Inheritance Of Narcolepsy In Canines

Unrelated narcoleptic poodles, beagles and dachshunds donated to the Stanford were bred, but none of the offspring from two primary crosses or a backcross were affected.13 Thus, it appears that in these breeds, narcolepsy seems to be sporadic and an involvement of a high penetrant single major gene is unlikely. In humans, about 95% of narcoleptic subjects are sporadic, but familial occurrences were noted in about 5% of narcoleptic subjects.14 In 1976, the Stanford Sleep Research Center received 4 affected Dobermans (including 2 littermates).4 These dogs were also bred, and it was discovered that all offspring from the 2 affected parents developed cataplexy around 2 months old. In 1978, familial narcolepsy in a Labrador Retriever was also discovered.4 Thereafter, more sporadic cases of canine narcolepsy were identified in Collies, Dachshunds, Beagles, Fox Terriers and in several mixed breeds 4.

Narcolepsy And Cataplexy

Figure 1. Cataplectic attacks in Doberman pinschers. Emotional excitations, appetizing food or playing easily elicit multiple cataplectic attacks in these animals. Most cataplexy attacks are bilateral (97.9%). Atonia initiated partially in the hind legs (79.8%), front legs (7.8%) neck/face (6.2%), or whole body/complete attacks (6.2%) Progression of attacks was also seen (49% of all attacks).92

Figure 1. Cataplectic attacks in Doberman pinschers. Emotional excitations, appetizing food or playing easily elicit multiple cataplectic attacks in these animals. Most cataplexy attacks are bilateral (97.9%). Atonia initiated partially in the hind legs (79.8%), front legs (7.8%) neck/face (6.2%), or whole body/complete attacks (6.2%) Progression of attacks was also seen (49% of all attacks).92

Genetic transmission in Dobermans and Labradors has been well established as autosomal recessive with full penetrance.4,15 Puppies born from narcoleptic Doberman

Pinscher-Labrador Retriever crosses are all affected. Thus, both breeds are likely to have mutations at the same locus, coined canarc-1.4,15 As in human cases,16 the disease onset in familial cases is earlier than in sporadic cases.13,17 In sporadic cases, the disease (cataplexy onset) begins as early as 7 weeks and as late as 7 years old,13 suggesting the

Inheritance Narcolepsy

Figure 2. Percent of Time Spent in, Mean Frequency of, and Mean Duration for Each Vigilance State of Narcoleptic and Control Canines during Daytime 6-Hour Recordings (10:00 to 16:00). (a, b) No significant difference was found in percent of time spent in each vigilance state between narcoleptic and control dogs. However, the mean duration of wake, drowsy, and deep sleep episodes were significantly shorter in the narcoleptics, suggesting a fragmentation of the vigilance states (wake and sleep) in these animals. To compensate for the influence of cataplectic episodes on wake and drowsy those episodes interrupted by the occurrence of cataplexy were excluded. (c) Mean latency (min) to each sleep stage and occurrences (number/total sessions) of cataplexy and sleep onset REM periods (SOREMPs) during the multiple sleep latency test (MSLT) in narcoleptic and control Dobermans. Drowsy and light sleep occurred in all sessions. Deep sleep, REM sleep or cataplexy (for narcoleptic dogs) occurred in some sessions, and the number of sessions where each state occurred/total number of sessions are shown in parentheses. Narcoleptic dogs exhibited cataplexy in 9 out of 100 sessions, and these events were differentiated from REM sleep episodes. Narcoleptic dogs show a significantly shorter latency to drowsy and light sleep in overall sessions. Note that narcoleptic dogs exhibited SOREMPs (i.e., REM sleep occurring within 15 min of sleep onset) significantly more often than control animals, although both narcoleptic (36.0 % of total session) and control dogs (21.7 %) showed REM sleep during the MSLT.

acquired nature of the disease in these cases. In Dobermans, affected dogs display spontaneous complete cataplexy as early as 4 weeks, but almost always by 6 months.4,17 Symptom severity increases until 5-6 months of age (with females being more affected during development), and it appears to decrease slowly and then remains stable through old age.1718

Genetic canine narcolepsy was thought to be an invaluable model in searching for narcolepsy genes, since it is possible that the canine narcolepsy gene (its equivalent or genes with a functional relationship with the canine narcolepsy gene) may also be involved in some human cases.

