A
            <i>prepro-orexin</i>
            gene polymorphism is associated with narcolepsy

Genčík, Martin; Dahmen, Norbert; Wieczorek, Stefan; Kasten, Meike; Bierbrauer, Jürgen; Anghelescu, Ion; Szegedi, Armin; Saecker, A. M. M. Vieira; Epplen, Jörg T.

doi:10.1212/wnl.56.1.115

Cited by 57 publications

(28 citation statements)

References 7 publications

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“…The human preprohypocretin gene (HCRT; preproorexin) is located on chromosome 17 and encodes a hypothalamic neuropeptide precursor protein that could play a role in the pathophysiology of narcolepsy [40]. HCRT gene polymorphisms are located on position -909T, -22C>T and -20C>A in the 5´ UTR, which have been studied in relation to the occurrence of sleep attacks in patients with PD [40][41][42].…”

Section: Preprohypocretinmentioning

confidence: 99%

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Pharmacogenetics of Antiparkinsonian Drug Treatment: A Systematic Review

et al. 2007

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Pharmacotherapy is the mainstay in the treatment of Parkinson’s disease and the armamentarium of drugs available for the therapy of this disease is still expanding. Anti-Parkinson’s disease drugs are effective in reducing the physical symptoms, such as hypokinesia, bradykinesia, rigidity and tremor. However, there is a large interindividual variability in response to anti-Parkinson’s disease drugs with respect to both drug efficacy and toxicity. It is thought that genetic variability in genes encoding drug-metabolizing enzymes, drug receptors and proteins involved in pathway signaling is an important factor in determining interindividual variability in drug response. Pharmacogenetics aims at identifying genetic markers associated with drug response. Ideally, knowledge of these genetic markers will enable us to predict an individual’s drug response in terms of both efficacy and toxicity. The role of pharmacogenetics in the treatment of Parkinson’s disease is relatively unexplored. Therefore, we aim to present a systematic review of the published pharmacogenetic studies in Parkinson’s disease and to describe polymorphic genes of interest for future research.

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Section: Preprohypocretinmentioning

confidence: 99%

“…HCRT gene polymorphisms are located on position -909T, -22C>T and -20C>A in the 5´ UTR, which have been studied in relation to the occurrence of sleep attacks in patients with PD [40][41][42]. The gene coding for HCRT is considered to be an indirect gene for dopaminergic therapy.…”

Section: Preprohypocretinmentioning

confidence: 99%

Pharmacogenetics of Antiparkinsonian Drug Treatment: A Systematic Review

et al. 2007

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“…Two neuropeptides, orexin-A and -B (hypocretin-1 and -2), are derived from the prepro-orexin gene and act at two G-protein-coupled receptors, orexin receptor-1 and -2 (de Sakurai et al, 1998). In the human, mutations of the prepro-orexin or orexin receptor genes appear to be extremely rare (Peyron et al, 2000;Gencik et al, 2001). However, undetectable to very low levels of orexin-A neuropeptide in the CSF have been described in most patients with narcolepsy-cataplexy, whereas orexin-A levels of patients presenting with other disorders were comparable with those of healthy controls ; Ripley et al, 2001; Mignot et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Expression of a Poly-Glutamine-Ataxin-3 Transgene in Orexin Neurons Induces Narcolepsy–Cataplexy in the Rat

Beuckmann¹,

Sinton²,

Williams³

et al. 2004

J. Neurosci.

174

101

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The sleep disorder narcolepsy has been linked to loss of hypothalamic neurons producing the orexin (hypocretin) neuropeptides. Here, we report the generation of transgenic rats expressing a human ataxin-3 fragment with an elongated polyglutamyl stretch under control of the human prepro-orexin promoter (orexin/ataxin-3 rats). At 17 weeks of age, the transgenic rats exhibited postnatal loss of orexinpositive neurons in the lateral hypothalamus, and orexin-containing projections were essentially undetectable. The loss of orexin production resulted in the expression of a phenotype with fragmented vigilance states, a decreased latency to rapid eye movement (REM) sleep and increased REM sleep time during the dark active phase. Wakefulness time was also reduced during the dark phase, and this effect was concentrated at the photoperiod boundaries. Direct transitions from wakefulness to REM sleep, a defining characteristic of narcolepsy, occurred frequently. Brief episodes of muscle atonia and postural collapse resembling cataplexy were also noted while rats maintained the electroencephalographic characteristics of wakefulness. These findings indicate that the orexin/ataxin-3 transgenic rat could provide a useful model of human narcolepsy.

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“…The fact that the sleep disorder narcolepsy can result from rare sequence variants in orexin system genes, such as the Leu16Arg and the 5 0 -UTR C3250T sequence variants of the prepro-orexin gene [Gencik et al, 2001], demonstrates that disruptions to orexin genes can result in sleep disorders. Narcolepsy has a prevalence of 1 in 2,000 in the general population.…”

Section: Introductionmentioning

confidence: 99%

Variants of the orexin2/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette's syndrome comorbidity

Thompson

Comings²,

Abu-Ghazalah

et al. 2004

American J of Med Genetics Pt B

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The orexin-2/hypocretin-2 (OX2R) receptor gene is mutated in canine narcolepsy and disruption of the prepro-orexin/hypocretin ligand gene results in both an animal model of narcolepsy and sporadic cases of the human disease. This evidence suggests that the structure of the OX2R gene, and its homologue, the OX1R gene, both members of the G protein-coupled receptor (GPCR) family, and the gene encoding the peptide ligands, the prepro-orexin/hypocretin gene, may be variables in the etiology of sleep disorders. We report a single stranded conformational polymorphism (SSCP) analysis of the coding regions of these genes in idiopathic sleep disorder patients diagnosed with excessive daytime sleepiness (EDS) (n = 28), narcolepsy (n = 28), Tourette's syndrome/chronic vocal or motor tic disorder (n = 70), and control subjects (n = 110). Two EDS patients showed a Pro11Thr change. One Tourette's syndrome patient was found to have a Pro10Ser alteration. The Pro10Ser and Pro11Thr variants were not found in non-disease populations. Analysis of the ability of the mutant receptors to mobilize calcium compared to the wild-type receptor in response to orexin agonists indicated that they resulted in decreased potency at high (etaM) concentrations of orexin ligands. Further work is warranted to study the variability of the orexin/hypocretin system in a variety of disorders characterized by EDS.

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A prepro-orexin gene polymorphism is associated with narcolepsy

Cited by 57 publications

References 7 publications

Pharmacogenetics of Antiparkinsonian Drug Treatment: A Systematic Review

Pharmacogenetics of Antiparkinsonian Drug Treatment: A Systematic Review

Expression of a Poly-Glutamine-Ataxin-3 Transgene in Orexin Neurons Induces Narcolepsy–Cataplexy in the Rat

Variants of the orexin2/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette's syndrome comorbidity

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