Narcolepsy and the Hypocretin Receptor 2 Gene

hund narcoleptics. Similar analysis of cDNA from narco-leptic Labradors showed a 123 bp deletion of exon 6 and a G to A transition in the 5Ј splice junction consensus sequence. Thus, the genetic abnormality in Doberman Human narcolepsy, a chronic disorder that occurs in narcoleptics differs from that in Labrador narcoleptics, about 1 in 3000 individuals, is characterized by (1) exces-but both involve the same gene. The disrupted splicing sive daytime sleepiness, (2) brief episodes of muscle of the Hcrtr2 mRNAs is predicted to lead to truncated weakness triggered by emotions (cataplexy), and (3) ab-receptor proteins, with consequent disruption of intra-normalities of rapid eye movement (REM) sleep (Bassetti cellular signaling mediated by the G proteins to which and Aldrich, 1996). The disorder has a genetic basis: most this receptor is linked. affected persons carry the human leukocyte antigen These findings represent a major advance in under-(HLA) HLA-DQB1*0602, and first-degree relatives of nar-standing the pathogenesis of canine narcolepsy, and coleptics have a 40-fold increased risk of developing probably human narcolepsy as well. A key feature of narcolepsy (Guilleminault et al., 1989). However, most narcolepsy is the tendency to enter REM sleep directly persons with HLA-DQB1*0602 do not develop narco-from wakefulness. The REM sleep state is generated lepsy, the concordance rate in identical twins is low, and by neurons of the dorsolateral pons that are largely or narcolepsy does not cosegregate with HLA-DQB1*0602 entirely cholinergic. Monoaminergic neurons of the loin some multiplex families. Thus, one or more additional cus coeruleus (LC) and dorsal raphe (DR) inhibit the genes as well as environmental factors appear to be cholinergic generator neurons and prevent the expres-involved in the pathogenesis of narcolepsy. sion of REM sleep; reduced or absent firing of DR and In the August 6 issue of Cell, Lin et al. (1999) report LC neurons allows REM sleep to be expressed. Hypo-that canine narcolepsy, a disorder with close phenotypic thalamic neurons containing hypocretins project to similarity to human narcolepsy, is caused by a mutation brainstem areas critical for REM sleep, including the of the hypocretin receptor 2 gene (Hcrtr2). Hypocretins, pedunculopontine and parabrachial nuclei, LC, and DR. also called orexins, are recently identified neuropep-Thus, hypocretins may well have modulatory effects on tides with homology to secretin. Within the central ner-neurons involved in REM sleep expression, and Hcrtr2 vous system, cell bodies containing hypocretins are present exclusively in the tuberal region of the hypothal-mutations may …