DSPP – Dentinogenesis Imperfecta Type III

Dentin sialophosphoprotein (DSPP) encodes the precursor of dentin sialoprotein and dentin phosphoprotein, essential for dentin biomineralization. Heterozygous variants in DSPP cause autosomal dominant dentinogenesis imperfecta type III (Dentinogenesis imperfecta type III), characterized by amber opalescent teeth, “shell‐teeth” radiographic appearance, and rapid tooth attrition.

To date, 12 independent families with DGI-III have been reported, accounting for at least 12 probands and segregation in ≥6 additional affected relatives (PMID:35627243). The first mutation involved a 36 bp deletion plus an 18 bp insertion in exon 5 of DSPP, truncating the DPP repeat region by six amino acids in a multiplex pedigree presenting with severe attrition (PMID:15690376). Subsequent case series identified heterozygous missense variants affecting the signal peptide: c.50C>T (p.Pro17Leu) in a Korean kindred (PMID:23509818) and c.38C>A (p.Ala13Glu) in a Chinese family (PMID:40040554).

The DSPP variant spectrum in DGI-III includes N-terminal signal peptide missense changes, frameshift mutations in the acidic DPP domain, and splice‐junction alterations. A hotspot at codon 17 underscores the critical IPV leader motif for ER export and normal protein secretion (PMID:23509818).

Functional splicing assays demonstrate that canonical splice‐site mutations (e.g., c.135+1G>A) cause exon skipping and transcript misprocessing (PMID:21736673). In vitro secretion studies reveal that p.Pro17Leu and p.Ala13Glu mutants accumulate in the rough endoplasmic reticulum, reduce DSPP secretion, and induce ER stress, indicative of a dominant-negative mechanism (PMID:23509818)(PMID:40040554).

Cellular models show that mutant DSPP forms Ca2+-dependent complexes that sequester wild-type protein in the ER, impairing dentin matrix formation (PMID:22392858). Proteolytic assays further confirm that proper BMP1‐mediated DSPP cleavage is essential for activation, which is disrupted by pathogenic DSPP variants.

Collectively, autosomal dominant inheritance in ≥12 families, segregation in multiple affected relatives, and concordant functional data support a Strong clinical validity classification for DSPP in DGI-III. These findings underpin genetic testing, inform prognostic counseling, and direct future therapies targeting DSPP processing.

Key Take-home: DSPP variant analysis is critical for diagnosing DGI-III, with secretion and processing defects driving pathogenesis.

References

• American journal of medical genetics. Part A • 2005 • Dentin phosphoprotein compound mutation in dentin sialophosphoprotein causes dentinogenesis imperfecta type III. PMID:15690376
• BioMed research international • 2013 • A DSPP mutation causing dentinogenesis imperfecta and characterization of the mutational effect. PMID:23509818
• Molecular genetics & genomic medicine • 2025 • A Novel Variant in Dentin Sialophosphoprotein (DSPP) Gene Causes Dentinogenesis Imperfecta Type III: Case Report. PMID:40040554
• Genes • 2022 • The Modified Shields Classification and 12 Families with Defined DSPP Mutations. PMID:35627243
• Oral diseases • 2011 • Functional splicing assay of DSPP mutations in hereditary dentin defects. PMID:21736673
• Journal of bone and mineral research • 2012 • Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects. PMID:22392858

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