The Modified Shields Classification and 12 Families with Defined DSPP Mutations.

Area of Science:

• Genetics
• Molecular Biology
• Dentistry

Background:

• Mutations in the Dentin Sialophosphoprotein (DSPP) gene cause various dental anomalies, including dentinogenesis imperfecta (DGI) types II and III.
• DSPP mutations are categorized into 5′- and 3′-groups, affecting protein targeting or translation, respectively.

Purpose of the Study:

• To identify disease-causing DSPP mutations in families with inherited dental disorders.
• To propose a refined classification system for DGI based on the specific type of DSPP mutation.

Main Methods:

• Whole-exome sequencing (WES) and Single Molecule Real-Time (SMRT) sequencing were employed to identify DSPP mutations in 12 families.
• Literature review and analysis of cell pathology in knockin mouse models with distinct DSPP mutations.

Main Results:

• Three novel DSPP mutations (c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80)) were identified.
• Distinct cellular pathologies were observed between 5′-DSPP and 3′-DSPP mutations in mouse models.
• A modified Shields Classification is proposed, differentiating DGI-III from 5′-DSPP defects and DGI-II from 3′-DSPP defects.

Conclusions:

• Genetic analysis, starting with WES, can identify DSPP mutations and guide diagnosis for inherited dental anomalies.
• The proposed classification based on mutation type (5′-DSPP vs. 3′-DSPP) offers a more precise diagnostic framework for DGI.