Novel PAX9 mutation associated with syndromic tooth agenesis

Tooth agenesis is the most common anomaly of dental development. The purpose of the present study was to identify the causative mutation(s) in a family with a syndromic form of hypodontia. The male proband lacked 19 permanent teeth and showed defects of hair, but lacked ectodermal symptoms of skin and nails. Direct sequencing of the coding regions, including exon/intron boundaries of the msh homeobox 1 (MSX1), paired box 9 (PAX9), ectodysplasin A (EDA), and wingless-type MMTV integration site family, member 10 (WNT10A) genes, was carried out in affected family members. All identified nucleotide variations were tested in 200 healthy individuals using high-resolution melting (HRM) curve analysis to exclude the possibility that they represent rare polymorphisms. A novel heterozygous c.59delC mutation, segregating in the autosomal-dominant model, was identified in the PAX9 gene of the proband and the family members studied. This one-nucleotide deletion, located in a highly conserved paired box sequence, resulted in a frameshift (p.Pro20Argfs65) and in premature termination of translation, yielding a truncated protein 258 amino acids shorter than the wildtype protein. No pathogenic mutations were found in the MSX1, EDA, and WNT10A genes. In conclusion, the novel PAX9 deletion might be responsible for tooth agenesis and trichodysplasia in the investigated family. This c.59delC mutation potentially leads to PAX9 transcription factor haploinsufficiency.