A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains
Abstract
We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Selective loss of hypocretin-producing neurons causes sleepiness and cataplexy in over 90% of patients with narcolepsy.
“Selective loss of the hypocretin-producing neurons causes sleepiness and cataplexy in over 90% of patients with narcolepsy,5–9”
From Loss of hypocretin (orexin) neurons with traumatic brain injury (2009) · cites this paper as [7]
In controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.
“In controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.7,8,14,15”
From Loss of hypocretin (orexin) neurons with traumatic brain injury (2009) · cites this paper as [7]
Cites
The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity
de Lecea, L., Kilduff, T. S., Peyron, C., Gao, X.-B., Foye, P. E., Danielson, P. E., Fukuhara, C., Battenberg, E. L. F., Gautvik, V. T., Bartlett, F. S., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.1.322 · Cited by 3,878 · see citing works
Neurons containing hypocretin (orexin) project to multiple neuronal systems
Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., & Kilduff, T. S. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09996.1998 · Cited by 3,466 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Hypothalamic regulation of sleep and circadian rhythms
Saper, C. B., Scammell, T. E., & Lu, J. (2005) · Nature · doi:10.1038/nature04284 · Cited by 2,804 · see citing works
Berridge, C. W., & Waterhouse, B. D. (2003) · Brain Research Reviews · doi:10.1016/s0165-0173(03)00143-7 · Cited by 2,529 · see citing works
The sleep switch: hypothalamic control of sleep and wakefulness
Saper, C. B., Chou, T. C., & Scammell, T. E. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)02002-6 · Cited by 1,656 · see citing works
Control of sleep and wakefulness
Brown, R. E., Basheer, R., McKenna, J. T., Strecker, R. E., & McCarley, R. W. (2012) · Physiological Reviews · doi:10.1152/physrev.00032.2011 · Cited by 1,477 · see citing works
Saper, C. B., Fuller, P. M., Pedersen, N. P., Lu, J., & Scammell, T. E. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.032 · Cited by 1,404 · see citing works
The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness
Sakurai, T. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2092 · Cited by 1,276 · see citing works
Mignot, E., Lammers, G. J., Ripley, B., Okun, M., Nevsimalova, S., Overeem, S., Vankova, J., Black, J., Harsh, J., Bassetti, C., et al. (2002) · Archives of Neurology · doi:10.1001/archneur.59.10.1553 · Cited by 1,126 · see citing works
Self-citationThe Neurobiology of Sleep: Genetics, cellular physiology and subcortical networks
Pace-Schott, E. F., & Hobson, J. A. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn895 · Cited by 937 · see citing works
Fos Expression in Orexin Neurons Varies with Behavioral State
Estabrooke, I. V., McCarthy, M. T., Ko, E., Chou, T. C., Chemelli, R. M., Yanagisawa, M., Saper, C. B., & Scammell, T. E. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-05-01656.2001 · Cited by 654 · see citing works
Complex HLA-DR and -DQ Interactions Confer Risk of Narcolepsy-Cataplexy in Three Ethnic Groups
Mignot, E., Lin, L., Rogers, W., Honda, Y., Qiu, X., Lin, X., Okun, M., Hohjoh, H., Miki, T., Hsu, S. H., et al. (2001) · The American Journal of Human Genetics · doi:10.1086/318799 · Cited by 594 · see citing works
