Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype

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• 作者：Luciane Martins ; Thaisangela L. Rodrigues ; Mariana Martins Ribeiro ; Miki Taketomi Saito ; Ana Paula Oliveira Giorgetti ; M¨¢rcio Z. Casati ; Enilson A. Sallum ; Brian L. Foster ; Martha J. Somerman ; Francisco H. Nociti Jr.
• 关键词：Hypophosphatasia ; Odontohypophosphatasia ; Tissue non-specific alkaline phosphatase ; ALPL ; Collagen-binding site ; Compound heterozygous mutations
• 刊名：Bone
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：56
• 期：2
• 页码：390-397
• 全文大小：1039 K

文摘

Hypophosphatasia (HPP) is an inherited disorder of mineral metabolism caused by mutations in m>ALPLm>, 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 m>ALPLm> 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.