Genes Involved in Orofacial Development and Dental Defects

GENES IN THE OROFACIAL
DEVELOPMENT
INDIAN DENTAL ACADEMY
Leader in continuing Dental Education
www.indiandentalacademy.com

REFERENCES
• Thesleff I. The genetic basis of tooth development and
dental defects. Am J Med Genet A 2006;140:2530-5.
• McCollum MA, Sharpe PT. Developmental genetics
and early hominid craniodental evolution. Bioessays
2001;23:481-93.
• Pekka Nieminen; Molecular genetics and tooth
morphology
• Davidson D. The function and evolution of MsX
genes: Pointers and paradoxes. Trends Genet
1995;11:405-11.

INTRODUCTION
• Genetic disorders are far more common than is
widely appreciated .
• The lifetime frequency of genetic diseases is
estimated to be 670 per 1000.
• Humans have a mere 30,000 genes and in recent
years the explosion of knowledge in this field resulted
in the evolution of genetics into genomics.

• Progress in genetics and molecular biology has
resulted in the emergence of new concepts to explain
the etiology and pathogenesis of many human disease
processes including oro-dental diseases.

GENES INVOLVED IN TOOTH
DEVELOPMENT
• More than 300 genes are involved in determination of
the position, number, and shape of different types of
teeth.
• Mutations in those genes encoding transcription
factors and signaling molecules is responsible for
numerous abnormalities of the teeth

HOMEOBOX GENES
• A homeobox (HOX) is a DNA sequence of about 180
base pairs long, found within genes that are involved
in the regulation of development (morphogenesis) of
animals, fungi, and plants.
• Genes that have a homeobox are called homeobox
genes and form a homeobox gene family.

• HOX genes are a particular cluster of homeobox
genes which function in patterning the body axis
thereby providing the identity of particular body
region and they determine where body segments
grow in a developing foetus.
• Mutations in any one of these genes can lead to the
growth of extra, typically non-functional body parts.

• Humans generally contain homeobox genes in four
clusters, called HOXA (or HOXI), HOXB, HOXC, or
HOXD, on chromosomes 2, 7, 12, and 17,
respectively.
• HOX gene network appears to be active in human
tooth germs between 18 and 24 weeks of
development.
• PAX, MSX, DLX, LHX, BARX, and RUNX-2

PAX 9
• PAX-9 belongs to a transcription factor family with
nine members characterized by a DNA-binding
domain called paired domain.
• They are important regulators of organogenesis that
can trigger cellular differentiation.

• PAX-9 gene is mapped onto 14q12-q13 and
mutations in this gene can lead to non-syndromic
tooth agenesis.

• PAX-9-/- mice show cleft of secondary palate besides
other skeletal alterations, lack thymus and
parathyroid glands, and show absence of teeth.
• It is expressed in the dental mesenchyme prior to the
first morphological manifestation of odontogenesis.

• In mouse null mutants of Pax9, tooth development
is arrested at the bud stage, the condensation of the
ectomesenchymal cells is reduced, and, in addition to
tooth agenesis and cleft palate, several derivatives of
the pharyngeal pouches fail to develop and limb
abnormalities are observed

• PAX 9 play a special role in the development of
molar teeth which shows a development distinct from
that of other permanent teeth as they lack deciduous
predecessors, instead arising directly from distal
extension of dental lamina.

MSX 1
• The MSX gene is a member of MSX homeobox gene
family, a small family of homeobox genes related to
the drosophila gene muscle segment homeobox
(msh).
• Two human MSX genes-MSX-1 and MSX-2
• MSX-1 gene is mapped onto 4p16.1.

Normal function of the MSX1 gene
• The MSX1 gene provides instructions for making a
protein that regulates the activity of other genes.
• Specifically, this gene is critical for the normal
development of the teeth and other structures in the
mouth.
• It may also be important for development of the
fingernails and toenails.

Changes in the MSX1 gene related to health
conditions
• The MSX1 gene is often deleted in people with Wolf-
Hirschhorn syndrome.
• A loss of the MSX1 gene probably disrupts the
regulation of several other genes, particularly genes
involved in the development of the mouth and teeth.

• A loss of the MSX1 gene probably also causes cleft
palate and/ or cleft lip in some people with Wolf-
Hirschhorn syndrome.
• Changes in the MSX1 gene are also associated with
other abnormalities of mouth and tooth development.

• At least six MSX1 mutations are responsible for
oligodontia, a condition in which multiple teeth fail to
develop.
• Some individuals with MSX1 mutations have a
combination of oligodontia and cleft lip and/or cleft
palate.

• Mutations in the MSX1 gene likely reduce the
amount of functional MSX1 protein within cells,
which disrupts the early development of structures in
the mouth.
• MSX -/- mice have cleft secondary palate, lack all
teeth whose development is arrested at bud stage, and
have skull, jaw, and middle ear defects.

• Another mutation in the MSX1 gene has been found
to cause Witkop syndrome (also known as tooth-and-
nail syndrome).
• This rare condition is characterized by a variable
number of missing teeth and abnormalities of the
fingernails and toenails.

• The MSX1 mutation responsible for Witkop
syndrome, leads to the production of an abnormally
short, nonfunctional version of the MSX1 protein.
• A loss of this protein disrupts the formation of the
teeth and nails during early development.

DLX GENE
• DLX (Distal less) family of homeobox genes consists
of six members (DLX 1-6) and is expressed in the
epithelium and mesenchyme of the branchial arches,
tooth bud mesenchyme, dental lamina, cranial neural
crest, dorsal neural tube, and frontonasal process.

