Braz J Oral Sci. April/June 2005 - Vol.

4 - Number 13

Hypodontia: genetics and future

perspectives
Trevor J Pemberton1
Parimal Das3
Pragna I Patel1,2
1
Institute for Genetic Medicine and the 2Center
for Craniofacial Molecular Biology, Keck School
of Medicine, University of Southern California,
CA-USA and 3Department of Surgical Oncology,
M.D. Anderson Cancer Center, Houston, TX-USA
Received for publication: February 14, 2005
Accepted: May 10, 2005
Abstract
Tooth development is a complex process of reciprocal interactions
that we have only recently begun to understand. With the large number
of genes involved in the odontogenic process, the opportunity for
mutations to disrupt this process is high. Tooth agenesis (hypodontia)
is the most common craniofacial malformation with patients missing
anywhere from one tooth to their entire dentition. Hypodontia can
occur in association with other developmental anomalies (syndromic)
or as an isolated condition (non-syndromic). Recent advances in genetic
techniques have allowed us to begin understanding the genetic processes
that underlie the odontogenic process and to identify the mechanisms
responsible for tooth agenesis. Thus far two genes have been identified
by mutational analysis as the major causes of non-syndromic
hypodontia; PAX9 and MSX1. Haploinsufficiency of either has been
observed to cause the more severe forms of hypodontia whilst point
mutations cause hypodontia to varying degrees of severity. With the
prevalence of hypodontia having been observed to have increased during
the 20th century, the future identification and analysis of its genetic
basis is essential to allow us to better treat the condition. The clinician
can facilitate this process by collaborating with the human geneticist
and referring patients/families with familial hypodontia for investigative
research.

Key Words:
hypodontia, tooth agenesis, PAX9, MSX1, prevalence, mutations

Correspondence to:
Pragna I Patel
Institute for Genetic Medicine, Keck School of
Medicine, University Of Southern California,
2250 Alcazar Street, CSC-240, Los Angeles, CA
90033, USA.
Tel: +1 (323) 442 2751
Fax: +1 (323) 442 2764
E-mail: pragna@usc.edu

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Introduction
The smile is a unique facial expression distinct to primates. The
main physical component of the smile is a complete dentition
set comprising four different types of teeth. Vertebrate
comparative histology has indicated that the continued
evolution of teeth throughout the emergence of modern man is
due to the increased fitness they have offered us. Our modern
lifestyle also has a special attachment to a complete set of
dentition aside from their use as merely mastigatory appendages
for food. For this reason, naturalists, biologists and dentists
have for a long time been trying to unravel the cause for the
congenital loss of teeth leading to several clinical phenotypes
such as hypodontia, oligodontia and anodontia.
While a number of clinical studies have been carried out on
disorders that involve the congenital lack of teeth1-11, until
recently very little effort has been made to understand the
genetic component responsible for mammalian tooth
development. Advancements in molecular biology
approaches coupled with the now complete human genome
sequence12 has allowed a number of putative disease genes/
loci associated with the hypodontia/oligodontia phenotypes
to be identified6,13-16. Functional studies of these disease
genes have started to reveal their precise role in tooth
development allowing us to better understand their role in
disease pathology and the molecular morphogenetic fields
within which they function17.
