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
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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.
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