Self-citationHypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish
Prober, D. A., Rihel, J., Onah, A. A., Sung, R.-J., & Schier, A. F. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4332-06.2006 · Cited by 508 · see citing works
Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior
Boutrel, B., Kenny, P. J., Specio, S. E., Martin-Fardon, R., Markou, A., Koob, G. F., & de Lecea, L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507480102 · Cited by 520 · see citing works
Lane, J. M., Vlasac, I., Anderson, S. G., Kyle, S. D., Dixon, W. G., Bechtold, D. A., Gill, S., Little, M. A., Luik, A., Loudon, A., et al. (2016) · Nature Communications · doi:10.1038/ncomms10889 · Cited by 312 · see citing works
Circadian regulation of sleep in mammals: Role of the suprachiasmatic nucleus
Mistlberger, R. E. (2005) · Brain Research Reviews · doi:10.1016/j.brainresrev.2005.01.005 · Cited by 318 · see citing works
<i>Hypothalamic Regulation of Sleep and Arousal</i>
Szymusiak, R., & McGinty, D. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1417.027 · Cited by 294 · see citing works
Neuronal Mechanisms for Sleep/Wake Regulation and Modulatory Drive
Eban-Rothschild, A., Appelbaum, L., & de Lecea, L. (2018) · Neuropsychopharmacology · doi:10.1038/npp.2017.294 · Cited by 282 · see citing works
Neurophysiology of sleep and wakefulness: basic science and clinical implications
Schwartz, J., & Roth, T. (2008) · Current Neuropharmacology · doi:10.2174/157015908787386050 · Cited by 289 · see citing works
The neurobiological basis of narcolepsy
Mahoney, C. E., Cogswell, A., Koralnik, I. J., & Scammell, T. E. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0097-x · Cited by 289 · see citing works
Unearthing the phylogenetic roots of sleep
Allada, R., & Siegel, J. M. (2008) · Current Biology · doi:10.1016/j.cub.2008.06.033 · Cited by 280 · see citing works
Gerashchenko, D., Kohls, M. D., Greco, M., Waleh, N. S., Salin-Pascual, R., Kilduff, T. S., Lappi, D. A., & Shiromani, P. J. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-18-07273.2001 · Cited by 272 · see citing works
Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2
Rosin, D. L., Weston, M. C., Sevigny, C. P., Stornetta, R. L., & Guyenet, P. G. (2003) · Journal of Comparative Neurology · doi:10.1002/cne.10860 · Cited by 252 · see citing works
The Neurobiology of Sleep and Wakefulness
Schwartz, M. D., & Kilduff, T. S. (2015) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2015.07.002 · Cited by 207 · see citing works
Clasadonte, J., Scemes, E., Wang, Z., Boison, D., & Haydon, P. G. (2017) · Neuron · doi:10.1016/j.neuron.2017.08.022 · Cited by 200 · see citing works
REM sleep characteristics in narcolepsy and REM sleep behavior disorder
Dauvilliers, Y., Rompré, S., Gagnon, J.-F., Vendette, M., Petit, D., & Montplaisir, J. (2007) · Sleep · doi:10.1093/sleep/30.7.844 · Cited by 197 · see citing works
Loss of hypocretin (orexin) neurons with traumatic brain injury
Baumann, C. R., Bassetti, C. L., Valko, P. O., Haybaeck, J., Keller, M., Clark, E., Stocker, R., Tolnay, M., & Scammell, T. E. (2009) · Annals of Neurology · doi:10.1002/ana.21836 · Cited by 185 · see citing works
“In controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.(7,8,14,15) Hypothalami from TBI patients also contained intense perivascular hypocretin immunoreactivity (Fig 3).”
