Genetic linkage of autosomal recessive canine narcolepsy with a mu immunoglobulin heavy-chain switch-like segment.

Abstract

Identification of genes determining narcolepsy susceptibility is important not only for understanding that disorder but also for possible clues to general sleep-control mechanisms. Studies in humans reveal at least one such gene related to the major histocompatibility complex and in dog anas-yet-unmapped single, autosomal recessive gene canarc-1. Gene markers for canarc-l were therefore sought by DNA restriction fragment length polymorphisms in our colony of narcoleptic dogs. A human ,I-switch immunoglobulin probe and the enzyme Hae III identified a gene cosegregating with canarc-l in backcrossed animals (logarithm of odds scores: m = 24, Z max = 7.2 at 0 = 0%). canarc-1 was also shown not to be tightly linked with the dog major histocompatibility complex (m = 40, Z < -2 at 0 < 4.8%). These results represent the mapping of a non-major histocompatibility complex narcolepsy gene and strongly suggest involvement of the immune system in the pathophysiology of that disease. Human narcolepsy is a sleep disorder characterized by excess daytime sleepiness, disturbed nocturnal sleep, and pathological manifestations of rapid eye movement sleep, including sleeponset rapid eye movement periods, cataplexy, sleep paralysis, and hypnagogic hallucinations. The cause and the pathogenesis of narcolepsy are unclear but involve both genetic and environmental factors (1, 2). One genetic factor appears in association with the major histocompatibility complex (MHC) haplotype HLA-DRw1S (DR2), Dw2, DQw6 (DQw1), which is present in 32.8% of Caucasian and 7.7% of Asian normal controls, respectively, compared with 90-95% of Caucasian and 100%o of Asian narcoleptic patients (1,(3)(4)(5).This finding has led to the hypothesis that narcolepsy may be an autoimmune disorder or that a gene encoding an essential protein for sleep control may be located within the MHC complex. Studies to date, however, have not found evidence for or against these hypotheses. None of the general tests of immunopathology described in other autoimmune disorders (peripheral blood erythrocyte sedimentation rate, C-reactive protein, complement, immunoglobulins and lymphocyte subpopulations, cerebrospinal fluid oligoclonal bands) have been found abnormal in narcoleptic patients (6-9), DNA studies have thus far failed to reveal differences between the DRw15 and DQw6 genes of narcoleptics and those of normals (10, 11), and numerous nonimmunological genes cloned within the MHC region do not seem related to sleep.The paucity of multicase families has hindered further genetic studies. Nevertheless, sufficient patients without the DRw15 (DR2) haplotype, as well as multiplex families with disease not linked to HLA, have been reported (1, 2), strongly suggesting the existence of human non-MHC nar- MATERIALS AND METHODSBackcrosses and Diagnosis of Narcolepsy. Canine narcolepsy is an autosomal recessive disorder with full penetrance. Cataplexy can be observed spontaneously or after induction, by using the food-elicited cataplexy test (12) in all adult animals born from nar...

Segregation of HLA genes in multicase narcolepsy families

“…Compared to 12.23% in a times higher to have one or more parasomnias. In multiplex French study (Billiard 1994) and 40% in an American study families, index patients have a higher frequency for all (Guilleminault et al 1989) this is a small number. The difference symptoms than first degree relatives.…”

“…One of the reasons narcolepsy may indicate that a different gene is involved in the might be that we have investigated three or more generations susceptibility, which may be located outside the HLA system, instead of only two as in the French study (Billiard et al 1994). like the recessive carnarc-1 gene in dogs (Mignot et al 1991).…”

Single-Nucleotide-Polymorphism-Based Association Mapping of Dog Stereotypes

“…Segregation in planned crosses or within a breed population can be used to identify loci for simple and complex phenotypes. This approach takes advantage of the large LD distances that can be attributed to founder effects and bottlenecks (for example, Mignot et al 1991;Acland et al 1998Acland et al , 1999Lingaas et al 1998;Van de Sluis et al 1999;Jonasdottir et al 2000;Chase et al 2005aChase et al , 2006Todhunter et al 2005). 2.…”

Finding cardiovascular disease genes in the dog

“…The identification of the hypocretin 2 receptor as an important component of sleep biology 63 by Emmanuel Mignot and colleagues offers a clear example. Linkage analysis and eventual cloning of the disease gene using pedigrees of Doberman pinschers affected with narcolepsy 31 led to significant advances in understanding the biology of sleep, and development of new programs in neuroscience focused on the molecular biology of sleep.…”