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Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype.

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.

SUBMITTER: Martins L

PROVIDER: S-EPMC3872001 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype.

Martins Luciane L Rodrigues Thaisângela L TL Ribeiro Mariana Martins MM Saito Miki Taketomi MT Giorgetti Ana Paula Oliveira AP Casati Márcio Z MZ Sallum Enilson A EA Foster Brian L BL Somerman Martha J MJ Nociti Francisco H FH

Bone 20130619 2

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 heterozyg ...[more]

PMID: 23791648

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Dataset Information

Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype.

Publications

Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype.

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