ResultSleep-Wake Disturbances After Traumatic Brain Injury: Synthesis of Human and Animal Studies
Sandsmark, D. K., Elliott, J. E., & Lim, M. M. (2017) · Sleep · doi:10.1093/sleep/zsx044 · Cited by 183 · see citing works
Sleep Neurobiology for the Clinician
(2004) · Sleep · doi:10.1093/sleep/27.4.811 · Cited by 151 · see citing works
Kristensson, K., Nygård, M., Bertini, G., & Bentivoglio, M. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.12.001 · Cited by 140 · see citing works
Psychiatric Manifestations of Paraneoplastic Disorders
Kayser, M. S., Kohler, C. G., & Dalmau, J. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2010.09101547 · Cited by 129 · see citing works
The discovery of suvorexant, the first orexin receptor drug for insomnia
Coleman, P. J., Gotter, A. L., Herring, W. J., Winrow, C. J., & Renger, J. J. (2017) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104837 · Cited by 128 · see citing works
The hypocretins as sensors for metabolism and arousal
Adamantidis, A., & De Lecea, L. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2008.164400 · Cited by 112 · see citing works
Sexually dimorphic expression of prepro-orexin mRNA in the rat hypothalamus
Jöhren, O., Neidert, S. J., Kummer, M., & Dominiak, P. (2002) · Peptides · doi:10.1016/s0196-9781(02)00052-9 · Cited by 112 · see citing works
Genetic contributions to behavioural diversity at the gene-environment interface
Bendesky, A., & Bargmann, C. I. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3065 · Cited by 103 · see citing works
Amygdala lesions reduce cataplexy in orexin knock-out mice
Burgess, C. R., Oishi, Y., Mochizuki, T., Peever, J. H., & Scammell, T. E. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5632-12.2013 · Cited by 108 · see citing works
Shining light on wakefulness and arousal
de Lecea, L., Carter, M. E., & Adamantidis, A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.01.032 · Cited by 103 · see citing works
de Lecea, L., & Sutcliffe, J. G. (2005) · The FEBS Journal · doi:10.1111/j.1742-4658.2005.04981.x · Cited by 105 · see citing works
Orexins and fear: Implications for the treatment of anxiety disorders
Flores, Á., Saravia, R., Maldonado, R., & Berrendero, F. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.06.005 · Cited by 102 · see citing works
REM sleep: A biological and psychological paradox
Siegel, J. M. (2011) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2011.01.001 · Cited by 102 · see citing works
Altered Skin-Temperature Regulation in Narcolepsy Relates to Sleep Propensity
Fronczek, R., Overeem, S., Lammers, G. J., van Dijk, J. G., & van Someren, E. J. W. (2006) · Sleep · doi:10.1093/sleep/29.11.1444 · Cited by 92 · see citing works
Self-citationThe immunopathogenesis of narcolepsy type 1
Liblau, R. S., Latorre, D., Kornum, B. R., Dauvilliers, Y., & Mignot, E. J. (2024) · Nature Reviews Immunology · doi:10.1038/s41577-023-00902-9 · Cited by 91 · see citing works
Self-citationCSF biomarkers in suicide attempters – a principal component analysis
Lindqvist, D., Janelidze, S., Erhardt, S., Träskman‐Bendz, L., Engström, G., & Brundin, L. (2011) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.2010.01655.x · Cited by 86 · see citing works
Hypocretin as a Hub for Arousal and Motivation
Tyree, S. M., Borniger, J. C., & de Lecea, L. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00413 · Cited by 83 · see citing works
Acuna-Goycolea, C., Li, Y., & van den Pol, A. N. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.5416-03.2004 · Cited by 69 · see citing works
Overview of orexin/hypocretin system
Mieda, M., & Sakurai, T. (2012) · Progress in brain research · doi:10.1016/b978-0-444-59489-1.00002-1 · Cited by 64 · see citing works
Neuroscience-driven discovery and development of sleep therapeutics
Dresler, M., Spoormaker, V. I., Beitinger, P., Czisch, M., Kimura, M., Steiger, A., & Holsboer, F. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.10.012 · Cited by 63 · see citing works
Jiang, W., Birtley, J. R., Hung, S.-C., Wang, W., Chiou, S.-H., Macaubas, C., Kornum, B., Tian, L., Huang, H., Adler, L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13234-x · Cited by 58 · see citing works
Herring, W. J., Roth, T., Krystal, A. D., & Michelson, D. (2019) · Journal of Sleep Research · doi:10.1111/jsr.12782 · Cited by 53 · see citing works
Manipulation of skin temperature improves nocturnal sleep in narcolepsy
Fronczek, R., Raymann, R. J. E. M., Overeem, S., Romeijn, N., van Dijk, J. G., Lammers, G. J., & Van Someren, E. J. W. (2008) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2008.143610 · Cited by 51 · see citing works
Self-citationOnofrj, M., Russo, M., Delli Pizzi, S., De Gregorio, D., Inserra, A., Gobbi, G., & Sensi, S. L. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02691-0 · Cited by 43 · see citing works
Chung, H.-S., Kim, J.-G., Kim, J.-W., Kim, H.-W., & Yoon, B.-J. (2014) · Regulatory Peptides · doi:10.1016/j.regpep.2014.11.003 · Cited by 32 · see citing works
Zeitzer, J. M., Buckmaster, C. L., Lyons, D. M., & Mignot, E. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00460.2007 · Cited by 31 · see citing works
Self-citationDo enteric neurons make hypocretin?
