Frameshift Mutations in DSPP Repeat Domain Cause DGI and DD

Objective: Analyze the DSPP gene in eight new kindreds with dentin dysplasia type-II (DD) and dentinogenesis imperfecta type-II (DGI). Methods: Diagnoses were independently confirmed by two dentists. Genomic DNA was sequenced after subcloning PCR reactions. Results: One or four nucleotides were lost within the technically challenging ~2.2kbp repeat portion of DSPP exon 5 (dentin phosphophoryn, DPP, with >200 nominal SerSerAsp repeats) in seven kindreds. The two DD families had different 4-basepair deletions while the five DGI patient/families were found to have single basepair deletions. Four of these apparently “unrelated” DGI kindreds shared both the same frameshift mutation and haplotype lineages, strongly suggesting a founder-effect mutation within the US population. No frameshift mutations were identified within the DSPP repeat domain in 100 chromosomes from normal individuals of diverse geographic locations, nor were such changes identified in unaffected family members. The remaining DGI kindred in our cohort had a splice-site mutation similar to one previously reported. Conclusions: Mutations resulting in net -1 frameshifts in the repeat domain of DSPP appear to explain a significant number of DD and DGI phenotypes. These frameshifts immediately change the hydrophilic SerSerAsp repeat into long hydrophobic polypeptides that are likely to aggregate/precipitate in the rER/Golgi and interfere with odontoblast processing of normal DSPP and/or other matrix proteins such as type I collagen. Furthermore, we propose that the splice-site mutation found in this study along with all other previously reported DSPP mutations (all of which are associated with exons 2 and 3) result in dominant phenotypes due to the disruption of signal peptide-processing and/or related biochemical events that result in interference with matrix protein processing. This hypothesis brings all reported dominant forms of the human disease (including the reported nonsense mutation) in agreement with the normal phenotype of the heterozygous null Dspp (-/+) mice. (supported by DIR/NIDCR/NIH/DHHS)