The congenital lack of one or more permanent teeth is a
common anomaly in man. By definition, congenitally missing
teeth are those that fail to erupt in the oral cavity and remain
invisible in a radiograph, which implies that this is caused
by disturbances during the early stages of tooth
development. These phenotypes most frequently involve
the second premolars and upper lateral incisors and
commonly lead to mild phenotypes that have no associated
systemic disorder. The term hypodontia has most frequently
been used for describing the phenomenon of congenitally
missing teeth, although a large number of missing teeth is
defined as oligodontia and the complete absence of teeth is
defined as anodontia. Hypodontia and oligodontia are also
classified as either nonsyndromic (isolated) or syndromic
(associated with their syndromes). A literature survey shows
various other terminologies describing a reduction in teeth
number; teeth aplasia, congenitally missing teeth, absence
of teeth, agenesis of teeth, and lack of teeth. Although no
distinct definition and classification exists in literature, the
following definitions have been widely used in scientific
literature:
1. Hypodontia: one of six missing teeth excluding 3rd molar
2. Oligodontia: More than six missing teeth excluding 3rd
molar
3. Anodontia: Complete absence of teeth
Identifying disease genes
Hypodontia: genetics and future perspectives
The online catalog of inherited human diseases (Online
Mendelian Inheritance in Man; OMIM 18) currently lists
almost 16000 inherited human disease genes. However, the
molecular etiology for only about 2000 of these has been
determined successfully. The cloning of disease genes is
the first step in understanding the detailed molecular basis
of the disease that ultimately facilitates the development of
suitable diagnostic and therapeutic agents. There are mainly
two different strategies that have been employed for
identifying human disease genes: functional cloning and
positional cloning (Figure I). As the name implies, functional
cloning identifies genes based on the known biochemical
function of their encoded proteins. For example, the
identification of the gene responsible for phenylketonuria
was achieved by purifying the mRNA for phenylalanine
hydroxylase, the enzyme normally responsible for the
oxidation of phenylalanine to tyrosine but absent in
sufferers, and using this to screen a cDNA library for the
corresponding DNA sequence 19 which facilitated the
identification of its chromosomal location20-21. However, in
reality for the vast majority of inherited disorders, knowledge
about their basic biochemical defect is unknown making the
use of functional cloning impossible which has led to a
second strategy, positional cloning.
The positional cloning approach employs one or both of the
following strategies; (a) analysis of genetic linkage in families
with a disease and/or (b) identification of a specific
chromosomal aberration(s) in the diseased individual.
Successful genetic analysis depends on the following
requirements; (a) identification of large families segregating
the disease phenotype, (b) a distinctive diagnostic criterion
to distinguish the affected individuals, (c) accurate
assessment of the individuals of the family for a known
Mendelian or complex pattern of segregation and (d) highly
polymorphic DNA markers.
In principle, the basis of linkage analysis is to observe the
closeness of two alleles for two different genes on a
chromosome. The closer the two alleles are to each other,
the more likely they are to segregate together during meiosis
due to the reduced chance of a recombinatorial event
occurring between them. Logically, this principle is applied
to determine the genetic distance of known genetic markers,
or site locators, from a disease locus by tracing its
segregation pattern in affected families. In figure II, the
disease locus D is closer to the marker locus represented by
allele X/x but distant from the locus represented by Y/y. Due
to this, the disease locus co-segregates with the X locus
whereas it shows random segregation pattern with respect
to the Y locus. Essentially, good genetic markers are those
which are polymorphic and can be easily assayed in genomic
DNA isolated either from lymphocytes or buccal cells.
The traditional definition of polymorphism is a natural
variation in nucleotide sequence which is observed in at
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least 1% of a population and is capable of distinguishing
the parental chromosomes which otherwise seem virtually
identical in every respect. The degree of polymorphism of
the genetic marker has direct bearings in scoring the
distinction. The information on segregation of polymorphic
markers with respect to the disease phenotype is then
analyzed using statistical programs in order to derive a LOD
score. LOD score, or the logarithm to the base 10 of the
odds, is defined as the relative probability of the observed
data being the result of true linkage versus the probability
due to chance. Conventionally, linkage is considered
established if the LOD score at any given recombination
fraction () is equal to or greater than 3, while linkage is
excluded if the LOD score is equal to or less than 2.
Statistically, a LOD score of 3 means that it is 103, or 1000
times more likely that the observed pattern of segregation
of one marker with respect to another marker or disease
locus occurred because of linkage rather than chance.
Multipoint linkage analysis for determining the disease gene
position with respect to a number of genetic markers in the
candidate region is then used to localize the position of the
disease gene between two flanking genetic markers. The success
of positional cloning efforts requires very tightly linked markers.
