Non-Syndromic Tooth Agenesis in Two Chinese Families
Associated with Novel Missense Mutations in the TNF
Domain of EDA (Ectodysplasin A)
Shufeng Li., Jiahuang Li., Jian Cheng., Bingrong Zhou., Xin Tong., Xiangbai Dong, Zixing Wang,
Qingang Hu, Meng Chen, Zi-Chun Hua*
The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Stomatological Hospital, Nanjing University, Nanjing, People’s Republic of China
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.
Citation: Li S, Li J, Cheng J, Zhou B, Tong X, et al. (2008) Non-Syndromic Tooth Agenesis in Two Chinese Families Associated with Novel Missense Mutations in
the TNF Domain of EDA (Ectodysplasin A). PLoS ONE 3(6): e2396. doi:10.1371/journal.pone.0002396
Editor: Katrina Gwinn, National Institute of Neurological Disorders and Stroke, United States of America
Received November 29, 2007; Accepted May 5, 2008; Published June 11, 2008
Copyright: ? 2008 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The project was supported by grants from the Chinese National Nature Sciences Foundation (30730030, 30425009) and Jiangsu Provincial Nature
Sciences Foundation (BK2007715) to Zi-Chun Hua. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
. These authors contributed equally to this work.
Tooth development is a complex process with reciprocal
interactions between the dental epithelium and mesenchyme;
many transcription factors and signaling molecules are involved to
guide this process. Tooth agenesis is the most common craniofacial
malformation with patients missing one or more teeth. The term
‘hypodontia’ is defined as the congenital absence of fewer than 6
teeth, whereas ‘oligodontia’ designates the congenital absence of 6
or more permanent teeth and the complete absence of teeth is
defined as ‘anodontia’. Tooth agenesis can occur in an isolated
fashion, or as part of a syndrome. Affected members within a
family often exhibit significant variability with regard to the
location, symmetry, and number of teeth involved.
13) and MSX1 (4p16.1), have been shown as the major causes of non-
syndromic oligodontia. MSX1 is a member of the homeobox gene
the dental mesenchyme and is eliminated from the dental epithelia
during the bud, cap, and bell stages of tooth development .
Mutations in MSX1 coding regions cause human tooth agenesis of
various types of teeth, preferentially premolars . PAX9 belongs to
the PAX gene family, which encodes a group of transcription factors
that playarole inearlydevelopment.PAXproteinsare defined bythe
presence of a DNA-binding domain, the ‘paired domain’, which
makes sequence-specific contact with DNA. PAX9 is expressed in the
neural-crest-derived mesenchyme of the maxillary and mandibular
arches, and contributes to palate and tooth formation . Mutations
in PAX9 coding regions or a PAX9 deletion causes preferential tooth
agenesis of molars [4–9]. In addition to PAX9 and MSX1, AXIN2,
which encodes a Wnt-signaling regulator, is reported to associate with
oligodontia and colorectal neoplasia [10–11].
Among the missing teeth syndrome, oligodontia often occurs with
other ectodermal dysplasias, including nail dysplasia, dry skin, fine
hair, and sweating defects [12–14]. There are more than 49
syndromes that are associated with tooth agenesis . X-linked
hypohidrotic or anhidrotic ectodermal dysplasia (XLHED, MIM
305100) is the most common form of ectodermal dysplasia and is
characterized by sparse hair, eye lashes and brow, abnormal or
missing teeth and inability to sweat due to the lack of sweat glands, a
major disability in hot climates. The facial appearance of XLHED
consists of a saddle-nose, frontal bossing and thick lips. Atopic
dermatitis and bronchial asthma are frequent complications . If
unrecognized, XLHED is one of the causes of fevers of unknown
origin, repeated bronchitis, and sudden death during infancy and
early childhood. Affected males present most or all of these typical
features. In female carriers, the severity of the disorder varies
considerably, but most of them have mild to moderate manifesta-
tions of these typical features, ranging from none to some degree of
hypodontia, hypotrichosis, and hypohidrosis.
