title: 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.
authors.affiliation: Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, University of Campinas-UNICAMP, Piracicaba, SP, Brazil.
authors.forename: Luciane
authors.initials: L
authors.lastname: Martins
authors.forename: Thaisângela L
authors.initials: TL
authors.lastname: Rodrigues
authors.forename: Mariana Martins
authors.initials: MM
authors.lastname: Ribeiro
authors.forename: Miki Taketomi
authors.initials: MT
authors.lastname: Saito
authors.forename: Ana Paula Oliveira
authors.initials: AP
authors.lastname: Giorgetti
authors.forename: Márcio Z
authors.initials: MZ
authors.lastname: Casati
authors.forename: Enilson A
authors.initials: EA
authors.lastname: Sallum
authors.forename: Brian L
authors.initials: BL
authors.lastname: Foster
authors.forename: Martha J
authors.initials: MJ
authors.lastname: Somerman
authors.forename: Francisco H
authors.initials: FH
authors.lastname: Nociti
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007014:Hypophosphatasia / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017433:Protein Structure, Secondary; D017001:Tooth Demineralization / Q000151:congenital* / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C548267:ALPL protein, human; D000469:Alkaline Phosphatase
keywords: ALPL; Collagen-binding site; Compound heterozygous mutations; Hypophosphatasia; Odontohypophosphatasia; Tissue non-specific alkaline phosphatase