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When I was a child, I liked history rather than science. But in high school, most students picked physics or chemistry as their science class, so the biology class I picked was very small and comfortable. My high school biology teacher was fantastic and gave fascinating lectures which piqued my interest in human genetics, medicine, and disease. I thought about a career in medicine, but my mother, who was a nurse, discouraged me from becoming a doctor, so instead, I pursued my interest in genetic research.

I did my graduate work at Tokyo University, Department of Human Genetics, where I became interested in sleep disorders. Sleep is a big mystery. We spend roughly one-third of our lives sleeping, but no one really knows why. I performed genome-wide association studies to identify narcolepsy-associated genes and I fortunately found one gene. However, many groups are studying narcolepsy, so I decided to change my target gene to IH, which few people are studying. Although narcolepsy and IH are both sleep disorders, they are different. Narcolepsy patients actually sleep for normal amounts of time. So, they might sleep for a total of about 7 hours per day and they wake up refreshed. On the other hand, IH patients sleep much more than normal, over 10 hours per day, but they’re always tired. So the questions we have for each disease are different. For narcolepsy, we want to know why patients suddenly fall asleep. For IH, we want to know why patients have trouble sleeping even though they are tired, and why sleep doesn’t cause patients to become refreshed. In many respects, IH may be a much more severe disease compared to narcolepsy.

In this paper, we found that orexin signaling is involved in IH. Reductions in orexin signaling are well-known to cause narcolepsy; narcolepsy in dogs can be caused by mutations in an orexin receptor, and narcolepsy in humans is caused by the death of orexin-producing cells. On the other hand, IH was thought to be caused by a different mechanism because amounts of orexin in the cerebrospinal fluid of IH patients are relatively normal, and because the two diseases have very different symptoms. However, when we sequenced the orexin and orexin receptor genes in IH patients and controls, we found that the frequency of a rare missense variant in the prepro-orexin gene was significantly higher in IH patients. Mature orexin is produced by cleavage of a longer prepro-orexin peptide, and we found that the cleavage efficiency of the rare variant was lower than that of wild-type. Further, we found that activation of orexin receptors by uncleaved prepro-orexin is decreased relative to activation by mature orexin peptides. Overall, our results demonstrate that at least some types of IH are associated with decreased orexin signaling.