@misc{10481/75320,
year = {2022},
month = {4},
url = {http://hdl.handle.net/10481/75320},
abstract = {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.},
organization = {Instituto de Salud Carlos III
European Commission	PI21/01069	
PI18-01235	
CM19/00188	
FI19/00118	
FI17/00178	
PI18-00803},
organization = {European Commission},
organization = {Junta de Andalucia	PI-0268-2019	
RH-0141-2020},
organization = {University of Granada},
organization = {European Commission	CD20/00022	
8110},
organization = {Spanish Government	RYC-2015-18383},
publisher = {Frontiers},
keywords = {Alkaline phosphatase},
keywords = {Bone},
keywords = {Hypophosphatasia},
keywords = {Mineralization},
keywords = {Genetic variant},
keywords = {Enzymatic activity},
keywords = {Pyridoxal 5' phosphate},
title = {Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia},
doi = {10.3389/fendo.2022.863940},
author = {Sanabria de la Torre, Raquel and Martínez Heredia, Luis and González Salvatierra, Sheila and Andújar Vera, Francisco Luis and Villa Suárez, Juan Miguel and Contreras Bolívar, Victoria and Corbacho Soto, Mario and Martínez Navajas, Gonzalo and Real Luna, Pedro José and García Fontana, Cristina and Muñoz Torres, Manuel Eduardo and García Fontana, Beatriz},
}