ArticleHuman mutation2020
Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia.
Article in Human mutation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 54 citations in OpenAlex.
- [Clinical and genetic characteristics and follow-up of 12 children with hypophosphatasia].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2026Article
- Hypophosphatasia: Results of a Country-Wide Selective Screening Program Using NGS Technology as a First-Tier Test.International journal of molecular sciences · 2026Article
- Evolving Therapeutic Paradigms in Pediatric Hypophosphatasia: From Survival-Driven Care to Integrated Precision Management.International journal of molecular sciences · 2026Review
- 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
- Integrated Genetic and Biochemical Approach to Patients with Bone Disorders Exhibiting Low Alkaline Phosphatase.Calcified tissue international · 2026Article
- Biochemical phenotype of hypophosphatasia in asymptomatic individuals carrying ALPL variants.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2026Article
- Seasonal Variation in WildMolecules (Basel, Switzerland) · 2026Article
- Article
- The Global Hypophosphatasia Registry: lessons learned from a decade of real-world data.Orphanet journal of rare diseases · 2025Review
- Functional andCells · 2025Article
- Revisiting the Genetics of Hypophosphatasia.Journal of inherited metabolic disease · 2025Review
- Genome sequencing in a cohort of 32 fetuses with genetic skeletal disorders.European journal of human genetics : EJHG · 2025Article
- A novel dominant negative variant ofJBMR plus · 2025Article
- Multigenerational genetic inheritance and clinical characteristics of the rare disease hypophosphatasia in 6 families: A case series.Bone reports · 2025Article
- Lifetime follow-up of an adult patient with pediatric-onset hypophosphatasia complicated with advanced chronic kidney disease.Bone reports · 2025Article
- Article
- Safety and efficacy of long term asfotase alfa treatment in childhood hypophosphatasia.Italian journal of pediatrics · 2025Article
- Article
- Comprehensive treatment approaches for skeletal deformities in hypophosphatasia: a case study ofFrontiers in pediatrics · 2025Article
- Severe hypoplastic enamel as a primary manifestation of hypophosphatasia: A case report.Journal of dental sciences · 2025Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypophosphatasia (HPP) is a rare metabolic disorder characterized by low tissue-nonspecific alkaline phosphatase (TNSALP) typically caused by ALPL gene mutations. HPP is heterogeneous, with clinical presentation correlating with residual TNSALP activity and/or dominant-negative effects (DNE). We measured residual activity and DNE for 155 ALPL variants by transient transfection and TNSALP enzymatic activity measurement. Ninety variants showed low residual activity and 24 showed DNE. These results encompass all missense variants with carrier frequencies above 1/25,000 from the Genome Aggregation Database. We used resulting data as a reference to develop a new computational algorithm that scores ALPL missense variants and predicts high/low TNSALP enzymatic activity. Our approach measures the effects of amino acid changes on TNSALP dimer stability with a physics-based implicit solvent energy model. We predict mutation deleteriousness with high specificity, achieving a true-positive rate of 0.63 with false-positive rate of 0, with an area under receiver operating curve (AUC) of 0.9, better than all in silico predictors tested. Combining this algorithm with other in silico approaches can further increase performance, reaching an AUC of 0.94. This study expands our understanding of HPP heterogeneity and genotype/phenotype relationships with the aim of improving clinical ALPL variant interpretation.
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