Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/200694
Type: Artigo de periódico
Title: Novel Alpl Genetic Alteration Associated With An Odontohypophosphatasia Phenotype.
Author: Martins, Luciane
Rodrigues, Thaisângela L
Ribeiro, Mariana Martins
Saito, Miki Taketomi
Giorgetti, Ana Paula Oliveira
Casati, Márcio Z
Sallum, Enilson A
Foster, Brian L
Somerman, Martha J
Nociti, Francisco H
Abstract: Hypophosphatasia (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.N440del). 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.[N440del];[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.
Subject: Alkaline Phosphatase
Carrier Proteins
Female
Genotype
Humans
Hypophosphatasia
Male
Mutation
Mutation, Missense
Pedigree
Phenotype
Protein Structure, Secondary
Tooth Demineralization
Alpl
Collagen-binding Site
Compound Heterozygous Mutations
Hypophosphatasia
Odontohypophosphatasia
Tissue Non-specific Alkaline Phosphatase
Rights: fechado
Identifier DOI: 10.1016/j.bone.2013.06.010
Address: http://www.ncbi.nlm.nih.gov/pubmed/23791648
Date Issue: 2013
Appears in Collections:Unicamp - Artigos e Outros Documentos

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