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



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.


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.


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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  1. 1.

    Mornet E (2015) Molecular genetics of hypophosphatasia and phenotype-genotype correlations. Subcell Biochem 76:25–43

    CAS  Article  Google Scholar 

  2. 2.

    Michigami T, Tachikawa K, Yamazaki M, Kawai M, Kubota T, Ozono K (2020) Hypophosphatasia in Japan: ALPL mutation analysis in 98 unrelated patients. Calcif Tissue Int 106:221–231

    CAS  Article  Google Scholar 

  3. 3.

    Cai G, Michigami T, Yamamoto T, Yasui N, Satomura K, Yamagata M, Shima M, Nakajima S, Mushiake S, Okada S, Ozono K (1998) Analysis of localization of mutated tissue-nonspecific alkaline phosphatase proteins associated with neonatal hypophosphatasia using green fluorescent protein chimeras. J Clin Endocrinol Metab 83:3936–3942

    CAS  PubMed  Google Scholar 

  4. 4.

    Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Ruther W, Amling M, Barvencik F (2017) Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int 28:2653–2662

    CAS  Article  Google Scholar 

  5. 5.

    Hofmann C, Girschick H, Mornet E, Schneider D, Jakob F, Mentrup B (2014) Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia. Eur J Hum Genet 22:1160–1164

    CAS  Article  Google Scholar 

  6. 6.

    Hogler W, Langman C, Gomes da Silva H, Fang S, Linglart A, Ozono K, Petryk A, Rockman-Greenberg C, Seefried L, Kishnani PS (2019) Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry. BMC Musculoskelet Disord 20:80

    Article  Google Scholar 

  7. 7.

    Sutton RA, Mumm S, Coburn SP, Ericson KL, Whyte MP (2012) “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res 27:987–994

    CAS  Article  Google Scholar 

  8. 8.

    Kato M, Hattori T, Shimizu T, Ninagawa K, Izumihara R, Nomoto H, Tanimura K, Atsumi T (2020) Intrafamilial phenotypic distinction of hypophosphatasia with identical tissue nonspecific alkaline phosphatase gene mutation: a family report. J Bone Miner Metab 38:903–907

    CAS  Article  Google Scholar 

  9. 9.

    Vaisman DN, McCarthy AD, Cortizo AM (2005) Bone-specific alkaline phosphatase activity is inhibited by bisphosphonates: role of divalent cations. Biol Trace Elem Res 104:131–140

    CAS  Article  Google Scholar 

  10. 10.

    Genest F, Claussen L, Rak D, Seefried L (2020) Bone mineral density and fracture risk in adult patients with hypophosphatasia. Osteoporos. Int Online ahead of print

  11. 11.

    Silvent J, Gasse B, Mornet E, Sire JY (2014) Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia. J Biol Chem 289:24168–24179

    CAS  Article  Google Scholar 

  12. 12.

    Brun-Heath I, Lia-Baldini AS, Maillard S, Taillandier A, Utsch B, Nunes ME, Serre JL, Mornet E (2007) Delayed transport of tissue-nonspecific alkaline phosphatase with missense mutations causing hypophosphatasia. Eur J Med Genet 50:367–378

    Article  Google Scholar 

  13. 13.

    Lia-Baldini AS, Brun-Heath I, Carrion C, Simon-Bouy B, Serre JL, Nunes ME, Mornet E (2008) A new mechanism of dominance in hypophosphatasia: the mutated protein can disturb the cell localization of the wild-type protein. Hum Genet 123:429–432

    CAS  Article  Google Scholar 

  14. 14.

    Ikenoue S, Miyakoshi K, Ishii T, Sato Y, Otani T, Akiba Y, Kasuga Y, Ochiai D, Matsumoto T, Ichihashi Y, Matsuzaki Y, Tachikawa K, Michigami T, Nishimura G, Ikeda K, Hasegawa T, Tanaka M (2018) Discordant fetal phenotype of hypophosphatasia in two siblings. Am J Med Genet A 176:171–174

    CAS  Article  Google Scholar 

  15. 15.

    Wan J, Zhang L, Liu T, Wang Y (2017) Genetic evaluations of Chinese patients with odontohypophosphatasia resulting from heterozygosity for mutations in the tissue-non-specific alkaline phosphatase gene. Oncotarget 8:51569–51577

    Article  Google Scholar 

  16. 16.

    Matsuda N, Takasawa K, Ohata Y, Takishima S, Kubota T, Ishihara Y, Fujiwara M, Ogawa E, Morio T, Kashimada K, Ozono K (2020) Potential pathological role of single nucleotide polymorphism (c.787T>C) in alkaline phosphatase (ALPL) for the phenotypes of hypophosphatasia. Endocr J Online ahead of print

  17. 17.

    Goseki-Sone M, Sogabe N, Fukushi-Irie M, Mizoi L, Orimo H, Suzuki T, Nakamura H, Orimo H, Hosoi T (2005) Functional analysis of the single nucleotide polymorphism (787T>C) in the tissue-nonspecific alkaline phosphatase gene associated with BMD. J Bone Miner Res 20:773–782

    CAS  Article  Google Scholar 

  18. 18.

    Taillandier A, Domingues C, Dufour A, Debiais F, Guggenbuhl P et al (2018) Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab 36:723–733

    CAS  Article  Google Scholar 

  19. 19.

    Wu LN, Genge BR, Lloyd GC, Wuthier RE (1991) Collagen-binding proteins in collagenase-released matrix vesicles from cartilage. Interaction between matrix vesicle proteins and different types of collagen. J Biol Chem 266:1195–1203

    CAS  Article  Google Scholar 

  20. 20.

    Bossi M, Hoylaerts MF, Millan JL (1993) Modifications in a flexible surface loop modulate the isozyme-specific properties of mammalian alkaline phosphatases. J Biol Chem 268:25409–25416

    CAS  Article  Google Scholar 

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We thank Dr. Olga Amengual for proofreading.


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Corresponding author

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).

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  • Hypophosphatasia
  • Adult hypophosphatasia
  • ALPL gene
  • Novel mutation