Genetic Etiology and Dental Pulp Cell Deficiency of Hypophosphatasia

Abstract

Hypophosphatasia is caused by mutations of the tissue-non-specific alkaline phosphatase (TNSALP) gene with deficiency of dentin structure. The aim of this study was to examine whether TNSALP mutation in dental pulp cells contributes to dentin dysplasia in hypophosphatasia. Mutation analysis showed that compound heterozygous mutations of TNSALP were identified in three hypophosphatasia patients, including 3 novel mutation sites. Exfoliated teeth from the patients showed abnormal dentin mineralization and loss of cementum, as assessed by ground sections and scanning electron microscope analysis. Dental pulp cells isolated from one of the patients showed a significantly reduced TNSALP activity and mineralization capacity when compared with those in dental pulp cells from the unaffected individuals. Our results suggested that dentin dysplasia in hypophosphatasia may be associated with the decreased mineralization ability of dental pulp cells.

Hypophosphatasia-associated Deficiencies in Mineralization and Gene Expression in Cultured Dental Pulp Cells Obtained from Human Teeth

“…Compromised periodontal attachment and exfoliation of teeth because of aplasia or severe hypoplasia of acellular cementum is consistently described in case reports and is well documented (5, 7–9, 11, 18–25). Reports on pulp and dentin in cases of HPP are much more variable, with authors frequently citing no observed pathology.…”

“…One consequence of HPP is the severely defective formation of acellular cementum, resulting in poor periodontal attachment and premature tooth exfoliation (5), a phenotype recapitulated in the Akp2 -null mouse model for HPP (6). Yet, in both humans and mice with reduced ALP, dentin has been reported to be unaffected or less affected than cementum (6–9) although clinical case reports of thin dentin and wide pulp cavities have been described (8–11). …”

Dual Role of the Trps1 Transcription Factor in Dentin Mineralization

“…Although phosphate homeostasis is controlled at the systemic level, many of the proteins involved in this process are highly expressed in cells producing mineralizing matrix, suggesting that they participate in the locally regulated phosphate availability at the sites of mineralization (17-21). In humans, mutations in genes coding for major matrix proteins as well as in genes involved in phosphate metabolism result in skeletal and dental defects, underscoring the critical role of matrix composition and phosphate homeostasis for tissue mineralization (17, [22][23][24][25][26]. For example, a genetically heterogeneous disorder, hypophosphatemic rickets, manifests as defective mineralization of skeletal and dental tissues due to dysregulated phosphate homeostasis (27,28).…”

Clinical and ALPL Gene Mutations Analysis in an Early Onset Chinese Odontohypophosphatasia Patient

“…A missense mutation in exon 10 c. 1162T>C (p.Y371H) was first reported at 2010 [16], the patient in the article has a heterozygous mutations in exon 10 c.1162T>C and is suffered from HP. It implies that odontohypophosphatasia is related to the missense mutation in exon 10 c.1162T>C.…”

“…As a result, the protein sequence composed of an additional 259 amino acids. Since this frame-shift mutation lead the propeptide changed, it may disturb the final maturation of the protein by modifying the recognition site of proteases involved in the final maturation process [16,19]. In fact the patient's mother carries a single mutation do not has the clinical manifestations of Odontohypophosphatasia indicates this novel frame-shift gene mutation is recessive inherited.…”