An alternative approach to associate gene(s) with a genetic
disorder is to analyze mutations in candidate genes, those
that have either a proven or speculated association either
directly or indirectly leading to the disease state. With the
advancement of our present day knowledge about disease
pathology and its consequences at both the biochemical
and physiological levels, mapping human disease genes by
the candidate gene approach plays an important role
especially in excluding the involvement of a gene for a given
phenotype. Using this approach, the association of multiple
growth factor and growth factor receptor gene(s) with
congenital teeth agenesis has been excluded22.
Fig. I: Segregation of loci within a two generation pedigree. The
disease locus is labelled N for normal or D for disease with the
two marker loci marked as X/x or Y/y where the change in case
indicates different alleles at that position. Allele x appears to
segregate with the disease (D) given their close proximity.
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Hypodontia: genetics and future perspectives
Fig. II: Methodology of positional and functional cloning of a
single gene defect.
Tooth Development
In mammals, tooth development is a complex process with
reciprocal interactions between the dental epithelium and
mesenchyme involving the shifting of the odontogenic
potential between these tissues (figure III). The first sign of
tooth development is the appearance of the primary epithelial
band within which the odontogenic process initiates with
the formation of an epithelial bud. Mesechymal cells then
differentiate around the bud to form the dental papilla, the
precursor of the tooth pulp and dentin-secreting
odontoblasts that appear after a few additional soft-tissue
phases that include the cap stage leading to the bell stage
when the enamel-depositing ameloblasts are formed. The
dentinal matrix then forms at the periphery of the dental papilla
during dentinogenesis and subsequently enamel deposition,
or amelogenesis, occurs at the dentino-enamel junction after
a few micrometers of dentin has been deposited. Finally,
apposition of dentin and enamel gives way to tooth eruption
and function.
Transcription factors and signaling molecules, which operate
both intra- and extra-cellularly, are expressed in a spatially-
and temporally-restricted pattern in the epithelium and
mesenchyme tissues throughout the odontogenic process
and guide tooth development (figure III). Tissue-
recombination experiments have helped greatly in developing
our understanding of the hierarchy and roles of the various
factors with the odontogenic process23-24.
BMP4, a member of the transforming growth factor- (TGF-)
family, and the transcription factors PAX9 and MSX1,
members of the paired-box domain and homeobox domain
gene families respectively, are examples of controlling factors
during the odontogenic process. The odontogenic potential
Braz J Oral Sci. 4(13):695-706
shifts from the epithelium to the dental mesenchyme
concomitantly with BMP4 expression25. Both PAX9 & MSX1
are expressed in the dental mesenchyme and their expression
is key to maintaining the odontogenic potential following
this shift25. PAX9 has been identified as a key controlling
factor during the odontogenic process with its expression
found specifically at the prospective sites of all teeth prior
to there being any morphological signs of odontogenesis25.
A general role for MSX1 in the development of ectodermal
derivatives has been suggested14 with it strongly expressed
in the dental mesenchyme but notably absent from the dental
epithelia during the bud, cap and bell stages of tooth
development26. Tooth development in both PAX9- and MSX1-
mutant mice is arrested at the bud stage27-28, suggesting they
have similar, non-redundant roles in signal progression to
the cap stage of tooth development. Interestingly, PAX9
and MSX1 have been reported to have an important
regulatory role in the maintenance of BMP4 expression and
signaling25 implying they may also have a role in odontogenic
Fig. III: Known protein factors involved in tooth development. Names
in bold indicate that they have only been identified as involved at
one stage and names in italics indicate those factors that have been
found to be involved in signalling from both the epithelium and
mesenchyme.
potential shifts.
