ArticleThe Journal of biological chemistry2014
Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 64 citations in OpenAlex.
- Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia.The Journal of clinical investigation · 2017Trial
- Identification of hypophosphatasia in adults with persistent hypophosphatasemia: clinical-genetic characterization and a validated diagnostic tool.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2026Article
- Evolving Therapeutic Paradigms in Pediatric Hypophosphatasia: From Survival-Driven Care to Integrated Precision Management.International journal of molecular sciences · 2026Review
- External validation of the proposed diagnostic criteria for hypophosphatasia in adults of a Spanish cohort.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2026Article
- Bilateral healing of pseudofractures in hypophosphatasia with teriparatide: a case report.Journal of medical case reports · 2026Article
- Lifetime follow-up of an adult patient with pediatric-onset hypophosphatasia complicated with advanced chronic kidney disease.Bone reports · 2025Article
- Article
- ROCK1 promotes B cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI.JCI insight · 2025Article
- Establishment of human periodontal ligament cell lines withFrontiers in cell and developmental biology · 2025Article
- Adult-onset hypophosphatasia diagnosed after consecutive tooth loss during orthodontic treatment: a case report.Journal of medical case reports · 2024Article
- Short stature with low serum alkaline phosphatase activity: a case report of hypophosphatasia.Annals of pediatric endocrinology & metabolism · 2023Article
- Musculoskeletal pain and muscular weakness as the main symptoms of adult hypophosphatasia in a Spanish cohort: clinical characterization and identification of a new ALPL gene variant.Journal of bone and mineral metabolism · 2023Article
- Current status ofRSC advances · 2023Review
- A unique case of childhood hypophosphatasia caused by a novel heterozygous 51-bp in-frame deletion in theClinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2023Article
- Atypical Femoral Fracture in Hypophosphatasia: A Systematic Review.International journal of endocrinology · 2023Article
- Systemic effects of hypophosphatasia characterization of two novel variants in theFrontiers in endocrinology · 2023Article
- Biochemical algorithm to identify individuals with ALPL variants among subjects with persistent hypophosphatasaemia.Orphanet journal of rare diseases · 2022Article
- Dissecting mutational allosteric effects in alkaline phosphatases associated with different Hypophosphatasia phenotypes: An integrative computational investigation.PLoS computational biology · 2022Article
- The Physiological and Pathological Role of Tissue Nonspecific Alkaline Phosphatase beyond Mineralization.Biomolecules · 2021Review
- Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family.Journal of bone and mineral metabolism · 2021Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ALPL encodes the tissue nonspecific alkaline phosphatase (TNSALP), which removes phosphate groups from various substrates. Its function is essential for bone and tooth mineralization. In humans, ALPL mutations lead to hypophosphatasia, a genetic disorder characterized by defective bone and/or tooth mineralization. To date, 275 ALPL mutations have been reported to cause hypophosphatasia, of which 204 were simple missense mutations. Molecular evolutionary analysis has proved to be an efficient method to highlight residues important for the protein function and to predict or validate sensitive positions for genetic disease. Here we analyzed 58 mammalian TNSALP to identify amino acids unchanged, or only substituted by residues sharing similar properties, through 220 millions years of mammalian evolution. We found 469 sensitive positions of the 524 residues of human TNSALP, which indicates a highly constrained protein. Any substitution occurring at one of these positions is predicted to lead to hypophosphatasia. We tested the 204 missense mutations resulting in hypophosphatasia against our predictive chart, and validated 99% of them. Most sensitive positions were located in functionally important regions of TNSALP (active site, homodimeric interface, crown domain, calcium site, …). However, some important positions are located in regions, the structure and/or biological function of which are still unknown. Our chart of sensitive positions in human TNSALP (i) enables to validate or invalidate at low cost any ALPL mutation, which would be suspected to be responsible for hypophosphatasia, by contrast with time consuming and expensive functional tests, and (ii) displays higher predictive power than in silico models of prediction.
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