Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia
Hypophosphatasia (HPP) a rare disease caused by mutations in the ALPL gene encoding for the tissue-nonspecific alkaline phosphatase protein (TNSALP), has been identified as a potentially under-diagnosed condition worldwide which may have higher prevalence than currently established. This is largely...
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.863940/full |
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| author | Raquel Sanabria-de la Torre Raquel Sanabria-de la Torre Luis Martínez-Heredia Luis Martínez-Heredia Sheila González-Salvatierra Sheila González-Salvatierra Francisco Andújar-Vera Francisco Andújar-Vera Francisco Andújar-Vera Iván Iglesias-Baena Juan Miguel Villa-Suárez Juan Miguel Villa-Suárez Victoria Contreras-Bolívar Victoria Contreras-Bolívar Mario Corbacho-Soto Gonzalo Martínez-Navajas Gonzalo Martínez-Navajas Pedro J. Real Pedro J. Real Pedro J. Real Cristina García-Fontana Cristina García-Fontana Cristina García-Fontana Manuel Muñoz-Torres Manuel Muñoz-Torres Manuel Muñoz-Torres Manuel Muñoz-Torres Beatriz García-Fontana Beatriz García-Fontana Beatriz García-Fontana |
| author_facet | Raquel Sanabria-de la Torre Raquel Sanabria-de la Torre Luis Martínez-Heredia Luis Martínez-Heredia Sheila González-Salvatierra Sheila González-Salvatierra Francisco Andújar-Vera Francisco Andújar-Vera Francisco Andújar-Vera Iván Iglesias-Baena Juan Miguel Villa-Suárez Juan Miguel Villa-Suárez Victoria Contreras-Bolívar Victoria Contreras-Bolívar Mario Corbacho-Soto Gonzalo Martínez-Navajas Gonzalo Martínez-Navajas Pedro J. Real Pedro J. Real Pedro J. Real Cristina García-Fontana Cristina García-Fontana Cristina García-Fontana Manuel Muñoz-Torres Manuel Muñoz-Torres Manuel Muñoz-Torres Manuel Muñoz-Torres Beatriz García-Fontana Beatriz García-Fontana Beatriz García-Fontana |
| author_sort | Raquel Sanabria-de la Torre |
| collection | DOAJ |
| description | Hypophosphatasia (HPP) a rare disease caused by mutations in the ALPL gene encoding for the tissue-nonspecific alkaline phosphatase protein (TNSALP), has been identified as a potentially under-diagnosed condition worldwide which may have higher prevalence than currently established. This is largely due to the overlapping of its symptomatology with that of other more frequent pathologies. Although HPP is usually associated with deficient bone mineralization, the high genetic variability of ALPL results in high clinical heterogeneity, which makes it difficult to establish a specific HPP symptomatology. In the present study, three variants of ALPL gene with uncertain significance and no previously described (p.Del Glu23_Lys24, p.Pro292Leu and p.His379Asn) were identified in heterozygosis in patients diagnosed with HPP. These variants were characterized at phenotypic, functional and structural levels. All genetic variants showed significantly lower in vitro ALP activity than the wild-type (WT) genotype (p-value <0.001). Structurally, p.His379Asn variant resulted in the loss of two Zn2+ binding sites in the protein dimer which may greatly affect ALP activity. In summary, we identified three novel ALPL gene mutations associated with adult HPP. The correct identification and characterization of new variants and the subsequent study of their phenotype will allow the establishment of genotype-phenotype relationships that facilitate the management of the disease as well as making it possible to individualize treatment for each specific patient. This would allow the therapeutic approach to HPP to be personalized according to the unique genetic characteristics and clinical manifestations of each patient. |
| first_indexed | 2024-12-10T13:09:44Z |
| format | Article |
| id | doaj.art-6b8f1fbf88af40f096d6a33378987f4e |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-10T13:09:44Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-6b8f1fbf88af40f096d6a33378987f4e2022-12-22T01:47:42ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-04-011310.3389/fendo.2022.863940863940Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult HypophosphatasiaRaquel Sanabria-de la Torre0Raquel Sanabria-de la Torre1Luis Martínez-Heredia2Luis Martínez-Heredia3Sheila González-Salvatierra4Sheila González-Salvatierra5Francisco Andújar-Vera6Francisco Andújar-Vera7Francisco Andújar-Vera8Iván Iglesias-Baena9Juan Miguel Villa-Suárez10Juan Miguel Villa-Suárez11Victoria Contreras-Bolívar12Victoria Contreras-Bolívar13Mario Corbacho-Soto14Gonzalo Martínez-Navajas15Gonzalo Martínez-Navajas16Pedro J. Real17Pedro J. Real18Pedro J. Real19Cristina García-Fontana20Cristina García-Fontana21Cristina García-Fontana22Manuel Muñoz-Torres23Manuel Muñoz-Torres24Manuel Muñoz-Torres25Manuel Muñoz-Torres26Beatriz García-Fontana27Beatriz García-Fontana28Beatriz García-Fontana29Department of Medicine, University of Granada, Granada, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainDepartment of Medicine, University of Granada, Granada, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainDepartment of Medicine, University of Granada, Granada, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainDepartment of Computer