Clinical features of Hypodontia
A congenital anomaly affecting the formation of the dentition
that results in a reduction in the usual number of the human
permanent dentition (a total of 32 teeth in both jaws) and/or
the deciduous dentition (20 total teeth in both jaws) is
commonly referred to as hypodontia. Recent studies have
shown that the occurrence of hypodontia has increased
during the 20 th century 29. 80-85% of hypodontia cases
studied involved the agenesis of just one or two teeth 30,
indicating that most people afflicted suffer from a mild form
of the disease. The tooth most commonly missing is the
third molar (or wisdom tooth) which is absent in as much as
20% of the population2,31-34. The second most commonly
Hypodontia: genetics and future perspectives
missing tooth is reported to be the maxillary lateral incisor
by some investigators 30,35-36 or the mandibular second
premolar by others 37-38. The lowest incidence of tooth
agenesis occurs in the lower central and lateral permanent
incisors with agenesis of maxillary permanent central incisors,
maxillary permanent cuspids and maxillary permanent first
molars also rare39.
Hypodontia affecting the primary dentition is rare (prevalence
rate of <0.5%) and has been observed to afflict both sexes
equally39-40. It is often followed by hypodontia in the same
region of the permanent dentition, which itself has a
prevalence, excluding third molars (wisdom teeth), ranging
between 2.3% and 10%41 and a third of sufferers typically
have at least one first-degree relative also afflicted40,42. Severe
hypodontia, also referred to as oligodontia, involves the
agenesis of six or more teeth and like hypodontia of the
primary dentition it is rare afflicting approximately 0.5% of
the population43.
Hypodontia has been identified as both non-syndromic,
where it is an independent congenital oral trait, or syndromic,
where it is acquired as part of a specific disease. It is an
associated finding in at least 49 syndromes listed in the Online
Mendelian Inheritance in Man database18 implying some
factors involved in tooth development have a wider role
within the human body. Other anomalies associated with
hypodontia include small tooth size (microdontia), large tooth
size (macrodontia) and anomalies in tooth shape, most
commonly tapering or peg-shaped teeth40,44.
The non-syndromic form of hypodontia can be sporadic or
familial and it has been most frequently reported as inherited
in an autosomal dominant45-52 (AD) fashion where it displays
phenotypic heterogeneity as measured by the nature of the
missing teeth and other alterations in the teeth. However,
autosomal recessive53 (AR), X-linked54-56 and polygenic57-60
inheritance has also been reported.
Geographical, population and gender prevalence
Hypodontia
Variation is seen in the number of teeth found in both the
primary and permanent dentition, although it is less common
in the primary dentition39, 41. Several population studies have
been carried out in the past to establish the epidemiological,
clinical and genetic characteristics and prevalence of
hypodontia both in primary and permanent dentition through
the collection of the dental history of individuals belonging
to several families representing various countries/
geographical locations and races. Table I shows the
summarized data representing the prevalence of hypodontia
in primary and permanent dentition in various geographical
locations. It is apparent from these studies that the population
prevalence of hypodontia varies with geographical location.
In the primary dentition, Japan shows the greatest prevalence
of hypodontia which is almost three times greater than the
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next highest, Finland. Great Britain shows the lowest
prevalence which is an eighth of that of Japan with the
remaining countries in table I also showing low prevalences
between 0.4-0.6%. In the permanent dentition, Saudi Arabia
shows the lowest prevalence whilst Iceland exhibits the
highest. The greatest differences are found in the
populations of both Iceland and Sweden which exhibit a
prevalence of hypodontia in their permanent dentition that
is 16 or 19 (respectively) times greater than in their primary
dentition. Europe has a prevalence of hypodontia in the
permanent dentition that is at least ten times greater than
any of the European component countries have exhibited in
the primary dentition. This pattern is also seen between the
primary dentition of New Zealand and the permanent dentition
of its neighbor country Australia, whereas Japan has a
prevalence in its primary dentition that is only a third of that
in the permanent dentition of its neighbor country China.
Interestingly, Saudi Arabia exhibits an equal prevalence of
hypodontia in both its primary and permanent dentition. It
therefore appears that people of Scandinavian decent are
the most susceptible to hypodontia in the permanent
dentition whilst those of Asian or Arabic descent are the
most susceptible in the primary dentition. There are
apparently no published reports of large scale studies of
populations in Latin American countries.
