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Conformational Change in the Ligand-Binding Pocket via a KISS1R Mutation (P147L) Leads to Isolated Gonadotropin-Releasing Hormone Deficiency
http://hdl.handle.net/10458/0002000406
http://hdl.handle.net/10458/0002000406d428f873-7c6d-40d7-b6d6-9b117489d500
| 名前 / ファイル | ライセンス | アクション |
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article (1.3 MB)
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| Item type | 学術雑誌論文 / Journal Article(1) | |||||||||
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| 公開日 | 2023-12-22 | |||||||||
| タイトル | ||||||||||
| タイトル | Conformational Change in the Ligand-Binding Pocket via a KISS1R Mutation (P147L) Leads to Isolated Gonadotropin-Releasing Hormone Deficiency | |||||||||
| 言語 | en | |||||||||
| 言語 | ||||||||||
| 言語 | eng | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| キーワード | congenital hypogonadotropic hypogonadism | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| キーワード | KISS1R | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| キーワード | kisspeptin receptor | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| キーワード | ligand binding | |||||||||
| キーワード | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| キーワード | missense mutation | |||||||||
| 資源タイプ | ||||||||||
| 資源タイプ | journal article | |||||||||
| 著者 |
清水, 浩一郎
× 清水, 浩一郎× Yonekawa, Tadato× Yoshida, Morikatsu
× Miyazato, Mikiya
× 三浦, 綾子× 迫田, 秀之× 山口, 秀樹× 中里, 雅光 |
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| 抄録 | ||||||||||
| 内容記述タイプ | Abstract | |||||||||
| 内容記述 | Context: Kisspeptin receptor (KISS1R) is expressed in hypothalamic gonadotropin-releasing hormone neurons and responsible for pubertal onset and reproductive functions. KISS1R mutations remain a rare cause of congenital hypogonadotropic hypogonadism (CHH). Objective: The aim of this study was to identify the genetic cause of CHH in a patient and to functionally characterize a KISS1R mutation. Design: The patient was a 47-year-old Japanese man whose parents were first cousins. He lacked secondary sexual characteristics owing to normosmic CHH. Exon segments for the KISS1R gene in this patient were screened for mutations. Functional analyses were performed using HEK293 cells expressing KISS1R mutants. Molecular dynamics simulations were performed to compare the ligand-KISS1R mutant complex with those of wild-type KISS1R variants. Results: A homozygous mutation (c.440C>T, p.P147L) in KISS1R was identified. The P147L mutation did not affect either receptor expression level or subcellular localization in the recombinant expression system. Intracellular calcium measurements and cellular dielectric spectroscopy demonstrated that the P147L mutation impaired receptor function to an extent more severe than that of a previously reported L148S mutation. A receptor-ligand binding assay showed the P147L mutation causes a substantial loss of ligand-binding affinity. Molecular dynamics simulations revealed the P147L mutation decreases the contact surface area of the ligand-receptor complex in an expanded ligand-binding pocket. Conclusion: We identified a loss-of-function mutation in KISS1R associated with CHH. Our results demonstrated that the P147L mutation causes a severe phenotype and functional impairment resulting from the loss of ligand-binding affinity due to an expanded ligand-binding pocket. |
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| 言語 | en | |||||||||
| 内容記述 | ||||||||||
| 内容記述タイプ | Other | |||||||||
| 内容記述 | citation: Shimizu K, Yonekawa T, Yoshida M, Miyazato M, Miura A, Sakoda H, Yamaguchi H, Nakazato M. Conformational Change in the Ligand-Binding Pocket via a KISS1R Mutation (P147L) Leads to Isolated Gonadotropin-Releasing Hormone Deficiency. J Endocr Soc. 2017 Sep 5;1(10):1259-1271. doi: 10.1210/js.2017-00277. PMID: 29264451; PMCID: PMC5686787. |
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| 言語 | en | |||||||||
| 書誌情報 |
en : Journal of the Endocrine Society 巻 1, 号 10, p. 1259-1271, 発行日 2017-09-05 |
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| 出版者 | ||||||||||
| 出版者 | Oxford | |||||||||
| 言語 | en | |||||||||
| DOI | ||||||||||
| 関連タイプ | isVersionOf | |||||||||
| 識別子タイプ | DOI | |||||||||
| 関連識別子 | https://doi.org/10.1210/js.2017-00277 | |||||||||
| 権利 | ||||||||||
| 言語 | en | |||||||||
| 権利情報 | © 2017 Endocrine Society | |||||||||
| 著者版フラグ | ||||||||||
| 出版タイプ | VoR | |||||||||
