinical features: Dogs with familial narcolepsy may show signs between 4 weeks to 6 months of age. Affected dogss are sleepy, and cannot maintain long stretches of wakefulness. Affected dogs fall asleep faster than normal dogs. Narcolepsy is neither progressive nor life-threatening (Tonokura et al., 2007). In response a positive emotional stimulus (such as food or play) affected animals experience cataplexy, which is a sudden loss of muscle tone without loss of consciousness (Tonokura et al., 2007).

During an attack of cataplexy, common first signs are buckling of both hindlimbs and drooping of the neck. The dog then collapses and is still for a period of seconds to minutes. The muscles are always flaccid during attacks. Dogs usually remain conscious and open-eyed during attacks, and are capable of following objects with their eyes. If an attack lasts for longer than a couple of minutes, the dog may fall asleep. Cataplexy can often be treated with tricyclic antidepressants such as imipramine or clomipramine (Tonokura et al., 2007). Prazosin and physostigmine increase cataplexy in narcoleptic dogs and lower hypocretin levels in normal dogs. Methamphetamine, labetalol, and phenylephrine decrease cataplexy in narcoleptic dogs and raise hypocretin levels in normal dogs (Wu et al., 2011).

Pathology: In normal dogs, hypocretin activity is reinforced by a positive feedback mechanism mediated by hypocretin-2 receptors, which is crucial to normal regulation of sleep and wakefulness (Wu et al., 2011). While affected dogs lack functional HCRTR2, they have normal hypocretin-1 receptors, normal CSF hypocretin levels, and normal numbers of hypocretin neurons (Wu et al., 2011).

Control: Relatives of affected dogs should be tested. Breeding of affected dogs or carriers is not recommended.

Genetic testing: There are tests available to detect the causative mutations in the dachshunds, Labrador retriever, and Doberman pinscher.

Breeds: Afghan Hound, Airedale, Beagle, Corgi, Dachshund, Doberman Pinscher, Giant Schnauzer, Irish Setter, Labrador Retriever, Malamute, Miniature Poodle, Rottweiler, Saint Bernard, Springer Spaniel, Standard Poodle, Wirehaired Griffon.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
HCRTR2 hypocretin (orexin) receptor 2 Canis lupus familiaris 12 NC_006594.3 (22517482..22623358) HCRTR2 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Labrador Retriever Narcolepsy HCRTR2 splicing 12 a deletion of exon 6 due to a "G to A transition in the 5′ splice junction consensus sequence (position +5, exon 6–intron 6)" 1999 10458611
Doberman Narcolepsy HCRTR2 splicing a "SINE insertion mutation [in the HCRTR2 gene] is the cause of narcolepsy in Dobermans" 1999 10458611
Dachshund Narcolepsy HCRTR2 missense CanFam3.1 12 g.22517939G>A c.160G>A p.E54K 2001 11282968 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2013 Toth, L.A., Bhargava, P. :
Animal models of sleep disorders. Comp Med 63:91-104, 2013. Pubmed reference: 23582416.
2009 Chen, L., Brown, RE., McKenna, JT., McCarley, RW. :
Animal models of narcolepsy. CNS Neurol Disord Drug Targets 8:296-308, 2009. Pubmed reference: 19689311.
2008 Mishima, K., Fujiki, N., Yoshida, Y., Sakurai, T., Honda, M., Mignot, E., Nishino, S. :
Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. Sleep 31:1119-26, 2008. Pubmed reference: 18714784.
2007 Tonokura, M., Fujita, K., Nishino, S. :
Review of pathophysiology and clinical management of narcolepsy in dogs. Vet Rec 161:375-80, 2007. Pubmed reference: 17873267.
2004 John, J., Wu, MF., Maidment, NT., Lam, HA., Boehmer, LN., Patton, M., Siegel, JM. :
Developmental changes in CSF hypocretin-1 (orexin-A) levels in normal and genetically narcoleptic Doberman pinschers. J Physiol 560:587-92, 2004. Pubmed reference: 15308685. DOI: 10.1113/jphysiol.2004.070573.
John, J., Wu, MF., Maidment, NT., Lam, HA., Boehmer, LN., Patton, M., Siegel, JM. :
Developmental changes in CSF hypocretin-1 (orexin-A) levels in normal and genetically narcoleptic Doberman pinschers. J Physiol 560:587-92, 2004.
