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Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia

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Abstract

A total of 22 Japanese patients with hypophosphatasia were included in a study analysing the relationship between mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene and the severity of the phenotype in Japanese patients with hypophosphatasia. The enzymatic activity of some of the identified mutant TNSALP proteins was also examined using corresponding expression vectors. Eighteen mutations, including 6 novel ones, were identified in the patients. Among them, the common mutations were F310L and T1559del. Of note, five patients with F310L mutation in one of the alleles exhibited a relatively mild phenotype without respiratory complications despite its perinatal onset. In contrast, the T1559del mutation is associated with perinatal lethal and infantile forms when not found in patients with the F310L mutation. The genotype-phenotype relationship was, to some extent, consistent with the enzymatic activity of the mutant ALP proteins; mutations K207E and G409C found in a surviving case of infantile hypophosphatasia, as well as F310L, retained some residual activities, whereas T1559del caused a complete loss of activity. Conclusion:In Japanese patients, the common mutations F310L and T1559del are associated with the relatively mild and lethal forms of hypophosphatasia, respectively. Our results may enhance the importance of genotyping patients with hypophosphatasia to predict their prognosis.

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Abbreviations

TNSALP :

tissue-nonspecific alkaline phosphatase

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Acknowledgements

We thank Dr. P. S. Henthorn of the University of Pennsylvania School of Veterinary Medicine for generously providing the TNSALP expression vector. We also thank the physicians listed below for referring patients with hypophosphatasia for TNSALP gene analysis: Drs. Kennichi Satomura and Hidehiko Kawabata, Osaka Medical Centre and Research Institute for Maternal and Child Health; Dr. Norio Miharu, Hiroshima University; Dr. Tsuyoshi Oikawa, Jikei Medical University; Dr. Yu Ikeda, Shiga Medical University; Dr. Yasushi Uchida, Nagahama Municipal Hospital; Dr. Go Hasegawa, Nikko Memorial Hospital; Drs. Hiroyuki Tanaka, Masaru Inoue, Okayama University School of Medicine; Dr. Toru Ogiwara, Osaka Medical School; Drs. Katshuhiko Tachibana, Masayuki Adachi, Tetshusi Ueno, Hiroshima Municipal Hospital; Dr. Hiroshi Mochizuki, Saitama Medical Centre; Dr. Oguchi, Hata Hospital; Dr. Shuichiro Akagi, Chifune Hospital; Dr. Yuka Sasamoto, St. Marianna University; Dr. Kusuki, Osaka Medical Centre; Dr. Ichiba, Osaka City University.

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Authors and Affiliations

  1. Department of Environmental Medicine, Osaka Medical Centre and Research Institute for Maternal and Child Health, Osaka, Japan

    Toshimi Michigami, Takayuki Uchihashi, Akira Suzuki & Kanako Tachikawa

  2. Department of Paediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Shigeo Nakajima & Keiichi Ozono

Authors
  1. Toshimi Michigami
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  2. Takayuki Uchihashi
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  3. Akira Suzuki
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  4. Kanako Tachikawa
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  5. Shigeo Nakajima
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  6. Keiichi Ozono
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Correspondence to Keiichi Ozono.

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Michigami, T., Uchihashi, T., Suzuki, A. et al. Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia. Eur J Pediatr 164, 277–282 (2005). https://doi.org/10.1007/s00431-004-1612-9

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  • DOI: https://doi.org/10.1007/s00431-004-1612-9

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