"Up to one-third of probands of familial cases of narcolepsy are DQB1*0602 negative (Guilleminault et al. 1989; Mignot 1997; Mignot et al. 1996; Singh et al. 1990), indicating that although HLA is still a predisposing factor, mutations at certain other loci are sufficient to cause narcolepsy. Consistent with this, non-DQB1*0602 narcolepsy pedigrees frequently display significant familial aggregation and no apparent linkage with HLA (Guilleminault et al. 1989; Mignot et al. 1996; Mignot 1997; Singh et al. 1990). Taken together these findings indicate that non-HLA genes are likely to account for much of the increase in susceptibility observed in first-degree relatives of narcoleptics . "
[Show abstract][Hide abstract] ABSTRACT: Narcolepsy is a disabling sleep disorder characterized by excessive daytime sleepiness and abnormal manifestations of rapid eye movement (REM) sleep including cataplexy, sleep paralysis, and hypnagogic hallucinations. It is known to be a complex disorder, with both genetic predisposition and environmental factors playing a role. In humans, susceptibility to narcolepsy is tightly associated with a specific HLA allele, DQB1*0602. In humans and canines, most cases are sporadic. In Doberman pinschers and Labrador retrievers, however, the disease is transmitted as an autosomal recessive gene canarc-1 with full penetrance. This gene is not linked with the dog leukocyte antigen complex, but is tightly linked with a marker with high homology to the human mu-switch immunoglobulin gene. We have isolated several genomic clones encompassing the canarc-1 marker and the variable heavy chain immunoglobulin region in canines. These have been partially sequenced and have been mapped onto specific dog chromosomes by fluorescence in situ hybridization (FISH). Our results indicate that the mu-switch-like marker is not part of the canine immunoglobulin machinery. We are continuing to extend the genomic contig using a newly developed canine BAC library and attempting to identify the corresponding human region of conserved synteny.
Journal of Heredity 01/1999; 90(1):129-32. DOI:10.1093/jhered/90.1.129 · 1.97 Impact Factor
[Show abstract][Hide abstract] 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 an as-yet-unmapped single, autosomal recessive gene canarc-1. Gene markers for canarc-1 were therefore sought by DNA restriction fragment length polymorphisms in our colony of narcoleptic dogs. A human mu-switch immunoglobulin probe and the enzyme Hae III identified a gene cosegregating with canarc-1 in backcrossed animals (logarithm of odds scores: m = 24, Z max = 7.2 at theta = 0%). canarc-1 was also shown not to be tightly linked with the dog major histocompatibility complex (m = 40, Z less than -2 at theta less than 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.
Proceedings of the National Academy of Sciences 05/1991; 88(8):3475-8. DOI:10.1073/pnas.88.8.3475 · 9.81 Impact Factor
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