2003 Fujiki, N., Yoshida, Y., Ripley, B., Mignot, E., Nishino, S. :
Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep 26:953-9, 2003. Pubmed reference: 14746368.
Tonokura, M., Fujita, K., Morozumi, M., Yoshida, Y., Kanbayashi, T., Nishino, S. :
Narcolepsy in a hypocretin/orexin-deficient chihuahua Veterinary Record 152:776-9, 2003. Pubmed reference: 12846289.
2002 Fujiki, N., Morris, L., Mignot, E., Nishino, S. :
Analysis of onset location, laterality and propagation of cataplexy in canine narcolepsy Psychiatry & Clinical Neurosciences 56:275-276, 2002.
Gulyani, S., Wu, M.F., Nienhuis, R., John, J., Siegel, J.M. :
Cataplexy-related neurons in the amygdala of the narcoleptic dog Neuroscience 112:355-365, 2002. Pubmed reference: 12044453.
2001 Hungs, M., Fan, J., Lin, L., Lin, X.Y., Grigoriadis, D., Maki, R.A., Mignot, E. :
Identification and functional analysis of mutations in the hypocretin (Orexin) genes of narcoleptic canines (vol 11, pg 531, 2001) Genome Research 11:919, 2001.
Hungs, M., Fan, J., Lin, L., Lin, X.Y., Maki, R.A., Mignot, E. :
Identification and functional analysis of mutations in the Hypocretin (Orexin) genes of narcoleptic canines Genome Research 11:531-539, 2001. Pubmed reference: 11282968. DOI: 10.1101/gr.161001.
Nishino, S., Fujiki, N., Ripley, B., Sakurai, E., Kato, M., Watanabe, T., Mignot, E., Yanai, K. :
Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptics dogs Neuroscience Letters 313:125-128, 2001. Pubmed reference: 11682143.
Ripley, B., Fujiki, N., Okura, M., Mignot, E., Nishino, S. :
Hypocretin levels in sporadic and familial cases of canine narcolepsy Neurobiology of Disease 8:525-534, 2001. Pubmed reference: 11442359. DOI: 10.1006/nbdi.2001.0389.
1999 Coleman, E.S. :
Canine narcolepsy and the role of the nervous system Compendium on Continuing Education for the Practicing Veterinarian 21:641-650, 1999.
Faraco, J., Lin, X., Li, R., Hinton, L., Lin, L., Mignot, E. :
Genetic studies in narcolepsy, a disorder affecting REM sleep Journal of Heredity 90:129-132, 1999. Pubmed reference: 9987919.
Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X.Y., Qiu, X.H., de, Jong, P.J., Nishino, S., Mignot, E. :
The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene Cell 98:365-376, 1999. Pubmed reference: 10458611.
Ostrander, E.A., Giniger, E. :
Let sleeping dogs lie? Nat Genet 23:3-4, 1999. Pubmed reference: 10471483. DOI: 10.1038/12591.
Reilly, C.E. :
Mutation in the hypocretin (orexin) receptor 2 gene causes canine narcolepsy Journal of Neurology 246:985-986, 1999. Pubmed reference: 10552257.
Siegel, J.M., Nienhuis, R., Gulyani, S., Ouyang, S., Wu, M.F., Mignot, E., Switzer, R.C., McMurry, G., Cornford, M. :
Neuronal degeneration in canine narcolepsy Journal of Neuroscience 19:248-257, 1999. Pubmed reference: 9870955.
1998 Cederberg, R., Nishino, S., Dement, W.C., Mignot, E. :
Breeding history of the Stanford colony of narcoleptic dogs Veterinary Record 142:31-36, 1998. Pubmed reference: 9481825.
1997 Honda, K., Riehl, J., Inoue, S., Mignot, E., Nishino, S. :
Central administration of vitamin B-12 aggravates cataplexy in canine narcolepsy Neuroreport 8:3861-3865, 1997. Pubmed reference: 9462456.
Nishino, S., Arrigoni, J., Shelton, J., Kanbayashi, T., Dement, W.C., Mignot, E. :
Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy Journal of Neuroscience 17:6401-6408, 1997. Pubmed reference: 9236248.
