WNT10A variants isolated from Japanese patients with congenital tooth agenesis

Machida, Junichiro; Goto, Hiroaki; Terada, Tadashi; Shibata, Akio; Miyachi, Hitoshi; Takahashi, Kazuyuki; Izumi, Hiroto; Nakayama, Atsuo; Shimozato, Kazuo; Tokita, Yoshihito

doi:10.1038/hgv.2017.47

Cited by 19 publications

(22 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relationship between the heterozygous WNT10A variants (c.511C > T and c.637G > A) and NSTA was characterized in large well-phenotyped population cohorts (Song et al, 2014;Machida et al, 2017). Both variants were significantly associated with tooth agenesis compared with healthy control individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in WNT10A are the most frequently found variants associated with NSTA in several populations studied to date (van den Boogaard et al, 2012;Mostowska et al, 2013;Song et al, 2014;Tardieu et al, 2017). In particular, the WNT10A c.511C > T and c.637G > A variants are predominant in Asian populations compared with Europeans (Song et al, 2014;Machida et al, 2017). According to multiple genetic databases, we observed the allele frequencies of WNT10A c.511C > T and c.637G > A variants in Asian populations up to 0.033 and 0.029, respectively, compared with those in non-Asians, which are 0.000-0.001.…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygous, homozygous, and compound heterozygous forms of WNT10A were associated with NSTA with phenotypic heterogeneity. Using WNT10A target sequencing, significantly elevated frequencies of WNT10A variants were observed in the tooth agenesis group compared with the control group (Song et al, 2014;Machida et al, 2017). Biallelic WNT10A variants were proposed to be a pathogenic factor for tooth agenesis with complete penetrance, while a single allelic variant, presenting in a significantly higher frequency in tooth agenesis patients, was considered to be a predisposing factor for tooth agenesis with reduced penetrance (Mues et al, 2014;Guazzarotti et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phenotypic and Genotypic Features of Thai Patients With Nonsyndromic Tooth Agenesis and WNT10A Variants

et al. 2020

View full text Add to dashboard Cite

Tooth agenesis is one of the most common orodental anomalies that demonstrate phenotypic and genotypic heterogeneity with a prevalence of 2.5%-7%. Mutations in WNT10A have been proposed to be the most common cause of nonsyndromic tooth agenesis (NSTA). The aim of this study was to characterize the dental features and genetic variants of NSTA in a Thai population. We recruited 13 unrelated patients with NSTA who attended the Faculty of Dentistry, Chulalongkorn University, Thailand, from 2017 to 2019. All 13 underwent whole exome sequencing that identified likely pathogenic genetic variants, all in WNT10A, in five patients. All five patients had second premolar agenesis, while three also had absent or peg-shaped upper lateral incisors. Patient 1 possessed a novel heterozygous duplication, c.916_918dupAAC (p.Asn306dup) in WNT10A. Patients 2 and 3 harbored a heterozygous and homozygous c.637G > A (p.Gly213Ser) in WNT10A, respectively. Patients 4 possessed a heterozygous c.511C > T (p.Arg171Cys) in WNT10A. Patient 5 harbored a homozygous c.511C > T (p.Arg171Cys) in WNT10A and a novel heterozygous c.413A > T (p.Asn138Ile) in EDARADD, suggesting digenic inheritance. We recruited another 18 family members of these five patients. Out of 23 participants, homozygous WNT10A variants were identified in 2 patients and heterozygous variants in 17 individuals. Both homozygous patients had NSTA. Eight out of 17 heterozygous individuals (8/17) had NSTA or a peg-shaped lateral incisor, indicating a 47% penetrance of the heterozygous variants or 53% (10/19) penetrance of either homozygous or heterozygous variants in WNT10A. The frequencies of the c.511C > T in our in-house 1,876 Thai exome database, Asian populations, and non-Asian populations were 0.016, 0.005-0.033, and 0.001, respectively; while those of the c.637G > A were 0.016, 0.004-0.029, and 0.000, respectively. In conclusion, our study reports two novel variants with one each in WNT10A and EDARADD, expanding the genotypic spectra of NSTA. Second premolar

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phenotypic and Genotypic Features of Thai Patients With Nonsyndromic Tooth Agenesis and WNT10A Variants

et al. 2020

View full text Add to dashboard Cite

show abstract

“…For example, RUNX2, MSX1, EDA, WNT10A, PAX9, and AXIN2 are known to be responsible for congenital tooth agenesis [34][35][36][37]. However, the majority of patients with congenital edentulous disease have causative mutations in WNT10A [38,39]. EDA is a causative gene of anhidrotic ectodermal dysplasia, which is a representative disease of syndromic congenital edentulous disease [40].…”

