Mouse Dspp frameshift model of human dentinogenesis imperfecta.

Area of Science:

• Genetics
• Developmental Biology
• Biochemistry

Background:

• Non-syndromic inherited dentin defects stem from mutations in dentin sialophosphoprotein (DSPP).
• These mutations are categorized into 5' (N-terminal targeting sequence) and 3' (translation frame shift) classes.
• DSPP defects lead to overlapping phenotypes like dentin dysplasia type II and dentinogenesis imperfecta types II and III.

Purpose of the Study:

• To investigate the distinct pathological mechanisms of 5' and 3' DSPP mutations.
• To characterize novel mouse models for these genetic defects.
• To differentiate the resulting dental malformations.

Main Methods:

• CRISPR/Cas9 gene editing to create a Dspp^-1fs mouse model.
• Generation of a Dspp^P19L mouse model.
• Morphological assessment, scanning electron microscopy (bSEM), nanohardness testing, histology, in situ hybridization, and immunohistochemistry on developing teeth.

Main Results:

• Dspp^P19L dentin showed slow growth, reduced hardness, and lower mineralization despite the presence of dentinal tubules.
• Dspp^P19L incisor enamel was softer, and molar enamel exhibited reduced structural definition.
• Dspp^-1fs dentin mimicked reparative dentin, lacking tubules and being significantly softer and thinner; its incisor enamel was normal.

Conclusions:

• 5' and 3' DSPP mutations result in dental malformations via divergent pathological pathways.
• The distinct mechanisms support classifying these DSPP-related disorders separately.
• Mouse models provide valuable insights into the pathogenesis of inherited dentin defects.