Nishino, S., Mignot, E. :
Pharmacological aspects of human and canine narcolepsy [Review] Progress in Neurobiology 52:27-78, 1997. Pubmed reference: 9185233.
Nishino, S., Tafti, M., Sampathkumaran, R., Dement, W.C., Mignot, E. :
Circadian distribution of rest/activity in narcoleptic and control dogs - assessment with ambulatory activity monitoring Journal of Sleep Research 6:120-127, 1997. Pubmed reference: 9377531.
Tafti, M., Nishino, S., Liao, W., Dement, W.C., Mignot, E. :
Mesopontine organization of cholinergic and catecholaminergic cell groups in the normal and narcoleptic dog Journal of Comparative Neurology 379:185-197, 1997. Pubmed reference: 9050784.
1996 Kanbayashi, T., Nishino, S., Tafti, M., Hishikawa, Y., Dement, W.C., Mignot, E. :
Thalidomide, a hypnotic with immune modulating properties, increases cataplexy in canine narcolepsy Neuroreport 7:1881-1886, 1996. Pubmed reference: 8905685.
Reid, M.S., Tafti, M., Nishino, S., Sampathkumaran, R., Siegel, J.M., Mignot, E. :
Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine Brain Research 733:83-100, 1996. Pubmed reference: 8891251.
Tafti, M., Nishino, S., Aldrich, M.S., Liao, W.N., Dement, W.C., Mignot, E. :
Major histocompatibility class II molecules in the CNS - increased microglial expression at the onset of narcolepsy in a canine model Journal of Neuroscience 16:4588-4595, 1996. Pubmed reference: 8764647.
1995 Nishino, S., Tafti, M., Reid, M.S., Shelton, J., Siegel, J.M., Dement, W.C., Mignot, E. :
Muscle atonia is triggered by cholinergic stimulation of the basal forebrain: Implication for the pathophysiology of canine narcolepsy Journal of Neuroscience 15:4806-4814, 1995. Pubmed reference: 7623112.
Nitz, D., Andersen, A., Fahringer, H., Nienhuis, R., Mignot, E., Siegel, J. :
Altered distribution of cholinergic cells in the narcoleptic dog Neuroreport 6:1521-1524, 1995. Pubmed reference: 7579139.
Shelton, J., Nishino, S., Vaught, J., Dement, W.C., Mignot, E. :
Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs Sleep 18:817-826, 1995. Pubmed reference: 8746387.
1994 Mignot, E., Bell, R.A., Rattazzi, C., Lovett, M., Grumet, F.C., Dement, W.C. :
An immunoglobulin switchlike sequence is linked with canine narcolepsy Sleep 17:S68-S76, 1994. Pubmed reference: 7701203.
Nishino, S., Reid, M.S., Dement, W.C., Mignot, E. :
Neuropharmacology and neurochemistry of canine narcolepsy Sleep 17:S84-S92, 1994. Pubmed reference: 7701206.
Reid, M.S., Siegel, J.M., Dement, W.C., Mignot, E. :
Cholinergic Mechanisms in Canine Narcolepsy .2. Acetylcholine Release in the Pontine Reticular Formation Is Enhanced During Cataplexy Neuroscience 59:523-530, 1994. Pubmed reference: 8008206.
Reid, M.S., Tafti, M., Geary, J.N., Nishino, S., Siegel, J.M., Dement, W.C., Mignot, E. :
Cholinergic Mechanisms in Canine Narcolepsy .1. Modulation of Cataplexy via Local Drug Administration into the Pontine Reticular Formation Neuroscience 59:511-522, 1994. Pubmed reference: 8008205.
Reid, M.S., Tafti, M., Nishino, S., Siegel, J.M., Dement, W.C., Mignot, E. :
Cholinergic regulation of cataplexy in canine narcolepsy in the pontine reticular formation is mediated by M2 muscarinic receptors Sleep 17:424-435, 1994. Pubmed reference: 7991953.
1993 Mignot, E.J.M., Dement, W.C. :
Narcolepsy in Animals and Man Equine Veterinary Journal 25:476-477, 1993. Pubmed reference: 8275992.