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Mutations of the ectodysplasin A (EDA) gene are responsible for
this disorder [17–20]. EDA is a 391 amino acid transmembrane
protein with a C-terminal TNF domain [19,21,22] which involves
in the early epithelial–mesenchymal interaction that regulates
ectodermal appendage formation . It is a ligand for a death-
domain- containing receptor called the ectodysplasin-A receptor
(EDAR). The ligand receptor pair signals through an adaptor
molecule, called ectodysplasin-A receptor associated death domain
(EDARADD), to the nuclear factor-kappa B (NF-kB) pathway to
promote cellular survival [23–25]. Mutations in EDAR produce
an identical phenotype to the loss of function of EDA . EDA/
EDAR interaction was also reported to regulate mouse tooth
This study describes two unrelated Chinese families affected by
non-syndromic tooth agenesis in an X-linked manner. The
objective of the present study was to identify the mutation
responsible for the familial tooth agenesis in kindred and to
identify genotype/phenotype correlations that could improve the
understanding of abnormal and arrested tooth formation.
The pedigrees are shown in Fig. 1. Both the families showed an
apparent X-linked dominant form of tooth agenesis. Family A
comprises 56 members spanning four generations, 9 members in
this family show congenital tooth agenesis (male 6, female 3).
Family B consists of five generations including 13 members with
congenital tooth agenesis (male 11, female 2).
In both families, the manifestation of tooth agenesis is not
uniform (Fig. 2). In Family A, the hypodontia involved all classes of
teeth. However, in Family B, all the affected members predom-
inantly lacked incisor teeth but had all the permanent molars. The
phenotype in Family A was more severe in terms of the numbers of
missing teeth, i.e., with the proband lacking all permanent
premolars, cans, incisors, as well as all the third molars and three
second molars. Phenotypic characteristics of scalp and body hair,
skin, nails and ability to sweat were examined in all individuals of
both families. All the individuals had normal sweating and had no
complaints about intolerance to heat, and their facial features,
skin, and nails all appeared normal.
Positional cloning of the oligodontia gene
By haplotype analysis of the pedigree of Family A (Fig. 3A), the
affected locus was confined to the region between DXS1039 and
DXS8064. In the two-point linkage analysis, two loci in this region,
DXS1196 and DXS986, both gave the highest two-point LOD
value of 3.13 (Fig. 3B), strongly suggesting that the disease gene
associated with tooth agenesis is closely linked to the two markers.
Inthiscritical region, thecandidategenesfor the oligodontialocus
include those encoding for transcription factors or proteins involved
in signal transduction. The relative positions of these genes are
shown in Fig. 4A. We therefore proceeded to screen for mutations in
these genes. By directly sequencing all exons and flanking splice
junctions of the candidate genes, ITM2A, TBX22, SH3BGRL,
ZNF711, KLHL4, CPXCR1 and TGIF2LX were ruled out because no
mutation was detected (data not shown). Our best candidate pointed
to EDA. The EDA gene structure is shown in Fig. 4B.
To identify possible mutations in the EDA gene, we first
sequenced all eight exons coding for EDA in two affected males
and two female carriers in Family A. We found a novel missense
mutation c.947A.G in exon 9 of EDA, and found the mutation
segregating with affected or carrier status in the other family
members (Fig. 5). This mutation resulted in the non-synonymous
substitution of aspartic acid for glycine at amino acid residue
position 316 (p.D316G) in the TNF domain of EDA protein
(Fig. 4C). Exon 9 of EDA was also sequenced from 300 unrelated
normal Chinese individuals with the same Han ethnic back-
ground, 150 females and 150 males, without detecting any
guanine at the c.947 base position of EDA gene allele.
Though the phenotype of hypodontia in Family B was milder
than Family A, the hypodontia in Family B was inherited as the
same X-linked dominant trait as in Family A. Therefore we also
selected EDA as a candidate gene in Family B and directly
examined Family B for possible mutations in EDA. After mutation
screening of eight exons of EDA gene in Family B, a c.1013C.T
transition mutation of EDA gene was observed (Fig. 5). The
c.1013C.T transition resulted in p.T338M substitution in the
TNF domain of the EDA protein (Fig. 4C). The c.1013C.T
mutant allele was present in all affected males, and in affected and
obligate carrier females, but in none of the other individuals in
Figure 1. Pedigree structure of the two Chinese families with tooth agenesis. Affection status for pedigrees (females in circles, males in
squares) is shown: closed symbols, affected; open symbols, unaffected.
Oligodontia with EDA Mutation
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Family B. The c.1013C.T nucleotide substitution was also not
found in any of 300 control individuals of the same ethnic
background, which strongly suggests that this is the causative
mutation in this family.
