PAX9 – Tooth Agenesis

PAX9 encodes a paired-domain transcription factor critical for dental mesenchyme patterning. Heterozygous loss-of-function variants in PAX9 cause autosomal dominant non-syndromic tooth agenesis, primarily affecting molar development. Mutations span missense, nonsense, frameshift, splice, and regulatory defects within the paired domain and flanking regions.

Genetic studies have reported over 50 probands with PAX9-related tooth agenesis across multiple populations (PMID:12786960, PMID:26266225). Both familial and sporadic cases display an autosomal dominant inheritance with incomplete penetrance. A de novo c.151G>A (p.Gly51Ser) transition was identified in a sporadic oligodontia case lacking third molars, second premolars and incisors (PMID:12786960).

Segregation analysis in at least eight kindreds demonstrated co-segregation of PAX9 variants with tooth agenesis phenotypes in 35 additional affected relatives (PMID:21443745). Variants include initiation codon mutations (c.2T>G) leading to haploinsufficiency (PMID:26571067), a 223-kb deletion encompassing PAX9 (PMID:20485064), and a g.-1258G>A regulatory change segregating with molar hypodontia (PMID:21443745).

The PAX9 variant spectrum encompasses 30+ unique alleles: missense substitutions within the paired domain (e.g., p.Arg28Pro, p.Leu27Pro), premature stop codons (e.g., c.480C>G (p.Tyr160Ter)), and frameshifts (e.g., c.321_322insG). Recurrent alleles such as c.2T>G (p.Met1Arg) and c.151G>A (p.Gly51Ser) have been observed in unrelated families, indicating mutational hotspots (PMID:12786960, PMID:26571067).

Functional assays reveal that frameshift mutations (e.g., 219InsG) abolish DNA binding and transactivation of target reporters, while maintaining protein expression but mislocalisation, consistent with a loss-of-function mechanism (PMID:14607846). In vivo, Pax9 hypomorphic and null mouse alleles show dose-dependent hypodontia and oligodontia, with arrested molar development and enamel defects, confirming haploinsufficiency as the pathogenic mechanism (PMID:16236760).

Integration of genetic segregation and functional data establishes a strong ClinGen evidence profile for PAX9 in non-syndromic tooth agenesis. Additional high-throughput studies underscore PAX9 specificity (98.2%) in nonsyndromic tooth agenesis among Wnt pathway genes (PMID:29969831).

Key take-home: PAX9 loss-of-function variants cause autosomal dominant tooth agenesis via haploinsufficiency, supporting routine PAX9 testing in individuals with hypodontia or oligodontia for accurate diagnosis and genetic counselling.

References

• European journal of oral sciences • 2003 • Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia. PMID:12786960
• Journal of clinical and diagnostic research : JCDR • 2015 • A Nonsyndromic Autosomal Dominant Oligodontia with A Novel Mutation of PAX9-A Clinical and Genetic Report. PMID:26266225
• The Journal of craniofacial surgery • 2010 • A 223-kb de novo deletion of PAX9 in a patient with oligodontia. PMID:20485064
• Clinical genetics • 2011 • A novel g.-1258G>A mutation in a conserved putative regulatory element of PAX9 is associated with autosomal dominant molar hypodontia. PMID:21443745
• The Journal of biological chemistry • 2004 • Functional analysis of a mutation in PAX9 associated with familial tooth agenesis in humans. PMID:14607846
• Human molecular genetics • 2005 • Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia. PMID:16236760
• Oral diseases • 2019 • Genetic analysis: Wnt and other pathways in nonsyndromic tooth agenesis. PMID:29969831

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