ID | 57592 |
フルテキストURL | |
著者 |
Yokoi, Katsuyuki
Department of Pediatrics, Fujita Health University School of Medicine
Nakajima, Yoko
Department of Pediatrics, Fujita Health University School of Medicine
Shinkai, Yasuko
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University
Sano, Yoshimi
Department of Plastic Surgery, Division of Pediatric Dentistry & Orthodontics, Fujita Health University of Medicine
Imamura, Mototaka
Department of Plastic Surgery, Division of Pediatric Dentistry & Orthodontics, Fujita Health University of Medicine
Yoshikawa, Tetsushi
Department of Pediatrics, Fujita Health University School of Medicine
Ito, Tetsuya
Department of Pediatrics, Fujita Health University School of Medicine
Kurahashi, Hiroki
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University
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抄録 | Background: Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from a dysfunctional tissue non-specific alkaline phosphatase enzyme (TNSALP). Although genotype-phenotype correlations have been described in HPP patients, only sparse information is currently available on the genetics of mild type HPP.
Methods: We investigated 5 Japanese patients from 3 families with mild HPP (patients 1 and 2 are siblings; patient 4 is a daughter of patient 5) who were referred to Fujita Health University due to the premature loss of deciduous teeth. Physical and dental examinations, and blood, urine and bone density tests were conducted. Genetic analysis of the ALPL gene was performed in all patients with their informed consent. Results: After a detailed interview and examination, we found characteristic symptoms of HPP in some of the study cases. Mobile teeth or the loss of permanent teeth were observed in 2 patients, and 3 out of 5 patients had a history of asthma. The serum ALP levels of all patients were 30% below the lower limit of the age equivalent normal range. ALPL gene analysis revealed compound heterozygous mutations, including Ile395Val and Leu520Argfs in family 1, Val95Met and Gly491Arg in family 2, and a dominant missense mutation (Gly456Arg) in family 3. The 3D-modeling of human TNSALP revealed three mutations (Val95Met, Ile395Val and Gly456Arg) at the homodimer interface. Severe collisions between the side chains were predicted for the Gly456Arg variant. Discussion: One of the characteristic findings of this present study was a high prevalence of coexisting asthma and a high level serum IgE level. These characteristics may account for the fragility of tracheal tissues and a predisposition to asthma in patients with mild HPP. The genotypes of the five mild HPP patients in our present study series included 1) compound heterozygous for severe and hypomorphic mutations, and 2) dominant-negative mutations. All of these mutations were at the homodimer interface, but only the dominant-negative mutation was predicted to cause a severe collision effect between the side chains. This may account for varying mechanisms leading to different effects on TNSALP function. |
キーワード | ALPL
Dominant-negative mutations
Hypophosphatasia
Premature loss of deciduous
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発行日 | 2019-12-31
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出版物タイトル |
Molecular Genetics and Metabolism Reports
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巻 | 21巻
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出版者 | Elsevier
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開始ページ | 100515
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ISSN | 22144269
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資料タイプ |
学術雑誌論文
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言語 |
英語
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OAI-PMH Set |
岡山大学
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著作権者 | © 2019 The Authors. Published by Elsevier Inc.
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論文のバージョン | publisher
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PubMed ID | |
DOI | |
Web of Science KeyUT | |
関連URL | isVersionOf https://doi.org/10.1016/j.ymgmr.2019.100515
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ライセンス | http://creativecommons.org/licenses/by-nc-nd/4.0/
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Citation | Yokoi K, Nakajima Y, Shinkai Y, et al. Clinical and genetic aspects of mild hypophosphatasia in Japanese patients. Mol Genet Metab Rep. 2019;21:100515. Published 2019 Oct 11. doi:10.1016/j.ymgmr.2019.100515
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オープンアクセス(出版社) |
OA
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オープンアーカイブ(出版社) |
非OpenArchive
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