PAX9 p.F15I Mutation and Familial Tooth Agenesis

Disease associated mutations (DAMs) in MSX1, PAX9, AXIN2, and EDA have been identified in kindreds with nonsyndromic familial tooth agenesis, while DAMs in genes encoding type I collagen (COL1A1/COL1A2) and dentin sialophosphoprotein (DSPP) have been reported in kindreds with nonsyndromic dentinogenesis imperfecta (DGI). We identified a Caucasian family with at least three generations of familial tooth agenesis in which the proband has tooth agenesis and DGI. No other members of the kindred have dentin defects. Objective: To characterize DAMs for the tooth agenesis and DGI in our proband. Methods: The family pedigree was constructed. Clinical photographs and radiographs were obtained. The MSX1, PAX9 and DSPP coding exons and intron junctions were amplified by PCR and characterized by direct DNA sequencing or by cloning and sequencing (DSPP exon 5). Results: The maternal grandfather, mother and the male proband exhibited tooth agenesis. The mother was missing tooth numbers 1, 5, 13, 16, 17, 24, 25, and 32. Tooth 10 was a peg lateral. The proband (age 5) was missing tooth numbers 20, 24, 25, and 29, but was too young to determine the third molars (1, 16, 17, 32). Tooth 10 was a peg lateral. His primary teeth had bulbous crowns with large pulp chamber and thin, opalescent dentin. The proband and his mother had a novel missense mutation (c.43T>A; p.F15I) in PAX9 and no potential disease-causing mutations in MSX1 or DSPP. Conclusion: The PAX9 (p.F15I) mutation changed a highly conserved residue in the PAX9 DNA binding domain and is the probable cause of the familial tooth agenesis. The genetic etiology of the dentin defects remains to be determined. A de novo mutation in the DSPP regulatory region or in COL1A1 or COL1A2 might explain the DGI phenotype. This study was supported by NIDCR grant DE015846.