Mutations in WNT10B Are Identified in Individuals with Oligodontia

Yü, Ping; Yang, Wenli; Han, Dong; Wang, Xi; Guo, Sen; Li, Jinchen; Li, Fang; Zhang, Xiaoxia; Wong, Sing‐Wai; Bai, Baojing; Liu, Yao; Du, Jie; Sun, Zhong Sheng; Shi, Songtao; Feng, Hailan; Cai, Tao

doi:10.1016/j.ajhg.2016.05.012

Cited by 87 publications

(86 citation statements)

References 36 publications

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“…The WNT10B variants in our patients seem to cause less severe isolated tooth agenesis than the oligodontia reported by Yu et al The dental phenotypes of our studied patients ranged from mild to severe hypodontia, short tooth roots, and taurodontism. However, only patients affected with severe hypodontia (oligodontia) were included in the study of Yu et al, so their selection criteria may have led to discovery of more severe mutations . In addition, our patients also had microdontia of the permanent incisors, taurodontism, and short tooth roots.…”

Section: Discussionmentioning

confidence: 99%

“…WNT10A variants have been reported to be responsible for the majority of isolated tooth agenesis cases . Recently, an association of WNT10B variants with oligodontia has been reported in a Chinese population . In addition, homozygous WNT10B variants have been reported in split hand‐foot malformation (SHFM) type 6; however, dental anomalies were not mentioned in those studies, perhaps because no dental investigation had been performed …”

Section: Introductionmentioning

confidence: 99%

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WNT10B mutations associated with isolated dental anomalies

et al. 2018

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Isolated hypodontia is the most common human malformation. It is caused by heterozygous variants in various genes, with heterozygous WNT10A variants being the most common cause. WNT10A and WNT10B are paralogs that likely evolved from a common ancestral gene after its duplication. Recently, an association of WNT10B variants with oligodontia (severe tooth agenesis) has been reported. We performed mutational analysis in our cohort of 256 unrelated Thai families with various kinds of isolated dental anomalies. In 7 families afflicted with dental anomalies we detected 4 heterozygous missense variants in WNT10B. We performed whole exome sequencing in the patients who had WNT10B mutations and found no mutations in other known hypodontia-associated genes, including WNT10A, MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, LPR6, TFAP2B, LPR6, NEMO, KRT17, and GREM2. Our findings indicate that the variants c.475G>C [p.(Ala159Pro)], found in 4 families, and c.1052G>A [p.(Arg351His)], found in 1 family, are most probably causative. They also show that WNT10B variants are associated not only with oligodontia and isolated tooth agenesis, but also with microdontia, short tooth roots, dental pulp stones, and taurodontism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

WNT10B mutations associated with isolated dental anomalies

et al. 2018

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“…), and Wnt family member 10B (WNT10B, OMIM 601906) (Yu et al. ), all of which have been implicated in oligodontia phenotypes. Furthermore, bioinformatics analyses of genes related to tooth agenesis have revealed additional gene pathways that may be involved in the etiology of the condition including those involved in tooth, skin, and gland development pathways, in addition to cancer pathways (Yin and Bian ).…”

Section: Introductionmentioning

confidence: 99%

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

Yuan

Zhao

Tandon

et al. 2017

Molec Gen & Gen Med

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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.

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“…Large families with clinically well-defined TA phenotypes have been valuable for the identification of novel loci and genes contributing to TA and may help elucidate the potentially complex genetic network underlying tooth development. Genes associated with nonsyndromic TA can display one of several modes of inheritance: AD with or without reduced penetrance such as MSX1 [Vastardis et al 1996], PAX9 [Frazier-Bowers et al 2002], WNT10B [Yu et al 2016], and GREM2 [Kantaputra et al 2015]; mixed AD and AR inheritance such as that observed with WNT10A [Kantaputra and Sripathomsawat 2011]; and XL inheritance observed with EDA [Song et al 2009; Yin and Bian 2015]. More recently, heterozygous loss-of-function variants in LRP6 have been associated with TA [Dinckan et al 2017; Massink et al 2015; Ockeloen et al 2016].…”

Section: Introductionmentioning

confidence: 99%

A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis

Dinçkan¹,

Du²,

Akdemir³

et al. 2018

American J of Med Genetics Pt A

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Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.

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Mutations in WNT10B Are Identified in Individuals with Oligodontia

Cited by 87 publications

References 36 publications

WNT10B mutations associated with isolated dental anomalies

WNT10B mutations associated with isolated dental anomalies

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

A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis

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