A novel nonsense mutation in PAX9 is associated with sporadic hypodontia.

The most important events during the regulation of tooth development were inductive interactions between the epithelial and mesenchymal tissues. The expression of Pax9 had been shown to specifically mark the mesenchymal regions at the prospective sites of all teeth prior to any morphological manifestations. Here, we investigated the PAX9 gene as a candidate gene for hypodontia in five unrelated Chinese patients with tooth agenesis. Direct sequencing and restriction enzyme analysis revealed a novel heterozygous mutation c.480C>G (p.160Tyr>X, Y160X) in a patient who was missing 20 permanent teeth (the third molars excluded) and 6 primary teeth. The mutation was a nonsense mutation, leading to a premature stop codon in exon 2 of PAX9 gene. PCR analysis of complementary DNA from cultured lymphocytes of the affected individual could not indicate the complete degradation of the mutated transcript. Promoter reporter assays revealed reduced transcriptional activity of the mutated PAX9 protein suggesting that the severe phenotype may result from haploinsufficiency of PAX9. In another patient with 15 missing permanent teeth (the third molars excluded), we found the c.219insG mutation previously reported by Stockton.