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

Dentinogenesis imperfecta 1 (DGI1, MIM 125490) is an autosomal dominant den tal disease characterized by abnormal dentin production and mineralization. The DGI1 locus was recently refined to a 2-Mb interval on 4q21 (ref. 1). H ere we study three Chinese families carrying DCI1. We find that the affecte d individuals of two families also presented with progressive sensorineural high-frequency hearing loss (gene DfNA39). We identified three disease-spe cific mutations within the dentin sialophosphoprotein gene (DSPP) in these three families. We detected a G-->A transition at the donor-splicing site o f 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 D FNA39, however, we identified two independent nucleotide transversions in e xons a and 3 of DSPP, respectively. that cause missense mutations of two ad jacent amino-acid residues in the predicted transmembrane region of the pro tein. Moreover, transcripts of DSPP previously reported to be expressed spe cifically in teeth(2) are also detected in the inner ear of mice. We have t hus demonstrated for the first time that distinct mutations in DSPP are res ponsible for the clinical manifestations of DGI1 with or without DFNA39.