Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia Sanabria de la Torre, Raquel Martínez Heredia, Luis González Salvatierra, Sheila Andújar Vera, Francisco Luis Villa Suárez, Juan Miguel Contreras Bolívar, Victoria Corbacho Soto, Mario Martínez Navajas, Gonzalo Real Luna, Pedro José García Fontana, Cristina Muñoz Torres, Manuel Eduardo García Fontana, Beatriz Alkaline phosphatase Bone Hypophosphatasia Mineralization Genetic variant Enzymatic activity Pyridoxal 5' phosphate This research was funded by the Instituto de Salud Carlos III grants (PI18-00803, PI21/01069 and PI18-01235), co-funded by the European Regional Development Fund (FEDER) and by Junta de Andalucia grant (PI-0268-2019). In addition, VC-B is supported by postdoctoral fellowship from Junta de Andalucia (RH-0141-2020) and JMV-S and SG-S are funded by predoctoral fellowships from Instituto de Salud Carlos III (CM19/00188 and FI19/00118 respectively). CG-F and RS-dT are funded by postdoctoral Sara Borrell fellowship and Research investigator grant in the framework of the youth guarantee Program from the Instituto de Salud Carlos III and the University of Granada with co-funding by FEDER respectively (CD20/00022 and 8110 grant number). GM-N is supported by the predoctoral program from Instituto de Salud Carlos III (FI17/00178) and PR is a Ramon y Cajal Researcher from the MINECO (RYC-2015-18383) at GENyO and University of Granada. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. 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. 2022-06-08T06:37:00Z 2022-06-08T06:37:00Z 2022-04-14 info:eu-repo/semantics/article Sanabria-de la Torre R... [et al.] (2022) Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia. Front. Endocrinol. 13:863940. doi: [10.3389/fendo.2022.863940] http://hdl.handle.net/10481/75320 10.3389/fendo.2022.863940 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España Frontiers