Baumann, C. R., Clark, E. L., Pedersen, N. P., Hecht, J. L., & Scammell, T. E. (2008) · Regulatory Peptides · doi:10.1016/j.regpep.2007.11.006 · Cited by 26 · see citing works
Detection of Orexin A Neuropeptide in Biological Fluids Using a Zinc Oxide Field Effect Transistor
Hagen, J., Lyon, W., Chushak, Y., Tomczak, M., Naik, R., Stone, M., & Kelley-Loughnane, N. (2013) · ACS Chemical Neuroscience · doi:10.1021/cn300159e · Cited by 22 · see citing works
de Zambotti, M., Pizza, F., Covassin, N., Vandi, S., Cellini, N., Stegagno, L., & Plazzi, G. (2014) · Journal of Sleep Research · doi:10.1111/jsr.12133 · Cited by 20 · see citing works
- Authors
- Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., Nevsimalova, S., Aldrich, M., Reynolds, D., Albin, R., Li, R., Hungs, M., Pedrazzoli, M., Padigaru, M., Kucherlapati, M., Fan, J., Maki, R., Lammers, G. J., Bouras, C., Kucherlapati, R., Nishino, S., & Mignot, E.
- Affiliations
- Stanford Medicine (US)
- Leiden University Medical Center (NL)
- University Hospital of Geneva (CH)
- University of Michigan (US)
- Albert Einstein College of Medicine (US)
- Neurocrine Biosciences (United States) (US)
- Corresponding author
- Mignot, Emmanuel
- ORCID
- Venue
- Nature Medicine
- Published
- 2000-09
- Volume
- 6
- Issue
- 9
- Pages
- 991-997
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1519232679
- Cited by
- 2,118
- References
- 2
- Citations by year
- 2026: 38 · 2025: 57 · 2024: 51 · 2023: 61 · 2022: 75 · 2021: 62 · 2020: 67 · 2019: 70 · 2018: 74 · 2017: 88 · 2016: 78 · 2015: 91 · 2014: 100 · 2013: 116 · 2012: 85
- FWCI
- 46.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1r01hl059601-01)
- National Heart, Lung, and Blood Institute (HL59601)
- National Institute of Neurological Disorders and Stroke (NS-23724, NS 33797)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Keywords
- narcolepsy, orexin, hypocretin receptor 2, hypocretin deficiency, perifornical area, genetic susceptibility, human leukocyte antigen, brain histopathology
- MeSH terms
- Orexins, Adult, Aged, Aged, 80 and over, Brain Chemistry, Carrier Proteins, Cerebral Cortex, Female, Genetic Testing, Humans, Hypothalamus, Male, Middle Aged, Molecular Sequence Data, Mutation, Narcolepsy, Neuropeptides, Pons, Protein Processing, Post-Translational, Tissue Distribution, Age of Onset, Receptors, Neuropeptide, Neurotransmitter Agents, Receptors, G-Protein-Coupled, White People, Intracellular Signaling Peptides and Proteins, Orexin Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