4. DOG LEUKOCYTE ANTIGEN (DLA) AND CANINE NARCOLEPSY

Since human narcolepsy-cataplexy is specifically associated with the HLA gene HLA DQ*0602 (and DR15 [see human narcolepsy section]), 3 populations of dogs were tested to determine if a specific dog leukocyte antigen (DLA) allele was present in affected animals as in narcoleptic humans. These included genetically-narcoleptic Doberman Pinschers and Labrador Retrievers and small breed dogs with sporadic narcolepsy. Unlike humans, narcoleptic dogs tested do not share any single DLA locus reactivity, suggesting that a specific MHC class II haplotype is not a requirement for the disease.19 In further experiments, a human HLA-DRb hybridization probe was used on DNA from narcoleptic dogs to determine whether there was an association between the DLA allele and susceptibility to narcolepsy.20 This probe detected polymorphisms in both Doberman Pinschers and Labrador Retrievers. Results of this study also excluded the possibility of a tight linkage between DLA and the canarc-1 locus in these narcoleptic dogs.20 However, it now appears that more extensive searches specifically in sporadic dogs (i.e., hypocretin ligand-deficient, see below), including other DLA regions are required to examine the involvement of the histocompatibility molecules/mechanisms in the development of narcolepsy in these animals.

5. DISCOVERY OF CANINE NARCOLEPY GENE (Canarc-1)

Screening of genetic markers, including mini satellite probes and functional candidate gene probes, revealed that canarc-1 cosegregates with a homolog of the switch region of the human immunoglobulin ^ heavy-chain gene (S^).15 The genuine S^ segments are involved in a complex somatic recombination process, allowing individual B cells to switch immunoglobulin classes upon activation (see ref. 15). Fluorescence in situ hybridization (FISH) indicates that canarc-1 is located on a different canine chromosome from the canine immunoglobulin switch loci.21 Sequence analysis of the S^-like marker indicates that the S^-like marker has high homology to the true gene but is not a functional part of the immunoglobulin switch machinery.22 Thus, positional cloning of the region where the S^-like marker is located was initiated.

After 10 years of work, canarc-1 was finally identified, and narcolepsy in Dobermans and Labradors was found to be caused by a mutation in the hypocretin receptor 2 gene (Hcrtr 2) (Fig. 3). The mutations in Dobermans and Labradors were found in the same gene, but different locus, and both mutations cause exon skipping deletions in the Hcrtr2 transcripts and the loss of function of Hcrtr 2, and thus impairs postsynaptic hypocretin neurotransmission. Therefore, it appears that these mutations occur independently in both breeds. Another mutation in Hcrtr 223 was also found in a new narcoleptic family of Dachshunds, but the reason that Hcrtr 2 mutation often occurs in canines (no human case was yet identified) is not unknown.

Mutated Narcolepsy Gene

Figure. 3. Genomic organization of the canine Hcrt 2 receptor locus. The Hcrtr 2 gene is encoded by 7 exons. Sequence of exon-intron boundary at the site for the deletion of the transcript revealed that the canine short interspersed nucleotide element (SINE) was inserted 35 bp upstream of the 5' splice donor site of the fourth encoded exon in narcoleptic Doberman pinschers. This insertion falls within the 5' flanking intronic region needed for pre-mRNA Lariat formation and proper splicing, causing exon 3 to be spliced directly to exon 5, and exon 4 to be omitted. This mRNA potentially encodes a non-functional protein with 38 amino acids deleted within the 5th transmembrane domain, followed by a frameshift and a premature stop codon at position 932 in the encoded RNA. In narcoleptic Labradors, the insertion was found 5 bp downstream of the 3' splice site of the fifth exon, and exon 5 is spliced directly to exon 7, omitting exon 6.

Almost simultaneously, along with the discovery of the canine narcolepsy gene, a report that preprohypocretin (preproorexin) knockout-mice also exhibited a narcolepsylike phenotype, including sleep fragmentation and episodes of behavioral arrest similar to cataplexy in canine narcolepsy,6 which was made by a group led by Dr. Yanagisawa. Considering how similar human and canine narcolepsy are at the phenotypic level, it was thought that abnormalities in the hypocretin system is likely to be involved in some human cases, either at the functional or the genetic level. Subsequent neurochemical screening revealed that the hypocretin ligand deficiency is indeed found in most human narcolepsy-cataplexy by CSF hypocretin measures and postmortem studies.7-9

Sleeping Sanctuary

Sleeping Sanctuary

Salvation For The Sleep Deprived The Ultimate Guide To Sleeping, Napping, Resting And  Restoring Your Energy. Of the many things that we do just instinctively and do not give much  of a thought to, sleep is probably the most prominent one. Most of us sleep only because we have to. We sleep because we cannot stay awake all 24 hours in the day.

Get My Free Ebook


Responses

  • Lotta
    What causes the mutation in the hypocretin receptor 2 gene in doberman pinscher?
    8 years ago

Post a comment