A number of investigations have attempted to take into
account any possible gender preference in tooth agenesis
(table II). Several reports mentioned a lower prevalence of
tooth agenesis in males30,38,61 with one study reporting a male
to female ratio62 of 2:3 whilst others have failed to confirm
Table I: Prevalence of hypodontia in the primary and permanent dentition in different countries/continents.
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Hypodontia: genetics and future perspectives
this63. The data in (table II) shows no clear pattern of gender
preference with fluctuations between male and female bias
where most studies show ratios that are close to parity.
Oligodontia
The congenital lack of more than six permanent teeth
(oligodontia; a severe hypodontia) is also quite prevalent in
the population. Studies on different populations have shown
variation in the prevalence of oligodontia with the difference
in the frequency of oligodontia between males and females
found to be not statistically significant 64-65 , nor is the
difference in distribution of missing teeth over mandible/
maxilla and right/left sides64-65. Collective data from six
different studies does however indicate that the frequency
of oligodontia is lower in males than females and that the
frequency of missing second premolars or upper lateral
incisors is higher in congenital oligodontia66.
Etiology
Both genetic and environmental factors have been found to
contribute to the etiology of tooth agenesis with many
theories having been suggested to explain their affects,
particularly prior to the intensive genetic studies performed
in recent years38,49,67-68.
Environmental Factors
Environmental factors can cause tooth agenesis by a variety
of means 69 that can be broadly placed into two groups:
invasive and non-invasive. These can act either additively
or independently to affect the positioning and physical
Braz J Oral Sci. 4(13):695-706
Table II: Studies comparing gender bias of tooth agenesis (excluding third molar) in the permanent dentition in various countries.
nr = not reported
development of the tooth.
Jaw fractures, surgical procedures, extraction of the
preceding primary tooth and changes in muscle pressure
from the facial and lingual sides are all examples of invasive
factors that can affect tooth development and positioning
leading to tooth agenesis and impaction38,49,65.
It has also been shown that developing teeth are irreversibly
affected by chemotherapy and irradiation in an age- and dose-
dependent manner, with the latter having been shown to
cause the more severe effects 4-5 . Thalidomide (N-
phthaloylglutamimide) has been reported to cause
congenitally missing teeth in children whose mothers took it
during their pregnancy1,70-71. Nutrient deprivation and serious
illness have also been linked to tooth developmental
problems, although no definite etiological relationship has
been found between hypodontia and systemic diseases38,49,
endocrine disturbances72 or ectodermal dysplasia73.
A developmental relationship has been proposed between
nerve and hard tissues74 with tooth agenesis linked to the
Hypodontia: genetics and future perspectives
development of the main innervation paths75-76 where it was
noted that the regions most commonly affected by
hypodontia were the last to undergo innervation. Brainstem
anomalies have been shown not to affect tooth
development77 indicating that it is local rather than global
nerve development that affects tooth agenesis.
Genetic Factors
In the majority of cases, hypodontia has a genetic basis.
Tooth agenesis is found more commonly among individuals
related to hypodontia patients than in the population in
general56 identifying it as a genetic disease. An exhaustive
study on a Swedish family with 685 family members, including
171 probands affected with hypodontia, showed that
hypodontia involving permanent teeth is primarily
determined by genetic factor(s) 38 . The frequency of
hypodontia among races varies30,78 and greater concordance
of hypodontia is apparent in identical twins than non-
identical 79-80 with no environmental etiology apparent in
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afflicted individuals. of positional candidate genes present in the candidate

Familial hypodontia is reported to exhibit mainly autosomal
dominant inheritance with incomplete penetrance and
variable expressivity49-52. However, an autosomal recessive
mode of inheritance for hypodontia has been reported in a
Pakistani family which mapped to chromosome 16q12.153 and
in another report on Finnish patients that are afflicted with a
specific type of hypodontia (Recessive Incisor Hypodontia;
RIH), where patients notably lacked both deciduous and
permanent incisors81. It has also been suggested that it can
follow sex-linked42,59,82 (Patel et al., unpublished results) or
polygenic inheritance patterns54-55,57-58.
