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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.

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Figure 1: Control and mutant Hcrt trafficking in Neuro-2A cells.
Figure 2: Distribution of hypocretin-containing cells in the human hypothalamus.
Figure 3: Hypocretin, MCH and HLA expression studies in the hypothalamus of control and narcoleptic subjects.
Figure 4: Hypocretin concentrations in the cortex and pons in narcoleptic and control subjects.

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Acknowledgements

We dedicate this publication to Michael Aldrich, a leading figure in the field of narcolepsy research, who died on 18 July 2000. We thank U. Francke, R. Scheller and M. Steegmaier for helpful expertise, reagents and advice, A. Voros, C. Campbell, B. Greggio, L. Lin and M. Okun for assistance and H.C. Heller for generously providing laboratory space and instrumentation. S. O., S. N., M. H. and M. P. were supported by the Fundatie van de Vrijvrouwe van Renswoude/ Dr. Hendrik Muller Vaderlandsch Fonds: grants GAUK 56/99, and MSM 111100001; the Deutsche Forschungsgemeinschaft (HU 827/2-1) and the Fundacao de Amparo 'a Pesquisa do Estado de Sao Paulo respectively. This work was supported by NIH NS 23724, NS33797 and HL59601 to E. M. and by NIHtraining grant HG00044 to J. F.

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Correspondence to Emmanuel Mignot.

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Peyron, C., Faraco, J., Rogers, W. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6, 991–997 (2000). https://doi.org/10.1038/79690

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