Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype

Author(s)

Martins, Luciane ^[1] ; Rodrigues, Thaisangela L. ^[1] ; Ribeiro, Mariana Martins ^[2] ; Saito, Miki Taketomi ^[1] ; Oliveira Giorgetti, Ana Paula ^[1] ; Casati, Marcio Z. ^[1] ; Sallum, Enilson A. ^[1] ; Foster, Brian L. ^[3] ; Somerman, Martha J. ^[3] ; Nociti, Jr., Francisco H. ^{[1, 3]}

Affiliation

^[1] Univ Campinas UNICAMP, Dept Prosthodont & Periodont, Div Periodont, Piracicaba Dent Sch, Piracicaba, SP - Brazil

^[2] Univ Campinas UNICAMP, Dept Morphol, Piracicaba Dent Sch, Piracicaba, SP - Brazil

^[3] Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Natl Inst Hlth NIH, Bethesda, MD - USA

• Document type: Journal article
• Source: BONE; v. 56, n. 2, p. 390-397, OCT 2013.
• Web of Science Citations: 5

Abstract

Hypopbosphatasia (HPP) is an inherited disorder of mineral metabolism caused by mutations in ALPL, encoding tissue non-specific alkaline phosphatase (TNAP). Here, we report the molecular findings from monozygotic twins, clinically diagnosed with tooth-specific odontohypophosphatasia (odonto-HPP). Sequencing of ALPL identified two genetic alterations in the probands, including a heterozygous missense mutation c.454C>T, leading to change of arginine 152 to cysteine (p.R152C), and a novel heterozygous gene deletion c.1318\_1320delAAC, leading to the loss of an asparagine residue at codon 440 (p.N440de1). Clinical identification of low serum TNAP activity, dental abnormalities, and pedigree data strongly suggests a genotype-phenotype correlation between p.N440del and odonto-HPP in this family. Computational analysis of the p.N440del protein structure revealed an alteration in the tertiary structure affecting the collagen-binding site (loop 422-452), which could potentially impair the mineralization process. Nevertheless, the probands (compound heterozygous: p.{[}N440de1];{[}R152C]) feature early-onset and severe odonto-HPP phenotype, whereas the father (p.{[}N440del];{[}=]) has only moderate symptoms, suggesting p.R152C may contribute or predispose to a more severe dental phenotype in combination with the deletion. These results assist in defining the genotype-phenotype associations for odonto-HPP, and further identify the collagen-binding site as a region of potential structural importance for TNAP function in the biomineralization. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 08/00534-7 - Regulation of dentin-pulp and periodontal ligament cells in healthy individuals and with hypophosphatasia
• Grantee: Márcio Zaffalon Casati
• Support Opportunities: Regular Research Grants
• FAPESP's process: 07/08192-5 - Regulation of dentin-pulp and periodontal ligament cells in HELTHY individuals and with hypophosphatasia
• Grantee: Thaisângela Rodrigues Lopes e Silva Gomes
• Support Opportunities: Scholarships in Brazil - Doctorate