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Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family

Abstract

Introduction

Hypophosphatasia (HPP) is caused by mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase (TNSALP) and inherited in either an autosomal recessive or autosomal dominant manner. It is characterized clinically by defective mineralization of bone, dental problems, and low serum ALP levels. In the current report, we demonstrate a novel mutation in the ALPL gene (c.244G > A p.Gly82Arg) in a Japanese family with low serum ALP levels.

Materials and methods

The ALPL gene analysis using hybridization capture-based next-generation sequencing was performed. The expression plasmids of the wild type and mutated TNSALP were introduced into COS-7 cells. The enzymatic activity of ALP in the cell lysates was measured using p-nitrophenylphosphate as a substrate.

Results

TNSALP with the novel ALPL mutation (c.244G > A p.Gly82Arg) completely lost its enzymatic activity and suppressed that of wild-type TNSALP, corroborating its dominant negative effect. The diagnosis of autosomal dominant HPP was confirmed in three members of the family.

Conclusion

Our approach would help to avoid the inappropriate use of bone resorption inhibitors for currently mis- or under-diagnosed HPP, given that the presence of further, yet undetected mutations of the ALPL gene are plausible.

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Acknowledgements

We thank Dr. Olga Amengual for proofreading.

Funding

No funding was received.

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Correspondence to Masaru Kato.

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Conflict of interests

Masaru Kato has received research grants from AbbVie, Actelion, and GlaxoSmithKline and speaking fees from Eli Lilly. Tatsuya Atsumi has received research grants from Astellas, Takeda, Mitsubishi Tanabe, Chugai, Daiichi-Sankyo, Otsuka, Pfize, Alexion, Bayer, Otsuka, Chugai, Takeda, Eisai, Bristol-Myers Squibb, Daiichi Sankyo, Mitsubishi Tanabe and AsahiKasei, consultant fees from Ono, Sanofi, Daiichi Sankyo and Pfizer and speaking fees from Mitsubishi Tanabe, Chugai, Astellas, Takeda, Pfizer, Daiichi Sankyo, Bristol-Myers Squibb and Eli Lilly. Other authors have nothing to declare.

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Kato, M., Michigami, T., Tachikawa, K. et al. Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family. J Bone Miner Metab 39, 804–809 (2021). https://doi.org/10.1007/s00774-021-01219-0

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Keywords

  • Hypophosphatasia
  • Adult hypophosphatasia
  • ALPL gene
  • Novel mutation