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

Li, Shufeng; Li, Jiahuang; Cheng, Jason Chia‐Hsien; Zhou, Biying; Tong, Xin; Dong, Xiangbai; Wang, Zixing; Hu, Qingang; Chen, Meng; Hua, Zhengli

doi:10.1371/journal.pone.0002396

Cited by 36 publications

(31 citation statements)

References 28 publications

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“…Recently, there have been several reports of mutations in the EDA-A1 gene leading to an isolated form of X-linked recessive hypodontia (XLRH) [7,10,11,12]. This observation was somewhat surprising, since perturbation of the EDA-A1 pathway is also implicated in the development of hair and sweat glands.…”

Section: Introductionmentioning

confidence: 99%

A Common Founder Mutation in the <i>EDA-A1</i> Gene in X-Linked Hypodontia

Kurban

Michailidis²,

Wajid³

et al. 2010

Dermatology

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Background: X-linked recessive hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a rare genodermatosis characterized clinically by developmental abnormalities affecting the teeth, hair and sweat glands. Mutations in the EDA-A1 gene have been associated with XLHED. Recently, mutations in the EDA-A1 gene have also been implicated in isolated X-linked recessive hypodontia (XLRH; OMIM 313500). Methods: We analyzed the DNA from members of 3 unrelated Pakistani families with XLRH for mutations in the EDA-A1 gene through direct sequencing and performed haplotype analysis. Results: We identified a common missense mutation in both families designated c.1091T→C (p.M364T). Haplotype analysis revealed that this is a founder mutation in the 3 families. Conclusion: XLHED is a syndrome with variable clinical presentations that contain a spectrum of findings, including hypodontia. We suggest that XLRH should be grouped under XLHED as both share several phenotypic and genotypic similarities.

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Section: Introductionmentioning

confidence: 99%

A Common Founder Mutation in the <i>EDA-A1</i> Gene in X-Linked Hypodontia

Kurban

Michailidis²,

Wajid³

et al. 2010

Dermatology

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“…In 2008, a Chinese study reported p.Asp316Gly mutation in EDA protein to be associated with non-syndromic congenital tooth agenesis affecting every tooth type. All affected members show differential expression [93]. Mutations detected so far in EDA and related genes are summed up in Tables 4-6.…”

Section: Eda1 Genementioning

confidence: 99%

Single Nucleotide Polymorphism (SNPs) in the Genes Associated with Tooth Agenesis

Shahid¹,

Joshi²,

Alqhtani³

et al. 2018

Eur J Exp Bio

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Objectives: The main focus of this review article was to collate up to date knowledge with regard to significance of single nucleotide polymorphisms (SNPs) in various genes associated with tooth agenesis. Failure to develop complete set of teeth also called tooth agenesis is a common developmental abnormality manifested mainly as an isolated condition. This anomaly is also associated with many developmental syndromes. Methods:We reviewed the evidence from the literature with regard to SNPs in many genes associated with this developmental anomaly. The information contained in this review deals only with non-syndromic form of tooth agenesis. This condition generally affects third molars or one or few other permanent teeth, however, in some cases its severity is relatively prevalent. Results and Conclusions:Mutations in genes such as Msh homeobox 1 (MSX1), Paired box gene 9 (PAX9), Axis inhibitor protein 2 (AXIN2) and Ectodysplasin A (EDA) have been identified that are associated with the familial form of the disease. It has been shown that the phenotypes associated with these mutations indicate the involvement of more complex mechanisms.Clinical Significance: Evidence collected so far has immense clinical significance to clinical dentists in providing comprehensive guide outlining the role of these gene mutations (SNPs) in various genes and also how the patients affected with this condition will be clinically diagnosed and managed in future.

