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A novel combination of biallelic ALPL mutations associated with adult hypophosphatasia: A phenotype-genotype association and computational analysis study.
Martins, Luciane; de Almeida, Amanda Bandeira; Dos Santos, Elis Janaína Lira; Foster, Brian L; Machado, Renato Assis; Kantovitz, Kamila Rosamilia; Coletta, Ricardo D; Nociti, Francisco H.
Afiliação
  • Martins L; Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, University of Campinas - UNICAMP, Piracicaba, SP, Brazil.
  • de Almeida AB; Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, University of Campinas - UNICAMP, Piracicaba, SP, Brazil.
  • Dos Santos EJL; Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, University of Campinas - UNICAMP, Piracicaba, SP, Brazil.
  • Foster BL; Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA.
  • Machado RA; Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas - UNICAMP, Piracicaba, SP, Brazil.
  • Kantovitz KR; Department of Pediatric Dentistry, Piracicaba Dental School, University of Campinas - UNICAMP, Piracicaba, SP, Brazil; Department of Dental Materials, São Leopoldo Mandic School of Dentistry and Research Center, Campinas, SP, Brazil.
  • Coletta RD; Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas - UNICAMP, Piracicaba, SP, Brazil.
  • Nociti FH; Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, University of Campinas - UNICAMP, Piracicaba, SP, Brazil. Electronic address: nociti@unicamp.br.
Bone ; 125: 128-139, 2019 08.
Article em En | MEDLINE | ID: mdl-31077853
Hypophosphatasia (HPP) is an inherited metabolic disorder that causes defective skeletal and dental mineralization. HPP exhibits a markedly heterogeneous range of clinical manifestations caused by dysfunction of the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP), resulting from loss-of-function mutations in the ALPL gene. HPP has been associated with predominantly missense mutations in ALPL, and a number of compound heterozygous genotypes have been identified. Here, we describe a case of a subject with adult-onset HPP caused by a novel combination of missense mutations p.Gly473Ser and p.Ala487Val, resulting in chronic musculoskeletal pain, myopathy, persistent fatigue, vomiting, and an uncommon dental phenotype of short-rooted permanent teeth. Pedigree and biochemical analysis indicated that severity of symptoms was correlated with levels of residual ALP activity, and co-segregated with the p.Gly473Ser missense mutation. Bioinformatic analysis to predict the structural and functional impact of each of the point mutations in the TNSALP molecule, and its potential contribution to the clinical symptoms, revealed that the affected Gly473 residue is localized in the homodimer interface and predicted to have a dominant negative effect. The affected Ala487 residue was predicted to bind to Tyr479, which is closely located the N-terminal α-helix of TNSALP monomer 2, suggesting that both changes may impair dimer stability and catalytic functions. In conclusion, these findings assist in defining genotype-phenotype associations for HPP, and further define specific sites within the TNSALP molecule potentially related to neuromuscular manifestations in adult HPP, allowing for a better understanding of HPP pathophysiology.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipofosfatasia / Mutação Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male Idioma: En Revista: Bone Assunto da revista: METABOLISMO / ORTOPEDIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipofosfatasia / Mutação Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male Idioma: En Revista: Bone Assunto da revista: METABOLISMO / ORTOPEDIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos