Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP

Abstract

Dentinogenesis imperfecta 1 (DGI1, MIM 125490) is an autosomal dominant dental disease characterized by abnormal dentin production and mineralization. The DGI1 locus was recently refined to a 2-Mb interval on 4q21 (ref. 1). Here we study three Chinese families carrying DGI1. We find that the affected individuals of two families also presented with progressive sensorineural high-frequency hearing loss (gene DFNA39). We identified three disease-specific mutations within the dentin sialophosphoprotein gene (DSPP) in these three families. We detected a G-->A transition at the donor-splicing site of intron 3 in one family without DFNA39, a mutation predicted to result in the skipping of exon 3. In two other families affected with both DGI1 and DFNA39, however, we identified two independent nucleotide transversions in exons 2 and 3 of DSPP, respectively, that cause missense mutations of two adjacent amino-acid residues in the predicted transmembrane region of the protein. Moreover, transcripts of DSPP previously reported to be expressed specifically in teeth are also detected in the inner ear of mice. We have thus demonstrated for the first time that distinct mutations in DSPP are responsible for the clinical manifestations of DGI1 with or without DFNA39.

Roles of Heparan Sulfate Sulfation in Dentinogenesis

“…This suggests that the functional role of Dspp mainly involves tooth formation and mineralization. In humans, several mutations in DSPP have been identified in patients with dentinogenesis imperfecta, which is an autosomal dominant disorder of the tooth that specifically affects dentin biomineralization (15)(16)(17)(18). A similar phenotype is found in Dspp null mutant mice, which disrupts dentin mineralization without affecting bone (19).…”

Porcine Dentin Sialoprotein Is a Proteoglycan with Glycosaminoglycan Chains Containing Chondroitin 6-Sulfate

“…DSPP mRNA has also been detected in the inner ear. The finding of progressive neurosensory hearing loss in some DGI patients suggests that DSPP gene products may play an important role in processes not yet identified (5), and these processes may or may not involve biomineralization. Rat DSP is not an effective nucleator of hydroxyapatite (HA) formation in vitro, and has low affinity for seed crystals (23), suggesting that DSP is unlikely to regulate mineralization directly.…”

“…As of this writing, eight mutations have been identified in the human DSPP gene that cause hereditary dentin defects (3)(4)(5)(6)(7). In each case, the phenotype is inherited in an autosomal dominant pattern and is usually limited to the teeth.…”

miRNA expression profiling identifies DSPP regulators in cultured dental pulp cells

“…Extensive evidence indicates that DSPP plays a crucial role during both enamel and dentin biomineralization and/or the formation of the structural diversity of tooth layers (i.e., enamel, mantle dentin, predentin and orthodentin) (1,9,10). DSPP mutations are reported to be associated with DD-II, DGI-II (11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and DGI-III (21), resulting in abnormal dentin formation. Furthermore, DSPP knockout mice display a widened predentin zone and develop defective mineralization similar to human dentinogenesis imperfecta III (22).…”