DQ (rather than DR) gene marks susceptibility to narcolepsy

Matsuki, Kazumasa; Grumet, F. Carl; Lin, Xiaoyan; Gelb, Michael; Guilleminault, Christian; Wc, Dement; Mignot, Emmanuel

doi:10.1016/0140-6736(92)90571-j

Cited by 138 publications

(75 citation statements)

References 5 publications

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“…Human narcolepsy is correlated with the presence of the human leukocyte antigen (HLA) DQB1*0602 genotype (Matsuki et al, 1992). The association of narcolepsy with the major histocompatibility complex marker, HLA-DR2 and DQB1*0602, is one of the highest disease-HLA linkages known (Behar et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Neuronal Degeneration in Canine Narcolepsy

et al. 1999

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Narcolepsy is a lifelong illness characterized by persistent sleepiness, hypnagogic hallucinations, and episodes of motor paralysis called cataplexy. We have tested the hypothesis that a transient neurodegenerative process is linked to symptom onset. Using the amino-cupric silver stain on brain sections from canine narcoleptics, we found elevated levels of axonal degeneration in the amygdala, basal forebrain (including the nucleus of the diagonal band, substantia innominata, and preoptic region), entopeduncular nucleus, and medial septal region. Reactive neuronal somata, an indicator of neuronal pathology, were found in the ventral amygdala. Axonal degeneration was maximal at 2-4 months of age. The number of reactive cells was maximal at 1 month of age. These degenerative changes precede or coincide with symptom onset. The forebrain degeneration that we have observed can explain the major symptoms of narcolepsy.Key words: narcolepsy; REM sleep; amygdala; basal forebrain; canine; amino-cupric silver; degeneration; cataplexy Narcolepsy, which occurs at a rate of 0.2-1.6 per thousand (Aldrich, 1990;Hublin et al., 1994), was first recognized 118 years ago by Gélineau (Passouant, 1976). Its symptoms include excessive daytime sleepiness, hypnagogic hallucinations (dream-like mentation in waking), REM sleep at sleep onset, cataplexy (a loss of muscle tone in waking, usually triggered by sudden, strong emotions), and sleep paralysis (an inability to move at sleep onset or awakening) . Narcolepsy has been reported in horses, cattle, and dogs (Mitler et al., 1976; Strain et al., 1984). C anine narcoleptics have been intensively studied. Like human narcoleptics, they are excessively sleepy and have cataplexy. Symptoms in canine and human narcoleptics display a similar response to pharmacological agents Nishino and Mignot, 1997). The cause of narcolepsy is unknown.Narcolepsy is not a progressive disease, in that once symptoms have become f ully established, in both human and canine narcoleptics, they do not become worse (or markedly better) with age. This suggests that narcolepsy may be caused by a transient degenerative process. E xaminations of postmortem tissue in human narcoleptics have not produced consistent evidence for degenerative changes. However, symptom onset is typically 50 or more years before autopsy, a sufficient interval for the removal of any debris resulting from degeneration at the time of disease onset. The age of onset of canine narcolepsy is between 1 and 4 months. In the current study, we have used the amino-cupric stain (de Olmos et al., 1994), an extremely sensitive indicator of degenerating neurons and axons (Switzer, 1991;Fix et al., 1996), to test the hypothesis that narcolepsy onset is linked to neuronal degeneration. MATERIALS AND METHODSEighteen Doberman pinscher dogs, nine narcoleptic and nine age-and breed-matched controls (four male narcoleptics and seven male controls), from six narcoleptic and five normal litters ranging from 1 to 8 months of age were used (Table 1). Control and narcole...

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Section: Discussionmentioning

confidence: 99%

Neuronal Degeneration in Canine Narcolepsy

et al. 1999

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“…1 Human narcolepsy has been shown to be closely associated with a specific human histocompatibility leukocyte antigen (HLA). 2 Because most diseases associated with a specific HLA are autoimmune in nature, the finding suggests that autoimmunity is involved in the pathophysiology of narcolepsy. However, at present, all attempts to demonstrate that human narcolepsy is an autoimmune disease have failed.…”

Section: Introductionmentioning

confidence: 99%

Hypocretin‐1 (orexin‐A) concentrations in cerebrospinal fluid are low in patients with Guillain–Barré syndrome

Kanbayashi

Ishiguro

Aizawa

et al. 2002

Psychiatry Clin Neurosci

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It is reported that cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) concentrations in patients with narcolepsy are significantly low. Human narcolepsy is also known to be closely associated with a specific human histocompatibility leukocyte antigen (HLA), suggesting that autoimmunity is involved in the pathophysiology of the disease. Thus, it is important to know whether hypocretin changes are found in definite neuroimmunological diseases such as multiple sclerosis and Guillain-Barré syndrome (GBS). The results of the present study indicate that some patients with GBS have lower levels of CSF hypocretin-1.

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“…Epistasis among HLA-DRB1, HLA-DQA1 and HLA-DQB1 loci has been shown to influence MS risk. [94][95][96][97][98]179 Narcolepsy HLA-DQB1*0602 HLA-DQB1*06011associated with protection [180][181][182] Rheumatoid arthritis Figure 1 Genes and genetic diversity in the MHC class II region. The classical MHC class I, class III and class II regions are shown together with a higher resolution plot showing the location of genes within the MHC class II region chr6:32 250 000-33 300 000 (hg18 build 36.1).…”

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Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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DQ (rather than DR) gene marks susceptibility to narcolepsy

Cited by 138 publications

References 5 publications

Neuronal Degeneration in Canine Narcolepsy

Neuronal Degeneration in Canine Narcolepsy

Hypocretin‐1 (orexin‐A) concentrations in cerebrospinal fluid are low in patients with Guillain–Barré syndrome

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

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