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Updated: Jun 1, 2026

Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Novel heterozygous tissue-nonspecific alkaline phosphatase (TNAP) gene mutations causing lethal perinatal
Kai-Chi Chang1, Po-Han Lin, Yi-Ning Su
1Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 100, Taiwan.
Abstract:
Hypophosphatasia is a rare inherited disorder characterized by poor bone mineralization and deficiency of alkaline phosphatase activity. It is caused by mutations in the liver/bone/kidney alkaline phosphatase gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNAP), which displays many allelic heterogeneities, leading to different clinical phenotypes. This study reports the case of a patient diagnosed with lethal perinatal hypophosphatasia. His gene analysis showed compound heterozygocity of two novel mutations: c.650delTinsCTAA and c.984_986delCTT, which led to p.217delVinsAK and p.328delF, respectively. The two mutations originated separately from his parents, consistent with autosomal recessive perinatal hypophosphatasia. For these two novel mutations, we analyzed their functions through three-dimensional structural analysis. This revealed that V217 is located in the β-sheet area, V217 is deleted, and insertion of alanine and lysine alter the secondary structure, causing instability in the hydrophobic region, which may influence the metal-binding vicinity. This mutant structure loses its catalytic activity. Deletion of 328F also results in protein structural alteration and affects TNAP functions. These results may provide an explanation of the two novel mutated alleles correlating with the lethal phenotype of our patient. In conclusion, we demonstrated the case of a patient with lethal perinatal hypophosphatasia caused by two novel heterozygous mutations.
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