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DSPP – Dentinogenesis imperfecta type II

Dentin sialophosphoprotein (DSPP) variants are established causes of autosomal dominant dentinogenesis imperfecta type II (Dentinogenesis imperfecta type II). A heterozygous splice-donor mutation, c.135+2T>C, was identified in a four-generation kindred with classical DGI-II features, including opalescent "shell" teeth and enlarged pulp chambers, co-segregating with disease in all affected relatives ([PMID:22125647]). No additional DSPP variants were found in unaffected family members, supporting pathogenicity.

Functional assays demonstrate that c.135+2T>C abolishes normal splicing of intron 3, resulting in aberrant exon skipping and extended DSPP transcripts in vitro ([PMID:22125647]). Complementary in vivo studies reveal that proteolytic processing of DSPP is essential for dentin mineralization: transgenic mice expressing a processing-deficient D452A-DSPP mutant fail to rescue dentin defects in Dspp-knockout backgrounds, confirming a loss-of-function mechanism ([PMID:22798071]).

Key Take-home: DSPP genetic testing, including splice-site analysis, is critical for molecular diagnosis and management of DGI-II.

References

  • Oral diseases • 2011 • A novel splicing mutation alters DSPP transcription and leads to dentinogenesis imperfecta type II PMID:22125647
  • The Journal of biological chemistry • 2012 • Proteolytic processing of dentin sialophosphoprotein (DSPP) is essential to dentinogenesis PMID:22798071

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single autosomal dominant family with co-segregation of c.135+2T>C variant and DGI-II ([PMID:22125647]).

Genetic Evidence

Limited

One DGI-II pedigree with a splice-donor DSPP mutation segregating in four generations.

Functional Evidence

Moderate

In vitro splicing assays show exon-skipping by c.135+2T>C ([PMID:22125647]), and mouse transgenic studies confirm necessity of DSPP proteolytic processing for dentinogenesis ([PMID:22798071]).