Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.3390/ijms24010282 http://hdl.handle.net/11449/249026 |
Resumo: | The 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. |
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Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface3D modelingalkaline phosphatasegenotype–phenotype associationhypophosphatasiapremature tooth lossThe 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.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Institute of Dental and Craniofacial ResearchSoft BonesDepartment of Community Medicine and Epidemiology CHS National Cancer Control CenterDepartment of Research São Leopoldo Mandic School of Dentistry and Research CenterCentro de Estudos do Genoma Humano e Células-Tronco Instituto de Biociências Universidade de São PauloClinical Genetics Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São PauloDepartment of Biomaterials São Leopoldo Mandic School of Dentistry and Research CenterCenter for Oral Health Research University of Kentucky College of DentistryDepartment of Diagnosis and Surgery Institute of Science and Technology São Paulo State University (UNESP)Division of Biosciences College of Dentistry The Ohio State UniversityCenter of Research and Molecular Diagnosis of Genetic Diseases Department of Biophysics UNIFESP and Biotecnologic Centre Energy and Nuclear Research Institute (IPEN) Universidade de São PauloDepartment of Diagnosis and Surgery Institute of Science and Technology São Paulo State University (UNESP)CNPq: #304680/2014-1CNPq: 301086/2019-2 (FHNJ)National Institute of Dental and Craniofacial Research: R03DE028411 (BLF)Soft Bones: R03DE028411 (BLF)CHS National Cancer Control CenterSão Leopoldo Mandic School of Dentistry and Research CenterUniversidade de São Paulo (USP)College of DentistryUniversidade Estadual Paulista (UNESP)The Ohio State UniversityMartins, LucianeLessa, Luis Gustavo F.Ali, Taccyanna M.Lazar, MonizeKim, Chong A.Kantovitz, Kamila R.Santamaria, Mauro P.Araújo, Cássia F. [UNESP]Ramos, Carolina J. [UNESP]Foster, Brian L.Franco, José Francisco S.Bertola, DéboraNociti, Francisco H.2023-07-29T14:00:23Z2023-07-29T14:00:23Z2023-01-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/ijms24010282International Journal of Molecular Sciences, v. 24, n. 1, 2023.1422-00671661-6596http://hdl.handle.net/11449/24902610.3390/ijms240102822-s2.0-85145887230Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengInternational Journal of Molecular Sciencesinfo:eu-repo/semantics/openAccess2023-07-29T14:00:23Zoai:repositorio.unesp.br:11449/249026Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462023-07-29T14:00:23Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface |
title |
Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface |
spellingShingle |
Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface Martins, Luciane 3D modeling alkaline phosphatase genotype–phenotype association hypophosphatasia premature tooth loss |
title_short |
Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface |
title_full |
Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface |
title_fullStr |
Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface |
title_full_unstemmed |
Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface |
title_sort |
Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface |
author |
Martins, Luciane |
author_facet |
Martins, Luciane Lessa, Luis Gustavo F. Ali, Taccyanna M. Lazar, Monize Kim, Chong A. Kantovitz, Kamila R. Santamaria, Mauro P. Araújo, Cássia F. [UNESP] Ramos, Carolina J. [UNESP] Foster, Brian L. Franco, José Francisco S. Bertola, Débora Nociti, Francisco H. |
author_role |
author |
author2 |
Lessa, Luis Gustavo F. Ali, Taccyanna M. Lazar, Monize Kim, Chong A. Kantovitz, Kamila R. Santamaria, Mauro P. Araújo, Cássia F. [UNESP] Ramos, Carolina J. [UNESP] Foster, Brian L. Franco, José Francisco S. Bertola, Débora Nociti, Francisco H. |
author2_role |
author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
CHS National Cancer Control Center São Leopoldo Mandic School of Dentistry and Research Center Universidade de São Paulo (USP) College of Dentistry Universidade Estadual Paulista (UNESP) The Ohio State University |
dc.contributor.author.fl_str_mv |
Martins, Luciane Lessa, Luis Gustavo F. Ali, Taccyanna M. Lazar, Monize Kim, Chong A. Kantovitz, Kamila R. Santamaria, Mauro P. Araújo, Cássia F. [UNESP] Ramos, Carolina J. [UNESP] Foster, Brian L. Franco, José Francisco S. Bertola, Débora Nociti, Francisco H. |
dc.subject.por.fl_str_mv |
3D modeling alkaline phosphatase genotype–phenotype association hypophosphatasia premature tooth loss |
topic |
3D modeling alkaline phosphatase genotype–phenotype association hypophosphatasia premature tooth loss |
description |
The 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. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-07-29T14:00:23Z 2023-07-29T14:00:23Z 2023-01-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.3390/ijms24010282 International Journal of Molecular Sciences, v. 24, n. 1, 2023. 1422-0067 1661-6596 http://hdl.handle.net/11449/249026 10.3390/ijms24010282 2-s2.0-85145887230 |
url |
http://dx.doi.org/10.3390/ijms24010282 http://hdl.handle.net/11449/249026 |
identifier_str_mv |
International Journal of Molecular Sciences, v. 24, n. 1, 2023. 1422-0067 1661-6596 10.3390/ijms24010282 2-s2.0-85145887230 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
International Journal of Molecular Sciences |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1803046274250833920 |