Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia
Metadatos
Mostrar el registro completo del ítemAutor
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, BeatrizEditorial
Frontiers
Materia
Alkaline phosphatase Bone Hypophosphatasia Mineralization Genetic variant Enzymatic activity Pyridoxal 5' phosphate
Fecha
2022-04-14Referencia bibliográfica
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]
Patrocinador
Instituto de Salud Carlos III European Commission PI21/01069 PI18-01235 CM19/00188 FI19/00118 FI17/00178 PI18-00803; European Commission; Junta de Andalucia PI-0268-2019 RH-0141-2020; University of Granada; European Commission CD20/00022 8110; Spanish Government RYC-2015-18383Resumen
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.