Non-Syndromic Tooth Agenesis in Two Chinese Families Associated with Novel Missense Mutations in the TNF Domain of EDA (Ectodysplasin A)

The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Stomatological Hospital, Nanjing University, Nanjing, People's Republic of China.
PLoS ONE (Impact Factor: 3.23). 06/2008; 3(6):e2396. DOI: 10.1371/journal.pone.0002396
Source: PubMed


Here we report two unrelated Chinese families with congenital missing teeth inherited in an X-linked manner. We mapped the affected locus to chromosome Xp11-Xq21 in one family. In the defined region, both families were found to have novel missense mutations in the ectodysplasin-A (EDA) gene. The mutation of c.947A>G caused the D316G substitution of the EDA protein. The mutation of c.1013C>T found in the other family resulted in the Thr to Met mutation at position 338 of EDA. The EDA gene has been reported responsible for X-linked hypohidrotic ectodermal dysplasia (XLHED) in humans characterized by impaired development of hair, eccrine sweat glands, and teeth. In contrast, all the affected individuals in the two families that we studied here had normal hair and skin. Structural analysis suggests that these two novel mutants may account for the milder phenotype by affecting the stability of EDA trimers. Our results indicate that these novel missense mutations in EDA are associated with the isolated tooth agenesis and provide preliminary explanation for the abnormal clinical phenotype at a molecular structural level.

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Available from: Jiahuang Li, Mar 25, 2014
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    • "In one study, a Chinese family with p.Asp316Gly mutation in EDA1 protein was found to be associated with non-syndromic congenital tooth agenesis affecting all tooth type. All the children, three females and one male showed hypodontia phenotype with differential expressivity.[36] This affection status closely resembles to that of the family we had identified. "
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    ABSTRACT: Congenital tooth agenesis in human is characterized by failure of tooth development during tooth organogenesis. 300 genes in mouse and 30 genes in human so far have been known to regulate tooth development. However, candidature of only 5 genes viz. PAX9, MSX1, AXIN2, WNT10A and EDA have been experimentally established for congenitally missing teeth like hypodontia and oligodontia. In this study an Indian family with multiple congenital tooth agenesis was identified. Pattern of inheritance was apparently autosomal dominant type with a rare possibility to be X-linked. Whole genome sequencing of two affected individuals was carried out which revealed 119 novel non-synonymous single nucleotide variations (SNVs) distributed among 117 genes. Out of these only one variation (c.956G>T) located at exon 9 of X-linked EDA gene was considered as pathogenic and validated among all the affected and unaffected family members and unrelated controls. This variation leads to p.Ser319Ile change in the TNF homology domain of EDA (transcript variant 1) protein. In silico analysis predicts that this Ser319 is well conserved across different vertebrate species and a part of putative receptor binding site. Structure based homology modeling predicts that this amino acid residue along with four other amino acid residues nearby, those when mutated known to cause selective tooth agenesis, form a cluster that may have functional significance. Taken together these results suggest that c.956G>T (p.Ser319Ile) mutation plausibly reduces the receptor binding activity of EDA leading to distinct tooth agenesis in this family.
    PLoS ONE 09/2014; 9(9):e106811. DOI:10.1371/journal.pone.0106811 · 3.23 Impact Factor
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    • "Several studies suggested that tooth agenesis is mainly caused by genetic factors [1,3,6–9]. To date, mutations in AXIN2 (axis inhibition protein 2), EDA (ectodysplasin A), MSX1 (msh homeobox 1), PAX9 (paired box 9) and WNT10A (wingless-type MMTV integration site family, member 10a) have been demonstrated to be associated with non-syndromic tooth agenesis [10–16]. However, there are still many cases that could not be identified mutations in these five genes. "
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    ABSTRACT: Tooth agenesis is one of the most common anomalies of human dentition. Recent studies suggest that a number of genes are related to both syndromic and non-syndromic forms of hypodontia. In a previous study, we observed that polymorphism in rs929387 of GLI3 might be associated with hypodontia in the Chinese Han population based on a limited population. To further confirm this observation, in this study, we employed 89 individuals diagnosed with sporadic non-syndromic oligodontia (40 males and 49 females) to investigate the relationship between polymorphism in rs929387 of GLI3 and tooth agenesis. These individuals were analyzed with 273 subjects (125 males and 148 females) diagnosed with non-syndromic hypodontia and 200 healthy control subjects (100 males and 100 females). DNA was obtained from whole blood or saliva samples and genotyping was performed by a Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) method. Significant differences were observed in the allele and genotype frequencies of rs929387 of GLI3. Distributions of genotypes TT, TC and CC of rs929387 polymorphism were significantly different between the case group and the control group (P = 0.013) and C allelic frequency was higher in case group [P = 0.002, OR = 1.690, 95% CI (1.200-2.379)]. Additionally, our analysis shows that this difference is more pronounced when compared between the male case group and the male control group. The function study suggests that variation in GLI3 caused by rs929387 leads to a decrease in its transcriptional activity. These data demonstrated an association between rs929387 of GLI3 and non-syndromic tooth agenesis in Chinese Han individuals. This information may provide further understanding of the molecular mechanisms of tooth agenesis. Furthermore, GLI3 can be regarded as a marker gene for the risk of tooth agenesis.
    PLoS ONE 11/2013; 8(11):e80860. DOI:10.1371/journal.pone.0080860 · 3.23 Impact Factor
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    • "These genes include PAX9, MSX1, AXIN2 and many others which have not yet been identified. Surprisingly, the search for an X-linked tooth agenesis gene led several researchers to the EDA gene [Tao et al., 2006; Tarpey et al., 2007; Fan et al., 2008; Han et al., 2008; Li et al., 2008; Rasool et al., 2008]. "
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    ABSTRACT: The history and the lessons learned from hypohidrotic ectodermal dysplasia (HED) may serve as an example for the unraveling of the cause and pathogenesis of other ectodermal dysplasia syndromes by demonstrating that phenotypically identical syndromes (HED) can be caused by mutations in different genes (EDA, EDAR, EDARADD), that mutations in the same gene (EDA) can lead to different phenotypes (HED and selective tooth agenesis) and that mutations in genes further downstream in the same signaling pathway (NEMO) may modify the phenotype quite profoundly (incontinentia pigmenti (IP) and HED with immunodeficiency). But it also demonstrates that diligent phenotype characterization and classification is extremely helpful in uncovering the underlying genotype. We also present a new mutation in the EDA gene which causes selective tooth agenesis and demonstrates the phenotype variation that can be encountered in the ectodermal dysplasia syndrome (HED) with the highest prevalence worldwide.
    American Journal of Medical Genetics Part A 09/2009; 149A(9):2037-41. DOI:10.1002/ajmg.a.32801 · 2.16 Impact Factor
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