A Novel ALPL Heterozygous Nonsense Mutation Causing Adult-Hypophosphatasia

Objectives: Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by dysfunction of the tissue-nonspecific alkaline phosphatase (TNAP). The aim of the present study was to performe a clinical and molecular/computational study on a 36-year-old Caucasian female (proband), suspected to present adult-onset HPP based on clinical symptoms and low serum alkaline phosphatase activity.
Methods: Full medical and dental histories were obtained for the proband and family members, and included serum levels of TNAP, radiographs, dental and periodontal exams. Genomic DNA was isolated from saliva, and primer sequences were designed to amplify all TNAP coding exons (2–12) allowing analysis of the whole coding sequence, including intron–exon borders by the Sanger sequencing method. 3D-models were constructed based on the human placental alkaline phosphatase (PLAP) using the SWISS-MODEL software.
Results: Proband presented a history of spontaneous fractures, severe back and musculoskeletal pain, and osteopenia. Proband featured classical dental findings reported to be associated with HPP, including early teeth loss and excessive dental mobility. While several teeth displayed gingival recession, without signs of gingivitis, bleeding on probing, or any evidence of periodontal pocketing, there was no evidence of relevant enamel/dentin mineralization defects. Radiographic analysis revealed a short-rooted and evidence of generalized atrophy/loss of alveolar bone.Mutational screening of all 12 exons of ALPL gene revealed that the proband was a carrier of a de novo heterozygous nonsense mutation (NP_000469.3:p.Trp256Ter), never reported before in association with HPP. Functional prediction analysis revealed that the p.Trp256Ter mutation led to the production of a shortened protein, with complete loss of the TNAP crown domain, extensive loss of other functional domains (calcium binding domain, active site vicinity and metal binding sites) and more than 60% of homodimer interface residues.
Conclusions: In conclusion, these findings assist in defining genotype-phenotype associations for HPP, and therefore, contribute to a better understanding of HPP pathophysiology.