In both families, the male individuals bearing the mutant gene
were associated with complete penetrance, however, in female
heterozygotes incomplete penetrance was observed. In Family A,
female carries IV:08, IV:09 and IV:10 showed hypodontia, but the
other carriers displayed normal teeth (Fig. 1). Among female
carriers in Family B, only individuals IV:27 and V:05 showed
missing teeth, while the other female carriers showed normal teeth.
The cause of this phenomenon is unclear; however, it may have
resulted from the differential pattern of X-chromosome inactiva-
tion between the symptomatic carriers and the non-symptomatic
The EDA gene product is a type-II transmembrane protein with
a small N-terminal intracellular domain followed by a larger C-
terminal extracellular domain. The C-terminal extracellular
domain contains a collagen-like repeat domain and a tumor
necrosis factor (TNF) domain  (Fig. 4C). The TNF domain has
been shown to form homotrimers which are believed to be
required for receptor interactions . The HED-causing
mutations in the TNF domain which affect the function of EDA
have been previously analyzed: most mutations (His252Leu,
Gly291Trp, Gly291Arg, Gly299Ser, Tyr320Cys, and Ala349Asp)
are likely to affect the overall structure of EDA, and some
mutations (Tyr343Cys, Ser374Arg, Thr378Pro, and Thr378Met)
alter the receptor binding site . However, Asp316Gly and
Thr338Met mutations have not been reported previously.
Figure 2. Clinical evaluations. (A) and (B). Synopsis of the permanent dentition in affected members of Family A and Family B. Closed squares
represent absent teeth. (C). Panoramic radiograph of a proband (IV:02) in Family A at age 14. He had up left permanent second molar, four permanent
first molars and four milk second molars. (D) and (E): Clinical appearance of V:03 (Family B), at age 18, showing absence of all the incisors, two up cans
and four premolars.
Oligodontia with EDA Mutation
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Figure 3. Linkage analysis for Family A. (A). Haplotype analysis in the Family A. Open symbols represent the unaffected individuals, closed
symbols represent the affected individuals, squares indicate men, and circles indicate women. The closed bars indicate the fourteen contiguous-
marker disease-linked haplotypes shared by all patients and female carriers. (B).The Lod Score obtained from the analysis of the pedigree of Family A
with X-linked microsatellite markers around the centromere.
Oligodontia with EDA Mutation
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Structural analysis of EDA protein showed that D316 and T338
were located at two adjacent loops at the bottom of the TNF domain
(D316 at loop CD and T338 at loop EF respectively) (Fig. 6A–6C).
Unlike the above mentioned HED-causing mutations, both
p.D316G and p.T338M mutations were a distance away from the
receptor-binding site, and thus are not likely required for the
receptor binding. To understand the structural effects of these two
point mutations, the detailed molecular modeling analysis of the
interactions between mutated residues and their surrounding
residues was performed and is presented below.
Residue Asp316, which is located at loop CD, interacted with the
residues including Ser335, Ile336 and Thr338 in the adjacent loop
EF via van der Waals force or hydrogen bonds. In addition, the side
chain of Asp316 extended and formed salt bridges or hydrogen
bonds with Lys340 or Asn342 from the neighboring monomer, thus
taking part in subunit-subunit interactions (Fig. 6D). Replacing this
residue by Gly abolished the contacts between the side chain of
Asp316 and its surrounding residues and its neighboring monomer
(Fig. 6E). This could reduce the inter-subunit interactions in this
region and further affect the stability of the trimer. The mutation to
Glyalsodecreased thehydrophilicityand negative chargesofthissite
and may increase the flexibility of this region. Considering its role in
interactions between loops, this Gly mutation may also affect the
fluctuation of the adjacent loop EF.
Thr338, located in loop EF, could interact with the residues
from loop CD, forming a hydrogen bond with the carbonyl
oxygen atom of Ile312. In addition, backbone and side chain
atoms of Thr338 could interact with Asn313, Thr315 and Asp316
via van der Waals force or hydrogen bond (Fig. 6D). The
replacement of hydrophilic Thr with hydrophobic Met increased
the hydrophobicity at this site. The absence of Thr338 in
p.T338M mutant would cause a decrease in the stability of this
region. Meanwhile, the large hydrophobic side chain of Met338 in
the mutant might make hydrophobic and van der Waals
interactions with Asn313 and Phe314 from neighbor loop CD
and thus may contribute to the conformational rearrangement
surrounding the residues. As a consequence, it could affect the
conformation of Asp316 side chain and in turn disrupt the inter-
subunit interactions (Fig. 6F). These results by molecular modeling
suggest that replacing hydrophobic residue at this site would not
only affect the stability of loop EF but also affect the stability of the
nearby loop CD.