Mignot, E., Nishino, S., Sharp, L.H., Arrigoni, J., Siegel, J.M., Reid, M.S., Edgar, D.M., Ciaranello, R.D., Dement, W.C. :
Heterozygosity at the canarc-1 Locus Can Confer Susceptibility for Narcolepsy - Induction of Cataplexy in Heterozygous Asymptomatic Dogs After Administration of a Combination of Drugs Acting on Monoaminergic and Cholinergic Systems Journal of Neuroscience 13:1057-1064, 1993. Pubmed reference: 8095066.
Nishino, S., Fruhstorfer, B., Arrigoni, J., Guilleminault, C., Dement, W.C., Mignot, E. :
Further Characterization of the Alpha-1 Receptor Subtype Involved in the Control of Cataplexy in Canine Narcolepsy Journal of Pharmacology and Experimental Therapeutics 264:1079-1084, 1993. Pubmed reference: 8095546.
1992 Nishino, S., Arrigoni, J., Sharp, L.H., Shelton, J.D., Dement, W.C., Mignot, E. :
Serum Prolactin Response to a D2 Antagonist in Narcoleptic and Control Canines Sleep 15:474-475, 1992. Pubmed reference: 1455131.
Valtier, D., Dement, W.C., Mignot, E. :
Monoaminergic Uptake in Synaptosomes Prepared from Frozen Brain Tissue Samples of Normal and Narcoleptic Canines Brain Research 588:115-119, 1992. Pubmed reference: 1393561.
1991 Kornberg, M., Kornberg, L., Blanke, E., Wagner, V., Dahme, E. :
A Case of Narcolepsy in a Giant-Schnauzer Kleintierpraxis 36:271, 1991.
Mignot, E., Wang, C., Rattazzi, C., Gaiser, C., Lovett, M., Guilleminault, C., Dement, W.C., Grumet, F.C. :
Genetic Linkage of Autosomal Recessive Canine Narcolepsy with a mu-Immunoglobulin Heavy-Chain Switch-Like Segment Proceedings of the National Academy of Sciences of the United States of America 88:3475-3478, 1991. Pubmed reference: 1673032.
Nishino, S., Arrigoni, J., Valtier, D., Miller, J.D., Guilleminault, C., Dement, W.C., Mignot, E. :
Dopamine-D2 Mechanisms in Canine Narcolepsy Journal of Neuroscience 11:2666-2671, 1991. Pubmed reference: 1831837.
Renaud, A., Nishino, S., Dement, W.C., Guilleminault, C., Mignot, E. :
Effects of SDZ NVI-085, a Putative Subtype-Selective alpha1- Agonist, on Canine Cataplexy, a Disorder of Rapid Eye Movement Sleep European Journal of Pharmacology 205:11-16, 1991. Pubmed reference: 1687464.
Valtier, D., Nishino, S., Guilleminault, C., Dement, W.C., Mignot, E. :
Platelet alpha2 Adrenoceptors in Human and Canine Narcolepsy Biological Psychiatry 29:376-382, 1991. Pubmed reference: 1645207.
1990 Miller, J.D., Faull, K.F., Bowersox, S.S., Dement, W.C. :
CNS Monoamines and Their Metabolites in Canine Narcolepsy - A Replication Study Brain Research 509:169-171, 1990. Pubmed reference: 1689603.
Nishino, S., Haak, L., Shepherd, H., Guilleminault, C., Sakai, T., Dement, W.C., Mignot, E. :
Effects of Central Alpha-2 Adrenergic Compounds on Canine Narcolepsy, a Disorder of Rapid Eye Movement Sleep Journal of Pharmacology and Experimental Therapeutics 253:1145-1152, 1990. Pubmed reference: 1972749.
1989 Dean, R.R., Kilduff, T.S., Dement, W.C., Grumet, F.C. :
Narcolepsy without unique MHC class II antigen association: studies in the canine model. Hum Immunol 25:27-35, 1989. Pubmed reference: 2523880.
Fruhstorfer, B., Mignot, E., Bowersox, S., Nishino, S., Dement, W.C., Guilleminault, C. :
Canine Narcolepsy Is Associated with an Elevated Number of Alpha-2-Receptors in the Locus Coeruleus Brain Research 500:209-214, 1989. Pubmed reference: 2557958.
Geisler, P., Albert, E. :
Immunogenetics of Narcolepsy Sleep 88 :117-122, 1989.
Motoyama, M., Kilduff, T.S., Lee, B.S.M., Dement, W.C., Mcdevitt, H.O. :
Restriction Fragment Length Polymorphism in Canine Narcolepsy Immunogenetics 29:124-126, 1989. Pubmed reference: 2563354.
