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論文
- タイトル
- タイトル（英）
- A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia
- 参照URL
- https://researchmap.jp/narcolepsy/published_papers/36755720
- 著者
- 著者（英）
- Taku Miyagawa,Susumu Tanaka,Mihoko Shimada,Noriaki Sakai,Kotomi Tanida,Nozomu Kotorii,Tatayu Kotorii,Yu Ariyoshi,Yuji Hashizume,Kimihiro Ogi,Hiroshi Hiejima,Takashi Kanbayashi,Aya Imanishi,Azusa Ikegami,Yuichi Kamei,Akiko Hida,Yamato Wada,Masayuki Miyamoto,Masanori Takami,Hideaki Kondo,Yoshiyuki Tamura,Yukari Taniyama,Naoto Omata,Tomoyuki Mizuno,Shunpei Moriya,Hirokazu Furuya,Mitsuhiro Kato,Kayoko Kato,Jun Ishigooka,Kazuhito Tsuruta,Shigeru Chiba,Naoto Yamada,Masako Okawa,Koichi Hirata,Kenji Kuroda,Kazuhiko Kume,Naohisa Uchimura,Masaaki Kitada,Tohru Kodama,Yuichi Inoue,Seiji Nishino,Kazuo Mishima,Katsushi Tokunaga,Makoto Honda
- 担当区分
- 概要
- 概要（英）
- Abstract Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10<sup>−8</sup>, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.
- 出版者・発行元
- 出版者・発行元（英）
- Springer Science and Business Media LLC
- 誌名
- 誌名（英）
- npj Genomic Medicine
- 巻
- 7
- 号
- 1
- 開始ページ
- 終了ページ
- 出版年月
- 2022年4月12日
- 査読の有無
- 査読有り
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- DOI URL
- https://doi.org/10.1038/s41525-022-00298-w
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