Section: Rescue Of Rudimental Tooth Germsmentioning

confidence: 99%

Development of tooth regenerative medicine strategies by controlling the number of teeth using targeted molecular therapy

et al. 2020

Self Cite

View full text Add to dashboard Cite

Analysis of various genetically modified mice, with supernumerary teeth, has revealed the following two intrinsic molecular mechanisms that increase the number of teeth. One plausible explanation for supernumerary tooth formation is the rescue of tooth rudiments. Topical application of candidate molecules could lead to whole tooth formation under suitable conditions. Congenital tooth agenesis is caused by the cessation of tooth development due to the deletion of the causative gene and suppression of its function. The arrest of tooth development in Runx2 knockout mice, a mouse model of congenital tooth agenesis, is rescued in double knockout mice of Runx2 and Usag-1. The Usag-1 knockout mouse is a supernumerary model mouse. Targeted molecular therapy could be used to generate teeth in patients with congenital tooth agenesis by stimulating arrested tooth germs. The third dentition begins to develop when the second successional lamina is formed from the developing permanent tooth in humans and usually regresses apoptotically. Targeted molecular therapy, therefore, seems to be a suitable approach in whole-tooth regeneration by the stimulation of the third dentition. A second mechanism of supernumerary teeth formation involves the contribution of odontogenic epithelial stem cells in adults. Cebpb has been shown to be involved in maintaining the stemness of odontogenic epithelial stem cells and suppressing epithelial-mesenchymal transition. Odontogenic epithelial stem cells are differentiated from one of the tissue stem cells, enamel epithelial stem cells, and odontogenic mesenchymal cells are formed from odontogenic epithelial cells by epithelial-mesenchymal transition. Both odontogenic epithelial cells and odontogenic mesenchymal cells required to form teeth from enamel epithelial stem cells were directly induced to form excess teeth in adults. An approach for the development of targeted therapeutics has been the local application of monoclonal neutralizing antibody/siRNA with cationic gelatin for USAG-1 or small molecule for Cebpb.

show abstract

“…Cases of more than six missing teeth can be caused by genetic factors 2 , and inherited tooth agenesis occurs in 10% of all individuals with congenital tooth agenesis 2 . Several different gene mutations have been identified in patients with congenitally inherited tooth agenesis 3 , 4 . In many cases, candidate genes were identified and determined, based on phenotypic changes observed in knockout (KO) mice.…”

mentioning

confidence: 99%

Local application of Usag-1 siRNA can promote tooth regeneration in Runx2-deficient mice

Mishima

Takahashi

Kiso

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

Runt-related transcription factor 2 (Runx2)-deficient mice can be used to model congenital tooth agenesis in humans. Conversely, uterine sensitization-associated gene-1 (Usag-1)-deficient mice exhibit supernumerary tooth formation. Arrested tooth formation can be restored by crossing both knockout-mouse strains; however, it remains unclear whether topical inhibition of Usag-1 expression can enable the recovery of tooth formation in Runx2-deficient mice. Here, we tested whether inhibiting the topical expression of Usag-1 can reverse arrested tooth formation after Runx2 abrogation. The results showed that local application of Usag-1 Stealth small interfering RNA (siRNA) promoted tooth development following Runx2 siRNA-induced agenesis. Additionally, renal capsule transplantation of siRNA-loaded cationized, gelatin-treated mouse mandibles confirmed that cationized gelatin can serve as an effective drug-delivery system. We then performed renal capsule transplantation of wild-type and Runx2-knockout (KO) mouse mandibles, treated with Usag-1 siRNA, revealing that hindered tooth formation was rescued by Usag-1 knockdown. Furthermore, topically applied Usag-1 siRNA partially rescued arrested tooth development in Runx2-KO mice, demonstrating its potential for regenerating teeth in Runx2-deficient mice. Our findings have implications for developing topical treatments for congenital tooth agenesis.

show abstract

WNT10A variants isolated from Japanese patients with congenital tooth agenesis

Cited by 19 publications

References 22 publications

Phenotypic and Genotypic Features of Thai Patients With Nonsyndromic Tooth Agenesis and WNT10A Variants

Phenotypic and Genotypic Features of Thai Patients With Nonsyndromic Tooth Agenesis and WNT10A Variants

Development of tooth regenerative medicine strategies by controlling the number of teeth using targeted molecular therapy

Local application of Usag-1 siRNA can promote tooth regeneration in Runx2-deficient mice

Contact Info

Product

Resources

About