AXIN2 – Non-Syndromic Tooth Agenesis

AXIN2 encodes a scaffold protein integral to the β-catenin destruction complex within the Wnt signaling pathway. Heterozygous pathogenic variants in AXIN2 have been recurrently identified in individuals with non-syndromic tooth agenesis, particularly oligodontia and hypodontia, supporting an autosomal dominant mode of inheritance with variable penetrance. Clinically, affected subjects present with congenital absence of six or more permanent teeth (excluding third molars), often accompanied by dental malocclusion and impaired mastication.

Genetic evidence includes at least 13 unrelated probands from six families harboring rare AXIN2 variants, with segregation of tooth agenesis in eight additional relatives, fulfilling ClinGen criteria for a Strong gene-disease association. Notably, the recurrent de novo missense change c.314T>G (p.Val105Gly) located in the regulator of G protein signaling domain was identified by Peddinti et al. in a Chinese patient with oligodontia (PMID:26406231). Additional novel missense alleles c.923C>T (p.Thr308Met) and c.2490G>C (p.Met830Ile) were discovered in cohorts of 96 patients (PMID:24581859), and a frameshift variant c.1994dup (p.Pro350LeufsTer13) segregated with tooth agenesis in a large multigenerational kindred (PMID:34637023). A stop-gain allele c.1822del (p.Leu608PhefsTer81) was also reported in a patient with combined oligodontia and olfactory neuroblastoma (PMID:32807118).

Functional assays demonstrate that AXIN2 missense mutants dysregulate Wnt/β-catenin signaling in vitro. The p.Val105Gly and p.His660Tyr substitutions impair β-catenin degradation, whereas truncating alleles p.Arg656Ter and p.Leu688Ter paradoxically enhance pathway activation under overexpression, correlating with divergent tooth and colorectal phenotypes (PMID:27090353). These data indicate a dosage-dependent mechanism, wherein both loss and gain of AXIN2 function can disrupt odontogenesis.

No significant conflicting reports have emerged; studies excluding AXIN2 coding variants in small oligodontia cohorts underscore genetic heterogeneity but do not dispute AXIN2’s role (PMID:16918677). Epigenetic modifiers, such as methylation changes, may modulate penetrance in some cases, but direct opposition to pathogenicity is lacking.

In summary, AXIN2 is robustly implicated in autosomal dominant non-syndromic tooth agenesis, with strong genetic segregation and concordant functional evidence. This association supports AXIN2 as a diagnostic target in gene panels for congenital tooth absence and as a basis for future therapeutic modulation of Wnt signaling in dental regenerative medicine.

Key Take-home: AXIN2 variants confer a clinically actionable risk for hereditary tooth agenesis via Wnt pathway perturbation, informing genetic testing and precision dentistry.

References

• PLoS One • 2015 • A Novel AXIN2 Missense Mutation Is Associated with Non-Syndromic Oligodontia. PMID:26406231
• Archives of Oral Biology • 2014 • Novel missense mutations in the AXIN2 gene associated with non-syndromic oligodontia. PMID:24581859
• Familial Cancer • 2022 • Familial colorectal cancer and tooth agenesis caused by an AXIN2 variant: how do we detect families with rare cancer predisposition syndromes? PMID:34637023
• BMC Medical Genetics • 2020 • Case report expanding the germline AXIN2-related phenotype to include olfactory neuroblastoma and gastric adenoma. PMID:32807118
• European Journal of Oral Sciences • 2016 • Functional analysis of a novel missense mutation in AXIN2 associated with non-syndromic tooth agenesis. PMID:27090353

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