Recently, direct evidence was gathered for the genetic basis
of tooth agenesis thanks to the mapping of human disease
genes using linkage analysis followed by mutation analysis
interval. Using this gene mapping strategy, autosomal
dominant hypodontia has been localized to at least three
chromosomal loci to date; MSX183, PAX913 and an unknown
locus on chromosome 106. Five mutations have thus far
been identified within MSX1 and ten within PAX9 (table III)
with both genes also having been found to be deleted in
separate studies of familial hypodontia45,84.
MSX1
Although one report has excluded the MSX1 gene as the
gene responsible for tooth agenesis85, recent research has
identified MSX1 as the causative gene for some forms of
congenital teeth agenesis with five mutations having been
identified within MSX1 thus far (table III). All of these

Table III: Identified mutations in MSX1 and PAX9 that have been found in people afflicted with hypodontia. Tooth is considered
absent if not present in >50% of patients. Mutation nomenclature used as previously described 124 and is used to denote gene
deletion or protein absence.

= tooth present; = tooth absent in both; = tooth absent in either mandibular/maxillary; AD = autosomal dominant.

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mutations have been point mutations with two leading to a
substitution mutation within the protein and the remaining
three form a stop codon that prematurely truncates the
protein. Two mutations fall within the N-terminal region prior
to the central homeodomain (M61K & S105X) with the
remaining three (Q187X, R196P & S202X) all falling within
the homeodomain itself (figure 4(A)).
Of the two substitution mutations, the M61K mutation15 falls
outside of the homeodomain of MSX1 and how it affects its
function remains unknown but it has been proposed that it
may be through the disruption of protein interactions15. The
R196P mutation 83 falls within helix-I of the MSX1
homeodomain disrupting its stability and functional
activity86.
Of the three premature termination mutations, S105X is the
only mutation to occur prior to the homeodomain of MSX1
(figure 4(A)). It was identified in a Dutch family suffering
from cleft lip-palate and hypodontia that were found to be
heterozygous for the 314C>A nucleotide substitution, which
creates a stop codon in MSX1 exon 1 truncating the protein
prior to the homeodomain87. The remaining two termination
mutations fall within the central region of the MSX1
homeodomain. A 559C>T nucleotide substitution was
identified in a Flemish family suffering from cleft lip-palate
and hypodontia where it forms a stop codon that truncates
the protein within helix-I of the MSX1 homeodomain (N187X;
figure 4(A))88. The S202X mutation, caused by a 605C>A
nucleotide substitution, was identified in a patient with Witkop
syndrome who was suffering from hypodontia 89 where it
generates a stop codon in helix-I of the homeodomain region
(figure 4(A)) truncating the protein and disrupting its
Fig. 4: Location of the mutations stated in table III in the MSX1 and
PAX9 proteins.
functional activity86,90.
Interestingly, two of the premature termination mutations
were identified in patients afflicted with both oligodontia
and cleft lip-palate (S105X & Q187X) with the third mutation
having been identified in an individual with Witkop tooth-
nail syndrome (S202X). They all suffer from additional
pathologies other than hypodontia which also afflicts those
with substitution mutations indicating that that whilst the
Hypodontia: genetics and future perspectives
substitution mutations disrupt MSX1 activity they do not
abolish it whereas the truncation mutations appear to abolish
MSX1 activity leading to a more severe phenotype. This is
supported by another study that identified
haploinsufficiency of MSX1 as the cause of severe
oligodontia within unrelated Finnish patients who also had
Wolf-Hirschhorn syndrome84. However, there is no clear
correlation between the severity of the hypodontia and the
severity of the effect on the MSX1 protein caused by the
identified missense mutations.
PAX9
In contrast to MSX1, both missense and frame-shift mutations
in PAX9 have been associated with hypodontia (table III).
Of the seven missense mutations identified to date, one is a
premature termination mutation (K114X) and the remaining
six are all residue substitution mutations. Of these latter
mutations, only five generate a substitution in the protein
(L21P, R26W, R28P, G51S & K91E) with one believed to
prevent PAX9 expression (1A>G). Three frame-shift
mutations have been identified, two of which are caused by
the insertion of a single nucleotide (G73fsX316 &
V265fsX316) and the other by the deletion of 8 nucleotides
with the insertion of 288 foreign nucleotides (R59fsX177).
