Potential pathological role of single nucleotide polymorphism (c.787T>C) in <i>alkaline phosphatase (ALPL)</i> for the phenotypes of hypophosphatasia
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- Matsuda Nozomi
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan Department of Pediatrics, Soka Municipal Hospital, Saitama 340-8560, Japan
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- Takasawa Kei
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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- Ohata Yasuhisa
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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- Takishima Shigeru
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan Department of Pediatrics, Soka Municipal Hospital, Saitama 340-8560, Japan
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- Kubota Takuo
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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- Ishihara Yasuki
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan The first Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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- Fujiwara Makoto
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan The first Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan
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- Ogawa Erika
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo 101-8309, Japan
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- Morio Tomohiro
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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- Kashimada Kenichi
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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- Ozono Keiichi
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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Abstract
<p>Hypophosphatasia (HPP; OMIM 241510, 241500, and 146300) is an inherited metabolic disease characterized by defects of bone and tooth mineralization, which is caused by loss-of-function mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP). In the last three decades, several studies have focused on the genotype-phenotype correlation in hypophosphatasia (HPP). In particular, functional tests based on in vitro analysis for the residual enzymatic activities of mutations have revealed a clear but imperfect genotype-phenotype correlation, suggesting that multiple potential factors modulate the phenotype. One of the missense variants identified in the tissue non-specific alkaline phosphatase (ALPL) gene, c.787T>C, has been considered as a benign polymorphism in HPP; however, its pathogenicity and role in disease manifestation remain controversial. We here report our recent experience of three unrelated families harboring the c.787T>C variant, suggesting clinical implications regarding the controversial pathogenicity of c.787T>C. First, despite the lack of obvious clinical phenotypes, homozygous c.787T>C would decrease the serum level of ALP activity. Second, c.787T>C might deteriorate phenotypes of a patient harboring another ALPL variant, especially one that has thus far presumed to be benign, e.g., the c.1144G>A variant. These cases contribute to the recent advances in understanding HPP to facilitate clinical recognition of more subtle phenotypes, further providing insights into the pathogenesis of HPP.</p>
Journal
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- Endocrine Journal
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Endocrine Journal 67 (12), 1227-1232, 2020
The Japan Endocrine Society