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“…The mutation is located in the TNFL domain of the EDA protein. Several mutations in the TNFL domain have previously been reported (8,9,22). Schneider et al (9) showed that all missense mutations in the TNFL domain resulted in abolished or impaired binding of EDA to its receptors.…”

Section: Mutationsmentioning

confidence: 99%

“…Affected males showed most or all of the typical phenotypes of XLHED. However, only a few studies have reported the relationship between nucleotide substitution and protein structure (8,21,22).In this study, we analyzed the ED1 gene in two unrelated Japanese patients with XLHED, and we identified two novel Abbreviations: DHPLC, denaturing high-performance liquid chromatography; EDA, ectodysplasin-A; HED, hypohidrotic ectodermal dysplasia; TNFL, tumor necrosis factor ligand; XLHED, X-linked HED 0031-3998/09/6504-0453 PEDIATRIC RESEARCH …”

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Two Novel Mutations in the ED1 Gene in Japanese Families With X-Linked Hypohidrotic Ectodermal Dysplasia

et al. 2009

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X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by hypodontia, hypotrichosis, and hypohidrosis, is caused by mutations in ED1, the gene encoding ectodysplasin-A (EDA). This protein belongs to the tumor necrosis factor ligand superfamily. We analyzed ED1 in two Japanese patients with XLHED. In patient 1, we identified a 4-nucleotide insertion, c.119-120insTGTG, in exon 1, which led to a frameshift mutation starting from that point (p.L40fsX100). The patient's mother was heterozygous for this mutation. In patient 2, we identified a novel missense mutation, c.1141GϾC, in exon 9, which led to a substitution of glycine with arginine in the TNFL domain of EDA (p.G381R). This patient's mother and siblings showed neither symptoms nor ED1 mutations, so this mutation was believed to be a de novo mutation in maternal germline cells. According to molecular simulation analysis of protein structure and electrostatic surface, p.G381R increases the distance between K375 in monomer A and K327 in monomer B, which suggests an alteration of overall structure of EDA. Thus, we identified two novel mutations, p.L40fsX100 and p.G381R, in ED1 of two XLHED patients. Simulation analysis suggested that the p.G381R mutation hampers binding of EDA to its receptor via alteration of overall EDA structure. (Pediatr Res 65: 453-457, 2009) H ypohidrotic ectodermal dysplasia (HED) is a congenital disorder characterized by the impaired development of teeth (hypodontia), hair (hypotrichosis), and eccrine sweat glands (hypohidrosis) (1). Most HED patients have shown an X-linked inheritance pattern, although a minority of patients had an autosomal dominant or recessive trait (2,3).The ED1 gene responsible for XLHED was mapped to chromosome Xq12-q13 and was identified by positional cloning (4). ED1 encodes the protein ectodysplasin-A (EDA) that belongs to the tumor necrosis factor ligand (TNFL) superfamily (5,6). EDA consists of a small N-terminal intracellular domain, a transmembrane domain, and a larger C-terminal extracellular domain containing a furin-cleavage site, a collagen-like domain, and a TNFL domain. The collagen-like domain has been believed to be necessary for trimerization of EDA proteins (7). However, it is not known whether the collagen-like domain is solely responsible for the trimerization: constructs of EDA-A1 and EDA-A2 lacking the collagenlike region can pack in the crystals as dimers of trimers (8). The TNFL domain has the ability to interact with the EDA receptor (EDAR) and X-linked ectodysplasin-A2 receptor (XEDAR) (9).EDA-A1 and EDA-A2 are the longest EDA isoforms, but they differ by only an insertion/deletion of two amino acids (E308, V309) as determined by alternative splicing of ED1 pre-mRNA. This insertion/deletion functions to regulate receptor-binding specificity, such that EDA-A1 binds EDAR, whereas EDA-A2 binds XEDAR (10). EDAR interacts with its adapter EDAR-associated death domain (EDARADD) to build an intracellular complex and activate the nuclear factor-B pathway, which is essen...

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

Cited by 36 publications

References 28 publications

A Common Founder Mutation in the <i>EDA-A1</i> Gene in X-Linked Hypodontia

A Common Founder Mutation in the <i>EDA-A1</i> Gene in X-Linked Hypodontia

Single Nucleotide Polymorphism (SNPs) in the Genes Associated with Tooth Agenesis

Two Novel Mutations in the ED1 Gene in Japanese Families With X-Linked Hypohidrotic Ectodermal Dysplasia

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