All but one of these mutations (V265fsX316) falls within the
N-terminal paired-domain (Figure 4(B)) with the exception
falling in the approximate middle of the C-terminal region.
This single nucleotide insertion falls within exon 4 of the
PAX9 gene creating a frame-shift at amino acid 264 (Figure
4(B)) which leads to premature truncation of the protein91.
The other single nucleotide insertion was a guanine
nucleotide that extends a series of five guanines to six
causing a frame-shift between the N- and C-terminal DNA
binding domains of the PAX9 paired-domain (Figure 4(B))
abolishing the C-terminal DNA binding domain13. By far the
most severe frame-shift mutation is caused by a 288bp
insertion in the paired domain of PAX9 (Figure 4(B)) in place
of eight deleted nucleotides which leads to a frame-shift that
disrupts the C-terminal DNA binding region of the paired-
domain47. Two nucleotide substitutions within the PAX9
paired domain were also identified during this study (L21P
and K91E), both of which fall within the DNA binding regions
of the PAX9 paired domain (Figure 4(B)), N- and C-terminal
respectively, which may affect PAX9s ability to associate
with DNA and thus its transcriptional activity.
The only substitution mutation to cause premature
termination was an A340T switch that creates a stop codon at
lysine 114 producing a truncated PAX9 protein that terminates
at the end of the N-terminal DNA binding region of the PAX9
Paired-box domain92 (figure 4(B)). The remaining three
missense mutations that lead to a residue substitution in the
PAX9 protein were all identified recently. An R26W mutation
was identified in the N-terminal DNA binding region of the
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Braz J Oral Sci. 4(13):695-706
PAX9 paired domain which has been hypothesized to affect
its target DNA specificity93. A mutation two residues further
into the N-terminal DNA binding region was identified (R28P)
and shown to dramatically reduce the DNA binding ability
of PAX994. The final missense mutation (G51S) lies within
the boundary region between the N- and C-terminal DNA
binding regions of the PAX9 paired domain95.
Haploinsufficiency of PAX9 has been reported in two studies
although its cause has been by two drastically different
mechanisms. One study identified a nucleotide substitution
in the first position of the ATG start codon that has been
hypothesized to abolish its expression 48 whilst another
identified a deletion of the entire PAX9 gene45.
All but one of the PAX9 mutations appear to disrupt the
DNA binding ability of its paired domain, thus reducing its
transcriptional activity, which appears to be the likely cause
of the hypodontia phenotype associated with them. It is
interesting to note that most of the PAX9 frame-shift, deletion
and missense termination mutations cause hypodontia in
both the permanent and the primary dentition, whereas
missense substitution mutations affect the permanent
dentition only.
Locus 10q11.2
A study on He-Zhao deficiency, a distinct form of permanent
teeth agenesis which is different from other previously
described disorders, in members of a large Chinese kindred
has identified an unknown locus on chromosome 10q11.2
using multipoint linkage analysis6.
With the increase in prevalence of hypodontia observed over
the 20th century, the identification of its causative factors is
essential for providing treatment to those afflicted in the
future. Modern molecular genetic techniques have allowed
us to start to identify the genetic factors responsible for
tooth agenesis but more work is required to discover how
malfunctions in these factors disrupt tooth development.
The identification of more families afflicted with hypodontia
is key to identifying the molecular processes that underlie
this pathology and our knowledge of tooth development.
More patients/families presenting familial hypodontia need
to be referred to the geneticist for investigative research to
increase the known population of mutations affecting the
dentition. To achieve this, dental professionals need to
collaborate with human geneticists like ourselves after the
identification of probands presenting familial hypodontia and
join in our gene discovery efforts.
Acknowledgements
Work in the authors laboratory was supported by NIH grant
DE014102 (to PIP).
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