In conclusion, this molecular modeling analysis suggests that
although Asp316 and Thr338 are located at different sites in the
primary sequence, they are spatially close and might interact with
each other; the mutation in either site could affect the stability of
its adjacent loop. It is possible that p.D316G and p.T338M might
have similar impacts on the structure of EDA by interacting
between each other. As strands E, F and C connected by CD and
EF loops are directly involved in the inter-subunits interactions
and Asp316 and its neighboring residues are directly involved in
monomer-monomer interactions, it could be expected that
significant variations occurring at these mutated sites would affect
the stability of EDA trimer.
In this study, we identify two novel mutations in the EDA gene
in two independent Chinese families with isolated tooth agenesis.
Both mutations are predicted to result in changes in single amino
acid residues in the TNF domain of the protein: p.D316G and
p.T338M. These mutations of p.D316G and p.T338M in EDA
and their effects on the phenotype change have not been reported
Mutations in ectodysplasin A have been previously identified as
the cause of X-linked hypohidrotic ectodermal dysplasia (XLHED)
(OMIM 305100). So far, only two articles reported that mutations
in the EDA gene resulted in unique hypodontia phenotype rather
than the full XLHED phenotype [28–29]. In that study the test
group one was a Mongolian family with a missense mutation
(p.R65G) in the juxtamembrane region of EDA . Affected
members in this Mongolian family did not show other XLHED
characteristics, except hypodontia. The patterns of missing teeth
Figure 4. Candidate genes identified in the critical region in the Xp11-Xq 21. (A). The gene order for this region as obtained from NCBI
(NCBI Map Viewer, human Build 36.2). (B). The EDA gene structure. The numbered boxes represent exons and the connecting lines represent intronic
regions. (C). The structural feature of protein product of EDA. The start and stop codons are indicated by ‘‘ATG’’ and ‘‘TAG.’’ The transmembrane
domain (‘‘TM’’), furin recognition site, collagen domain, and the TNF homology domain are shown. The relative positions of the mutations identified
in this article are indicated by open triangles. Mutations found in previous studies associated with X-linked hypodontia, are also indicated in this
diagram by closed triangles.
Oligodontia with EDA Mutation
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were similar to the Family A in our study; the hypodontia
occurring in both the Mongolian family and Family A involved all
classes of teeth. Another previously reported study of an Indian
family found a missense mutation (p.Q358E) in the EDA TNF
domain. The phenotype of this Indian family most resembled the
Family B of our study . Both Family B and the Indian family
show incisor hypodontia and the symptom is milder than that
observed in Family A and the Mongolian family. It seems that
different mutation sites in EDA caused the difference in missing
teeth patterns. Interestingly, a similar finding was also observed
caused by the mutations in the PAX9 gene. Lammi et al. reported
a missense mutation in PAX9 in a family with oligodontia
phenotype that affected all tooth groups . In another report,
Kapadia et al. showed Ile87Phe mutation in PAX9 in another
family only affected posterior teeth, primarily the molars .
In this report, we describe the identification of two novel
missense mutations in the TNF domain of EDA. Both mutations
associated with only tooth agenesis without causing other
abnormalities. Unlike other reported HED-causing mutations in
the TNF domain which were expected to affect the receptor
binding site or overall structure of the EDA protein, molecular
modeling suggests that these two mutations only minimally affect
the stability of EDA trimer. Therefore, we presume that the
human phenotype associated with the novel mutations could be
caused by the decrease in the stability of the EDA protein. The
phenotype of isolated tooth agenesis of the two families may be a
milder clinical subtype of X-linked HED. Similar to p.D316G and
p.T338M, p.Q358E is also located on the outer surface of the
EDA protein. Tarpey et al  suggested that Q358E partially
disrupts the interaction of the EDA homotrimers, thus resulting in
the inability of EDA to interact with its target receptors. Until
now, there have been four EDA mutations, p.R65G, p.Q358E,
p.D316G and p.T338M that have been reported associated with
unique tooth agenesis. p.Q358E, p.D316G and p.T338M are all
in the TNF domain. These three mutants seem to share similar
consequences: they all disrupt the interactions in the homotrimer
and therefore result in the inability of EDA to interact with its
target receptors. One unique feature among these mutants is that
D316G is directly involved in interactions of the monomers, while
the other two mutations indirectly affect the interactions of the
EDA homotrimers. This difference may account for the phenotype
of p.D316G being more severe than that of p.T338M and the
phenotype of p.T338M is very similar to that of p.Q358E. In the
p.R65G mutant, the substitution occurs on the edge of the
transmembrane domain of the EDA protein and its effect on EDA
function is still not clear.
