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Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface.
Martins, Luciane; Lessa, Luis Gustavo F; Ali, Taccyanna M; Lazar, Monize; Kim, Chong A; Kantovitz, Kamila R; Santamaria, Mauro P; Araújo, Cássia F; Ramos, Carolina J; Foster, Brian L; Franco, José Francisco S; Bertola, Débora; Nociti, Francisco H.
Afiliación
  • Martins L; Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Haifa 3436212, Israel.
  • Lessa LGF; Department of Research, São Leopoldo Mandic School of Dentistry and Research Center, Campinas, São Paulo 13045-755, Brazil.
  • Ali TM; Centro de Estudos do Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo 05508-090, Brazil.
  • Lazar M; Centro de Estudos do Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo 05508-090, Brazil.
  • Kim CA; Clinical Genetics, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil.
  • Kantovitz KR; Department of Biomaterials, São Leopoldo Mandic School of Dentistry and Research Center, Campinas, São Paulo 13045-755, Brazil.
  • Santamaria MP; Center for Oral Health Research, University of Kentucky, College of Dentistry, Lexington, KY 40536, USA.
  • Araújo CF; Department of Diagnosis and Surgery, Institute of Science and Technology, São Paulo State University (UNESP), São José dos Campos, São Paulo 12245-000, Brazil.
  • Ramos CJ; Department of Diagnosis and Surgery, Institute of Science and Technology, São Paulo State University (UNESP), São José dos Campos, São Paulo 12245-000, Brazil.
  • Foster BL; Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA.
  • Franco JFS; Center 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, São Paulo 05508-000, Brazil.
  • Bertola D; Centro de Estudos do Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo 05508-090, Brazil.
  • Nociti FH; Clinical Genetics, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil.
Int J Mol Sci ; 24(1)2022 Dec 23.
Article en En | MEDLINE | ID: mdl-36613725
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatasa Alcalina / Hipofosfatasia Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Child / Female / Humans Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatasa Alcalina / Hipofosfatasia Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Child / Female / Humans Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Suiza