Novel PAX9 mutations cause non-syndromic tooth agenesis

Area of Science:

• Genetics
• Developmental Biology
• Oral Biology

Background:

• Paired box 9 (PAX9) is a crucial transcription factor in tooth morphogenesis.
• Mutations in PAX9 are linked to non-syndromic tooth agenesis, primarily affecting molars.
• Pax9-deficient mice exhibit arrested tooth development at the bud stage.

Purpose of the Study:

• To identify and characterize novel mutations in the PAX9 gene associated with non-syndromic tooth agenesis in Japanese patients.
• To investigate the functional consequences of these PAX9 mutations on protein activity and tooth development.

Main Methods:

• Genetic sequencing to identify mutations in the PAX9 gene.
• Analysis of mutation effects on amino acid sequence and protein conservation.
• In vitro studies involving transfection of mutant PAX9 into COS7 cells.
• Assessment of nuclear localization and transcriptional activity of mutant PAX9 proteins on the BMP4 gene.

Main Results:

• Two novel mutations, a three-nucleotide deletion (73-75 delATC) and a missense mutation (C146T), were found in the PAX9 paired domain of two unrelated Japanese patients.
• Both mutations occurred in highly conserved, DNA-binding critical amino acids.
• Nuclear localization of the mutant PAX9 proteins remained unaffected.
• Mutant PAX9 proteins showed reduced expression and significantly diminished transcriptional activity on the BMP4 gene.

Conclusions:

• Haploinsufficiency of PAX9, resulting from these novel mutations, is the likely cause of non-syndromic tooth agenesis in the studied patients.
• The identified mutations impair PAX9 function by affecting its transcriptional activity, rather than its nuclear import.
• These findings contribute to understanding the genetic basis of tooth agenesis and the role of PAX9 in dental development.