Science and Artificial Intelligence, University of Granada, Granada, SpainAndalusian Research Institute in Data Science and Computational Intelligence (DaSCI Institute), Granada, SpainEuropean University Miguel de Cervantes, Valladolid, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainClinical Analysis Unit, University Hospital Clínico San Cecilio, Granada, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainEndocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, SpainDepartment of Medicine, University of Granada, Granada, SpainGene Regulation, Stem Cells and Development Lab, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, SpainDepartment of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Granada, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainGene Regulation, Stem Cells and Development Lab, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, SpainDepartment of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Granada, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainEndocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain0Biomedical Research Network in Fragility and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, SpainDepartment of Medicine, University of Granada, Granada, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainEndocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain0Biomedical Research Network in Fragility and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, SpainInstituto de Investigación Biosanitaria de Granada, Granada, SpainEndocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain0Biomedical Research Network in Fragility and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, SpainHypophosphatasia (HPP) a rare disease caused by mutations in the ALPL gene encoding for the tissue-nonspecific alkaline phosphatase protein (TNSALP), has been identified as a potentially under-diagnosed condition worldwide which may have higher prevalence than currently established. This is largely due to the overlapping of its symptomatology with that of other more frequent pathologies. Although HPP is usually associated with deficient bone mineralization, the high genetic variability of ALPL results in high clinical heterogeneity, which makes it difficult to establish a specific HPP symptomatology. In the present study, three variants of ALPL gene with uncertain significance and no previously described (p.Del Glu23_Lys24, p.Pro292Leu and p.His379Asn) were identified in heterozygosis in patients diagnosed with HPP. These variants were characterized at phenotypic, functional and structural levels. All genetic variants showed significantly lower in vitro ALP activity than the wild-type (WT) genotype (p-value <0.001). Structurally, p.His379Asn variant resulted in the loss of two Zn2+ binding sites in the protein dimer which may greatly affect ALP activity. In summary, we identified three novel ALPL gene mutations associated with adult HPP. The correct identification and characterization of new variants and the subsequent study of their phenotype will allow the establishment of genotype-phenotype relationships that facilitate the management of the disease as well as making it possible to individualize treatment for each specific patient. This would allow the therapeutic approach to HPP to be personalized according to the unique genetic characteristics and clinical manifestations of each patient.https://www.frontiersin.org/articles/10.3389/fendo.2022.863940/fullalkaline phosphatasebonehypophosphatasiamineralizationgenetic variantenzymatic activity |
| spellingShingle | Raquel Sanabria-de la Torre Raquel Sanabria-de la Torre Luis Martínez-Heredia Luis Martínez-Heredia Sheila González-Salvatierra Sheila González-Salvatierra Francisco Andújar-Vera Francisco Andújar-Vera Francisco Andújar-Vera Iván Iglesias-Baena Juan Miguel Villa-Suárez Juan Miguel Villa-Suárez Victoria Contreras-Bolívar Victoria Contreras-Bolívar Mario Corbacho-Soto Gonzalo Martínez-Navajas Gonzalo Martínez-Navajas Pedro J. Real Pedro J. Real Pedro J. Real Cristina García-Fontana Cristina García-Fontana Cristina García-Fontana Manuel Muñoz-Torres Manuel Muñoz-Torres Manuel Muñoz-Torres Manuel Muñoz-Torres Beatriz García-Fontana Beatriz García-Fontana Beatriz García-Fontana Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia Frontiers in Endocrinology alkaline phosphatase bone hypophosphatasia mineralization genetic variant enzymatic activity |
| title | Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia |
| title_full | Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia |
| title_fullStr | Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia |
| title_full_unstemmed | Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia |
| title_short | Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia |
| title_sort | characterization of genetic variants of uncertain significance for the alpl gene in patients with adult hypophosphatasia |
| topic | alkaline phosphatase bone hypophosphatasia mineralization genetic variant enzymatic activity |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.863940/full |
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