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

Abstract

Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). DSPP mutations fall into two groups: a 5′-group that affects protein targeting and a 3′-group that shifts translation into the −1 reading frame. Using whole-exome sequence (WES) analyses and Single Molecule Real-Time (SMRT) sequencing, we identified disease-causing DSPP mutations in 12 families. Three of the mutations are novel: c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80). We propose genetic analysis start with WES analysis of proband DNA to identify mutations in COL1A1 and COL1A2 causing dominant forms of osteogenesis imperfecta, 5′-DSPP mutations, and 3′-DSPP frameshifts near the margins of the DSPP repeat region, and SMRT sequencing when the disease-causing mutation is not identified. After reviewing the literature and incorporating new information showing distinct differences in the cell pathology observed between knockin mice with 5′-Dspp or 3′-Dspp mutations, we propose a modified Shields Classification based upon the causative mutation rather than phenotypic severity such that patients identified with 5′-DSPP defects be diagnosed as DGI-III, while those with 3′-DSPP defects be diagnosed as DGI-II.

• Authors: James P Simmer, Hong Zhang, Sophie J H Moon, Lori A-J Donnelly, Yuan-Ling Lee, Figen Seymen, Mine Koruyucu, Hui-Chen Chan, Kevin Y Lee, Suwei Wu, Chia-Lan Hsiang, Anthony T P Tsai, Rebecca L Slayton, Melissa Morrow, Shih-Kai Wang, Edward D Shields, Jan C-C Hu
• Journal: Genes (Genes (Basel)) Vol. 13 Issue 5 (05 12 2022) ISSN: 2073-4425 [Electronic] Switzerland
• PMID: 35627243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Extracellular Matrix Proteins
• Phosphoproteins
• Sialoglycoproteins

Topics

• Animals
• Dentinogenesis Imperfecta (genetics)
• Extracellular Matrix Proteins (genetics)
• Humans
• Mice
• Mutation
• Pedigree
• Phosphoproteins (genetics)
• Sialoglycoproteins (genetics)