Vanheerden, J., Eckersley, G.N. :
Narcolepsy in a Long-Haired Dachshund Journal of the South African Veterinary Association-Tydskrif Van Die Suid-Afrikaanse Veterinere Vereniging 60:151-153, 1989.
1987 Bowersox, S.S., Kilduff, T.S., Faull, K.F., Zeller-DeAmicis, L., Dement, W.C., Ciaranello, R.D. :
Brain dopamine receptor levels elevated in canine narcolepsy. Brain Res 402:44-8, 1987. Pubmed reference: 3828787.
1986 Bowersox, S.S., Kilduff, T.S., Kaitin, K.I., Dement, W.C., Ciaranello, R.D. :
Brain benzodiazepine receptor characteristics in canine narcolepsy. Sleep 9:111-5, 1986. Pubmed reference: 3010425.
Kaitin, K.I., Kilduff, T.S., Dement, W.C. :
Sleep fragmentation in canine narcolepsy. Sleep 9:116-9, 1986. Pubmed reference: 3704433.
Kilduff, T.S., Bowersox, S.S., Kaitin, K.I., Baker, T.L., Ciaranello, R.D., Dement, W.C. :
Muscarinic cholinergic receptors and the canine model of narcolepsy. Sleep 9:102-6, 1986. Pubmed reference: 3704431.
Lammers, G.J. :
[Narcolepsy in dogs: an unusual disease]. Tijdschr Diergeneeskd 111:985-7, 1986. Pubmed reference: 3775753.
Siegel, J.M., Fahringer, H., Tomaszewski, K.S., Kaitin, K., Kilduff, T., Dement, W.C. :
Heart rate and blood pressure changes associated with cataplexy in canine narcolepsy. Sleep 9:216-21, 1986. Pubmed reference: 3704445.
1984 Boehme, R.E., Baker, T.L., Mefford, I.N., Barchas, J.D., Dement, W.C., Ciaranello, R.D. :
Narcolepsy: cholinergic receptor changes in an animal model. Life Sci 34:1825-8, 1984. Pubmed reference: 6539848.
1983 Mefford, I.N., Baker, T.L., Boehme, R., Foutz, A.S., Ciaranello, R.D., Barchas, J.D., Dement, W.C. :
Narcolepsy: biogenic amine deficits in an animal model. Science 220:629-32, 1983. Pubmed reference: 6188216.
1982 Baker, T.L., Foutz, A.S., McNerney, V., Mitler, M.M., Dement, W.C. :
Canine model of narcolepsy: genetic and developmental determinants. Exp Neurol 75:729-42, 1982. Pubmed reference: 7199479.
1980 Foutz, A.S., Mitler, M.M., Dement, W.C. :
Narcolepsy. Vet Clin North Am Small Anim Pract 10:65-80, 1980. Pubmed reference: 6996290.
1979 Foutz, A.S., Mitler, M.M., Cavalli-Sforza, L.L., Dement, W.C. :
Genetic factors in canine narcolepsy. Sleep 1:413-21, 1979. Pubmed reference: 574310.
1977 Darke, P.G., Jessen, V. :
Narcolepsy in a dog. Vet Rec 101:117-8, 1977. Pubmed reference: 562026.
Mitler, M.M., Dement, W.C. :
Sleep studies on canine narcolepsy: pattern and cycle comparisons between affected and normal dogs. Electroencephalogr Clin Neurophysiol 43:691-9, 1977. Pubmed reference: 72649.
1976 Mitler, M.M., Soave, O., Dement, W.C. :
Narcolepsy in seven dogs. J Am Vet Med Assoc 168:1036-8, 1976. Pubmed reference: 945254.
1974 Mitler, M.M., Boysen, B.G., Campbell, L., Dement, W.C. :
Narcolepsy-cataplexy in a female dog. Exp Neurol 45:332-40, 1974. Pubmed reference: 4472992.
1973 Knecht, CD., Oliver, JE., Redding, R., Selcer, R., Johnson, G. :
Narcolepsy in a dog and a cat. J Am Vet Med Assoc 162:1052-3, 1973. Pubmed reference: 4736237.

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  • Created by Frank Nicholas on 12 Sep 2005
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