Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface

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Autor(es): dc.contributorCHS National Cancer Control Center-
Autor(es): dc.contributorSão Leopoldo Mandic School of Dentistry and Research Center-
Autor(es): dc.contributorUniversidade de São Paulo (USP)-
Autor(es): dc.contributorCollege of Dentistry-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorThe Ohio State University-
Autor(es): dc.creatorMartins, Luciane-
Autor(es): dc.creatorLessa, Luis Gustavo F.-
Autor(es): dc.creatorAli, Taccyanna M.-
Autor(es): dc.creatorLazar, Monize-
Autor(es): dc.creatorKim, Chong A.-
Autor(es): dc.creatorKantovitz, Kamila R.-
Autor(es): dc.creatorSantamaria, Mauro P.-
Autor(es): dc.creatorAraújo, Cássia F.-
Autor(es): dc.creatorRamos, Carolina J.-
Autor(es): dc.creatorFoster, Brian L.-
Autor(es): dc.creatorFranco, José Francisco S.-
Autor(es): dc.creatorBertola, Débora-
Autor(es): dc.creatorNociti, Francisco H.-
Data de aceite: dc.date.accessioned2025-08-21T17:22:43Z-
Data de disponibilização: dc.date.available2025-08-21T17:22:43Z-
Data de envio: dc.date.issued2023-07-29-
Data de envio: dc.date.issued2023-07-29-
Data de envio: dc.date.issued2022-12-31-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.3390/ijms24010282-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/249026-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/249026-
Descrição: dc.descriptionThe goal of this study was to perform a clinical and molecular investigation in an eight-year-old female child diagnosed with hypophosphatasia (HPP). The proband and her family were evaluated by medical and dental histories, biochemical analyses, radiographic imaging, and genetic analysis of the tissue-nonspecific alkaline phosphatase (ALPL) gene. A bioinformatic analysis was performed to predict the structural and functional impact of the point mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) molecule and to define their potential contribution to the phenotype. We identified a novel combination of heterozygous ALPL missense variants in the proband, p.Ala33Val and p.Asn47His, compatible with an autosomal recessive mode of inheritance and resulting in skeletal and dental phenotypes. Computational modeling showed that the affected Asn47 residue is located in the coil structure close to the N-terminal α-helix, whereas the affected Ala33 residue is localized in the N-terminal α-helix. Both affected residues are located close to the homodimer interface, suggesting they may impair TNSALP dimer formation and stability. Clinical and biochemical follow-up revealed improvements after six years of ERT. Reporting this novel combination of ALPL variants in childhood HPP provides new insights into genotype–phenotype associations for HPP and specific sites within the TNSALP molecule potentially related to a childhood-onset HPP and skeletal and dental manifestations. Beneficial effects of ERT are implicated in skeletal and dental tissues.-
Descrição: dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)-
Descrição: dc.descriptionNational Institute of Dental and Craniofacial Research-
Descrição: dc.descriptionSoft Bones-
Descrição: dc.descriptionDepartment of Community Medicine and Epidemiology CHS National Cancer Control Center-
Descrição: dc.descriptionDepartment of Research São Leopoldo Mandic School of Dentistry and Research Center-
Descrição: dc.descriptionCentro de Estudos do Genoma Humano e Células-Tronco Instituto de Biociências Universidade de São Paulo-
Descrição: dc.descriptionClinical Genetics Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo-
Descrição: dc.descriptionDepartment of Biomaterials São Leopoldo Mandic School of Dentistry and Research Center-
Descrição: dc.descriptionCenter for Oral Health Research University of Kentucky College of Dentistry-
Descrição: dc.descriptionDepartment of Diagnosis and Surgery Institute of Science and Technology São Paulo State University (UNESP)-
Descrição: dc.descriptionDivision of Biosciences College of Dentistry The Ohio State University-
Descrição: dc.descriptionCenter of Research and Molecular Diagnosis of Genetic Diseases Department of Biophysics UNIFESP and Biotecnologic Centre Energy and Nuclear Research Institute (IPEN) Universidade de São Paulo-
Descrição: dc.descriptionDepartment of Diagnosis and Surgery Institute of Science and Technology São Paulo State University (UNESP)-
Descrição: dc.descriptionCNPq: #304680/2014-1-
Descrição: dc.descriptionCNPq: 301086/2019-2 (FHNJ)-
Descrição: dc.descriptionNational Institute of Dental and Craniofacial Research: R03DE028411 (BLF)-
Descrição: dc.descriptionSoft Bones: R03DE028411 (BLF)-
Idioma: dc.languageen-
Relação: dc.relationInternational Journal of Molecular Sciences-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subject3D modeling-
Palavras-chave: dc.subjectalkaline phosphatase-
Palavras-chave: dc.subjectgenotype–phenotype association-
Palavras-chave: dc.subjecthypophosphatasia-
Palavras-chave: dc.subjectpremature tooth loss-
Título: dc.titleChildhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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