Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan 27;24(1):136.
doi: 10.1186/s12903-024-03888-5.

Compound heterozygous WNT10A missense variations exacerbated the tooth agenesis caused by hypohidrotic ectodermal dysplasia

Yiting Liu #  1   2   3   4 , Jing Sun #  1   2   3   4 , Caiqi Zhang #  1   2   3   4 , Yi Wu  1   2   3   4 , Siyuan Ma  1   2   3   4 , Xuechun Li  1   2   3   4 , Xiaoshan Wu  5   6   7   8   9 , Qingping Gao  10   11   12   13
Affiliations

Compound heterozygous WNT10A missense variations exacerbated the tooth agenesis caused by hypohidrotic ectodermal dysplasia

Yiting Liu et al. BMC Oral Health. .

Abstract

Background: The aim of this study was to analyse the differences in the phenotypes of missing teeth between a pair of brothers with hypohidrotic ectodermal dysplasia (HED) and to investigate the underlying mechanism by comparing the mutated gene loci between the brothers with whole-exome sequencing.

Methods: The clinical data of the patients and their mother were collected, and genomic DNA was extracted from peripheral blood samples. By Whole-exome sequencing filtered for a minor allele frequency (MAF) ≤0.05 non-synonymous single-nucleotide variations and insertions/deletions variations in genes previously associated with tooth agenesis, and variations considered as potentially pathogenic were assessed by SIFT, Polyphen-2, CADD and ACMG. Sanger sequencing was performed to detect gene variations. The secondary and tertiary structures of the mutated proteins were predicted by PsiPred 4.0 and AlphaFold 2.

Results: Both brothers were clinically diagnosed with HED, but the younger brother had more teeth than the elder brother. An EDA variation (c.878 T > G) was identified in both brothers. Additionally, compound heterozygous variations of WNT10A (c.511C > T and c.637G > A) were identified in the elder brother. Digenic variations in EDA (c.878 T > G) and WNT10A (c.511C > T and c.637G > A) in the same patient have not been reported previously. The secondary structure of the variant WNT10A protein showed changes in the number and position of α-helices and β-folds compared to the wild-type protein. The tertiary structure of the WNT10A variant and molecular simulation docking showed that the site and direction where WNT10A binds to FZD5 was changed.

Conclusions: Compound heterozygous WNT10A missense variations may exacerbate the number of missing teeth in HED caused by EDA variation.

Keywords: Development; Digenic variations; EDA; Hypohidrotic ectodermal dysplasia; Tooth agenesis; WNT10A.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Dental characteristics and facial features of the pair of brothers with HED. a-b Oral conditions, panoramic radiographs of the proband (II-1). c-d Oral conditions, panoramic radiographs of the little brother (II-2). e. Pedigree structure of the family with HED, and black squares represent HED patients. f. DNA sequencing chromatogram showing a heterozygous EDA variant of c.878 T > G (p.L293R) in the pair of brothers (II-1, II-2). g-h Two heterozygous WNT10A variants of c.511C > T (p.R171C) and c.637G > A (p.G213S) in the proband (II-1)
Fig. 2
Fig. 2
Secondary structure analysis of mutated proteins. a The predicted secondary structure of the wild-type EDA protein. b The predicted secondary structure of mutated EDA protein (p.L293R). c. The predicted secondary structure of the wild-type WNT10A protein. d. The predicted secondary structure of mutated WNT10A proteins (p.R171C). e. The predicted secondary structure of mutated WNT10A proteins (p.G213S). Sites of variants are indicated by green squares. The structural changes in these mutated proteins compared to the wild-type proteins (EDA and WNT10A) are indicated by orange squares. α-Helices are represented as pink squares, while coils are represented as grey squares
Fig. 3
Fig. 3
Prediction of tertiary structure of proteins. a-b Tertiary structure prediction and hydrogen bond analysis of WNT10A wild-type and WNT10A p.R171C and p.G213S. d Tertiary structure prediction and hydrogen bond analysis of EDA wild-type and EDA p.L293R. c, e (1)–(3). Simulation of molecular docking between WNT10A wild-type and FZD5, and three binding sites between them. c, e (1′)-(3′). Simulation of molecular docking between WNT10A (p.R171C and p.G213S) and FZD5, and three binding sites between them
Fig. 4
Fig. 4
Summary of molecular genetic data of EDA variations caused HED. a The distribution of various variation domains of EDA in HED patients. b The frequency of tooth retention caused by EDA variations at each dental position. c The average number of missing teeth caused by variations in each functional domain of EDA. There was no significant difference between groups (P > 0.5) by Kruskal-Wallis H test
See this image and copyright information in PMC

References

    1. Cobourne MT, Sharpe PT. Diseases of the tooth: the genetic and molecular basis of inherited anomalies affecting the dentition. Wiley Interdiscip Rev –Develop Biol. 2013;2(2):183–212. doi: 10.1002/wdev.66. - DOI - PubMed
    1. Chhabra N, Goswami M, Chhabra A. Genetic basis of dental agenesis - molecular genetics patterning clinical dentistry. Med Oral Patol Oral Y Cirugia Bucal. 2014;19(2):E112–E119. doi: 10.4317/medoral.19158. - DOI - PMC - PubMed
    1. Salama FS, Abdel-Megid FY. Hypodontia of primary and permanent teeth in a sample of Saudi children. Egyptian dental j. 1994;40(1):625–632. - PubMed
    1. De Coster PJ, Marks LA, Martens LC, Huysseune A. Dental agenesis: genetic and clinical perspectives. J Oral Pathol Med. 2009;38(1):1–17. doi: 10.1111/j.1600-0714.2008.00699.x. - DOI - PubMed
    1. Zhang J, Liu HC, Lyu X, Shen GH, Deng XX, Li WR, Zhang XX, Feng HL. Prevalence of tooth agenesis in adolescent Chinese populations with or without orthodontics. Chin j dental res: the off j Sci Section Chin Stomatol Assoc (CSA). 2015;18(1):59–65. - PubMed

Publication types

LinkOut - more resources