In other species: domestic cat , horse , sheep

Categories: Behaviour / neurological phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 161400 (trait) , 602393 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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 (Dog) (VBO_0200004), Airedale Terrier (Dog) (VBO_0200008), Alaskan Malamute (Dog) (VBO_0200017), Beagle (Dog) (VBO_0200131), Cockapoo (Dog) (VBO_0200370), Cocker Spaniel (Dog) (VBO_0200372), Dachshund (Dog) (VBO_0200406), Doberman Pinscher (Dog) (VBO_0200442), Giant Schnauzer (Dog) (VBO_0200604), Irish Setter (Dog) (VBO_0200702), Labrador Retriever (Dog) (VBO_0200800), Mixed Breed (Dog) (VBO_0200902), Pembroke Welsh Corgi (Dog) (VBO_0200995), Poodle, Miniature (Dog) (VBO_0201051), Poodle, Standard (Dog) (VBO_0201056), Rottweiler (Dog) (VBO_0201143), Saint Bernard (Dog) (VBO_0201160), Springer Spaniel (Dog) (VBO_0201287), Wirehaired Pointing Griffon (Dog) (VBO_0201427).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: