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<datestamp>2018-01-11</datestamp>
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<publisher>HAL CCSD</publisher>
<title lang=en>Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia</title>
<creator>Silvent, Jeremie</creator>
<creator>Gasse, Barbara</creator>
<creator>Mornet, Etienne</creator>
<creator>Sire, Jean-Yves</creator>
<contributor>Evolution et développement du squelette (EDS) ; Systématique, adaptation, évolution (SAE) ; Centre National de la Recherche Scientifique (CNRS) - Université Pierre et Marie Curie - Paris 6 (UPMC) - Centre National de la Recherche Scientifique (CNRS) - Université Pierre et Marie Curie - Paris 6 (UPMC) - Evolution Paris Seine ; Université des Antilles et de la Guyane (UAG) - Université Pierre et Marie Curie - Paris 6 (UPMC) - Université Nice Sophia Antipolis (UNS) ; Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA) - Centre National de la Recherche Scientifique (CNRS) - Université des Antilles et de la Guyane (UAG) - Université Nice Sophia Antipolis (UNS) ; Université Côte d'Azur (UCA) - Université Côte d'Azur (UCA)</contributor>
<contributor>CNRS</contributor>
<contributor> Universite Pierre Marie Curie</contributor>
<contributor> patients' support group Hypophosphatasie Europe</contributor>
<contributor> ``Societe Francaise de Biologie des Tissus Mineralises'' student award</contributor>
<description>International audience</description>
<source>ISSN: 0021-9258</source>
<source>EISSN: 1083-351X</source>
<source>Journal of Biological Chemistry</source>
<publisher>American Society for Biochemistry and Molecular Biology</publisher>
<identifier>hal-01545479</identifier>
<identifier>https://hal.archives-ouvertes.fr/hal-01545479</identifier>
<source>https://hal.archives-ouvertes.fr/hal-01545479</source>
<source>Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2014, 289 (35), pp.24168-24179. 〈10.1074/jbc.M114.576843〉</source>
<identifier>DOI : 10.1074/jbc.M114.576843</identifier>
<relation>info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M114.576843</relation>
<language>en</language>
<subject lang=en>Bioinformatics</subject>
<subject lang=en> Genetic Disease</subject>
<subject lang=en> Human Genetics</subject>
<subject lang=en> Mammal</subject>
<subject lang=en> Molecular Evolution</subject>
<subject>[SDV.BID.EVO] Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE]</subject>
<type>info:eu-repo/semantics/article</type>
<type>Journal articles</type>
<description lang=en>Background: We used evolutionary analysis of alkaline phosphatase (tissue nonspecific alkaline phosphatase, TNSALP) to predict missense mutations leading to hypophosphatasia. Results: We found 469 sensitive positions and validated 99% of the 204 known mutations. Conclusion: It is a more powerful method than in silico models to validate missense mutations in TNSALP. Significance: Such an approach should be widely used to support genetic diagnostics. 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.</description>
<date>2014-08</date>
</dc>
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