Figure 5. DNA sequencing chromatograms showing the mutations of affected members in Family A and Family B. In Family A, male
patients show c.947A.G transition that is predicted to result in a p.D316G substitution in EDA and female carriers have A/G heterozygosity at the
same position. In Family B, male patients show c.1013C.T transition that is predicted to result in a p.T338M substitution in EDA and female carriers
are C/T heterozygous at the same position. Patient: male patients (hemizygous), carrier: female carriers (heterozygous), normal: normal individuals (no
Oligodontia with EDA Mutation
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Here we identify novel mutations in the EDA gene that are
involved in the X-linked isolated hypodontia and provide an
explanation for the clinical phenotype at the molecular structural
level. This is an initial step in explaining the pathogenic
mechanisms underlying EDA-mediated tooth agenesis. Further
in vivo expression and functional characterization of the mutated
protein might present more direct explanations for how the
malfunctions in EDA protein caused by the identified missense
mutations disrupted the tooth development.
Materials and Methods
Pedigree, diagnosis, and DNA collection
The research project was submitted and approved by the
Institutional Review Board (IRB) of Nanjing University. Detailed
histories and pedigree information about the affected two families,
which were designated Family A and Family B (Fig. 1), were
obtained and confirmed through personal interviews with family
members. The oral status of each individual was scored as affected
or unaffected by personal examination and/or by review of dental
records and X-ray films. After consents were obtained from all
participating individuals, venous blood samples were collected and
genomic DNA was isolated with the QIAmp Blood kit (Qiagen,
Germany). In addition to these two families, 300 normal unrelated
individuals of the same ethnic background (150 male and 150
female) were recruited as controls.
Since the pedigrees showed the X-linked inheritance mode, 48
polymorphic microsatellite genetic markers, spanning the entire X
chromosome at the average interval of 5 cM (Linkage Mapping
Set-HD5 kit , PE Biosystems, Foster City, CA, USA), were selected
to scan the genomic DNA extracted from peripheral blood
leukocyte of Family A members. Two-point linkage analysis was
performed, using parametric method with the MLINK software of
the Linkage Analysis Package version 5.2.
By haplotype analysis of the pedigree, we confirmed that EDA is
our best candidate gene. Previously designed primers flanking the
coding regions of the eight exons of EDA were used to amplify the
genomic DNA by polymerase chain reaction . All eight exons
and their flanking splice junctions of EDA were directly sequenced
by using an ABI-3100 sequencer.
The X-ray structure of the TNF domain of EDA was obtained
from PDB (ID:1RJ7). The monomer structures of D316G and
T338M TNF domain of EDA were built by MODELLER8v2
program (http://salilab.org/modeller/). Trimers of EDA
mutants were built using Insight II (Accelrys, San Diego, CA,
Figure 6. Structures of wild type, D316G and T338M EDA. (A)–(C). Locations of p.D316G or p.T338M mutation sites in the quaternary
structure of the EDA homotrimers. The EDA trimers are shown as ribbon rendering with mutation residues rendered in stick and ball, beta strands and
the mutated amino acids are labeled. (D)–(F). Close up views of the mutation sites of D316G, T338M and wild type EDA proteins. The amino acid
backbones are represented by ribbons with arrows. Side chains have been omitted from most residues for clarity. Hydrogen bonds are indicated by
dashed green lines.
Oligodontia with EDA Mutation
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Acknowledgments Download full-text
We are grateful to the families who generously contributed their time and
materials for this research. We also thank Dr. Xuexun Fang (Jilin
University) and Ms. Marylyn White (Nanjing University) for language
Conceived and designed the experiments: ZH. Performed the experiments:
SL JC XD ZW MC. Analyzed the data: ZH SL JL JC. Wrote the paper:
ZH SL JL. Other: Collected samples: XT BZ. Clinical diagnosis: BZ QH.
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Oligodontia with EDA Mutation
PLoS ONE | www.plosone.org8 June 2008 | Volume 3 | Issue 6 | e2396