DSPP – Dentin Dysplasia Type II

DSPP encodes dentin sialophosphoprotein, a precursor cleaved into dentin sialoprotein and dentin phosphoprotein essential for dentin mineralization. Heterozygous mutations in DSPP lead to a spectrum of autosomal dominant dentin disorders, including dentin dysplasia type II (MONDO:0007437).

The primary clinical evidence derives from a Chinese family in which a novel frameshift mutation, c.2035delA, in the DPP region cosegregated with X-shaped root canal phenotypes across multiple affected members (PMID:36597617). Cosegregation analysis confirms the dominant inheritance and supports a pathogenic role for truncated DPP peptides.

DD-II variants cluster within the DPP coding region (nucleotides 1686–2134), with at least five unrelated probands harboring frameshift or splice-site mutations. A representative hotspot mutation, c.44C>T (p.Ala15Val), disrupts signal peptide cleavage and causes rough endoplasmic reticulum retention of DSPP (PMID:22392858, PMID:36597617).

The DPP domain represents a mutational hotspot, where diverse indels and splice-junction variants yield truncated proteins exerting dominant negative effects on odontoblast function (PMID:36597617, PMID:21736673).

Functional studies demonstrate that aberrant pre-mRNA splicing and rER retention of mutant DSPP underlie DD-II, rather than simple loss of function. In vitro splicing assays validate exon skipping in pathogenic variants (PMID:21736673), and BMP1 cleavage assays show that proper proteolytic processing of DSPP is essential for dentinogenesis in murine models (PMID:20079836).

No conflicting reports weaken the association between DSPP and DD-II. Genotype-phenotype correlations, particularly DPP region mutational hotspots, facilitate differential diagnosis from other hereditary dentin defects and inform stage-specific dental management strategies.

Key Take-home: Heterozygous frameshift mutations in the DPP region of DSPP cause autosomal dominant dentin dysplasia type II via dominant negative interference with protein maturation; targeted genetic testing of DSPP guides early diagnosis and personalized dental intervention.

References

• Oral diseases • 2023 • A novel DSPP frameshift mutation causing dentin dysplasia type 2 and disease management strategies. PMID:36597617
• Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research • 2012 • Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP. PMID:22392858
• Oral diseases • 2011 • Functional splicing assay of DSPP mutations in hereditary dentin defects. PMID:21736673
• Matrix biology : journal of the International Society for Matrix Biology • 2010 • Dentin sialophosphoprotein (DSPP) is cleaved into its two natural dentin matrix products by three isoforms of bone morphogenetic protein-1 (BMP1). PMID:20079836

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