Role of WNT10A in failure of tooth development in humans and zebrafish

Abstract

BackgroundOligodontia is a severe form of tooth agenesis characterized by the absence of six or more permanent teeth. Oligodontia has complex etiology and variations in numerous genes have been suggested as causal for the condition.MethodsWe applied whole‐exome sequencing (WES) to identify the cause of oligodontia in a 9‐year‐old girl missing 11 permanent teeth. Protein modeling and functional analysis in zebrafish were also performed to understand the impact of identified variants on the phenotype.ResultsWe identified a novel compound heterozygous missense mutation in WNT10A (c.637G>A:p.Gly213Ser and c.1070C>T:p.Thr357Ile) as the likely cause of autosomal recessive oligodontia in the child. Affected residues are located in conserved regions and variants are predicted to be highly deleterious for potentially destabilizing the protein fold and inhibiting normal protein function. Functional studies in zebrafish embryos showed that wnt10a is expressed in the craniofacies at critical time points for tooth development, and that perturbations of wnt10a expression impaired normal tooth development and arrested tooth development at 5 days postfertilization (dpf). Furthermore, mRNA expression levels of additional tooth development genes were directly correlated with wnt10a expression; expression of msx1, dlx2b, eda, and axin2 was decreased upon wnt10a knockdown, and increased upon wnt10a overexpression.ConclusionsOur results reveal a novel compound heterozygous variant in WNT10A as pathogenic for oligodontia, and demonstrate that perturbations of wnt10a expression in zebrafish may directly and/or indirectly affect tooth development recapitulating the agenesis phenotype observed in humans.

Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis

“…Nonetheless, it is intriguing that Wnt10a null mice present supernumerary teeth, in contrast with the tooth agenesis phenotype widely observed in humans. In zebrafish embryos, however, knockdown of wnt10a resulted in failure of tooth development, recapitulating the tooth agenesis phenotype in humans . These findings highlight that subtle differences in genetic requirements for tooth development among species may account for discordant phenotypes; further, these observations suggest that the exact role of WNT10A in tooth development is yet to be elucidated.…”

The Changing Landscape in the Genetic Etiology of Human Tooth Agenesis

“…Overall, WNT10A compound heterozygous mutations have been found in association with severe TA and a larger number of missing teeth in comparison to individuals with a single variant [ 108 , 109 , 110 , 148 ]. While there are no preferential patterns of missing teeth in individuals with WNT10A variants, the absence of maxillary and mandibular molars, as well as mandibular incisors is often reported [ 149 ]. Of note, heterozygous WNT10A variants have also been identified in unaffected individuals in TA families, as well as in unrelated control individuals with no TA or family history of TA [ 108 , 109 ].…”

“…A few WNT10A variants have been suggested to be common ‘hotspots’ for mutations in specific populations. For example, the c.637G > A (p.Gly213Ser) variant has been found more frequently in Asian populations [ 108 , 149 ], meanwhile the c.682T > A (p.Phe228Ile) variant has been widely reported in homozygous or heterozygous forms in Caucasian individuals with TA, but also in normal controls at a frequency of 2.3% [ 109 ]. The Phe228Ile variant is the most commonly found variant, and often described in combination with additional variants in WNT10A or in other genes [ 159 , 160 ].…”

Variations in AXIN2 predict risk and prognosis of colorectal cancer

“…1 Although the etiology of dental agenesis involved genetic and environmental factors, the genes more frequently associated with hypodontia in different populations are AXIN2, MSX1, PAX9, EDA , and WNT10 . 2,3…”