• Mutation in these genes results in abnormalities
affecting first four branchial arch derivatives
including mandible and calvaria.
• DLX genes have been involved in the patterning of
ectomesenchyme of the first brachial arch with
respect to tooth development.

• Loss of function mutation of these genes apparently
results in failure of development of upper molars.

LHX GENE
• Lim homeodomain transcription factors are expressed
in neural crest derived ectomesenchyme of first
branchial arch.
• Improper expression of this gene leads to abnormal
development of first arch derivatives including tooth
agenesis and cleft palate.

• Recently a Lim homeobox gene, LHX -8, is found to
be expressed in murine embryonic palatal
mesenchyme, and targeted deletion of this gene
resulted in a cleft secondary palate .

BARX GENE
• Telencephalon, diencephalon, mesencephalon,
hindbrain, spinalcord, cranial and dorsal root ganglia,
craniofacial structures, and palate are the expression
sites for Barx gene.

• Improper expression of this gene results in failure of
nervous system to develop and cleft palate formation.
BARX -1 is expressed in the mesenchyme of the
mandibular and maxillary process and in the tooth
primordial, while BARX -2 is expressed in the oral
epithelium prior to the tooth development

RUNX GENE
• RUNX 2 (Runt related protein) is a transcription
factor and a key regulator of osteoblast differentiation
and bone formation.
• Also, analysis of RUNX -2 showed that it is
restricted to dental mesenchyme between the bud and
early bell stages of tooth development.

• Epithelium-mesenchymal recombinants demonstrated
that the dental epithelium regulates mesenchymal
RUNX -2 expression during the bud and cap stages.

TOOTH AGENESIS (NON-
SYNDROMIC AND SYNDROMIC)
• This is the most common craniofacial malformation.
Its prevalence in permanent dentition reaches 20%
and its expressivity ranges from only one tooth,
usually a third molar, to the whole dentition.

• Tooth agenesis could be isolated and manifested as
the only phenotypic alteration in a person (non-
syndromic) or associated with other alterations as part
of a syndrome (syndromic).

Non-syndromic tooth agenesis
• Isolated, non-syndromic tooth agenesis can be
sporadic or familial and may be inherited as an
autosomal dominant, recessive, or X-linked mode.
• Molar oligodontia, second premolar and third molar
hypodontia, incisor-premolar hypodontia exemplify
non-syndromic agenesis.

• Mutations in PAX-9 gene mapped to 14q12-q13 were
found in patients affected by molar oligodontia.
Mutations responsible for second premolar and third
molar hypodontia were found in MSX-1 gene
mapped to 4p16.1.

Syndromic tooth agenesis
• Tooth agenesis is associated with many syndromes
because many genes take part in molecular
mechanisms common to tooth and other organs
development.

ECTODERMAL DYSPLASIA
• Ectodermal dysplasias are a group of 192 distinct
disorders that involve anomalies in at least two of the
following ectodermal-derived structures: Hair, skin,
nails, and teeth.
• The most common EDs are X-linked recessive
hypohidrotic ED ( Christ-Siemens-Touraine
syndrome ) and hidrotic ED (Clouston syndrome).

Hypohydrotic ectodermal
dysplasia
• This disease is produced by point
mutations, deletions, or translocations in
the EDA gene, mapped to Xq12-q13.1.
• It is characterized by abnormal or
missing teeth, missing or poorly
developed hair and lack of sweat glands.

• Hypodontia to anodontia, and conical shape of the
anterior teeth is a hallmark of HED.
• Delay in tooth eruption, and the height of the alveolar
processes is reduced due to hypodontia.
• The mucous membranes of the mouth are less moistened
because of a decrease in salivation.
• Craniofacial characteristics include a prominent
forehead, a small nose, and prominent lips.

Normal function of EDA gene
• Ectodysplasin plays a vital role during development
by promoting interaction between ectodermal and
mesodermal layers.
• Ectodermal-mesodermal interactions are essential for
many structures derived from ectoderm, including
skin, hair, nails, teeth, and sweat glands.

• The EDA gene provides instructions for producing
many slightly different versions of ectodysplasin A.
• One version, ectodysplasin A1, interacts with a
protein called the ectodysplasin A receptor .
• On the cell surface, ectodysplasin A1 attaches to this
receptor like a key in a lock.

• When these two proteins are connected, they trigger a
series of chemical signals that affect cell activities
such as division, growth, and maturation.
• Before birth, this signaling pathway controls the
formation of ectodermal structures such as hair
follicles, sweat glands, and teeth.

Changes in the EDA gene
• More than 80 different mutations in the EDA gene
have been identified in people with hypohidrotic
ectodermal dysplasia.
• Some mutations in the EDA gene change single DNA
building blocks (base pairs), whereas other mutations
insert or delete genetic material in the gene.

• Mutated EDA gene leads to the production of a non-
functional version of the ectodysplasin, a protein
which in turn cannot trigger the normal signals
needed for the normal ectodermal-mesodermal
interaction resulting in the defective formation of the
corresponding derivatives.

Hidrotic ectodermal dysplasia
(Clouston Syndrome)
• Nail dystrophy associated with hair defects and
palmoplantar dyskeratosis.
• Scalp hair is sparse, fine and brittle.
• Eyebrows are thinned or absent.
• Patients have normal facies, normal sweating and no
specific dental defect defect seen.

• Hidrotic ED (Clouston syndrome) is an autosomal
dominant disorder caused by mutations in GJB-6,
which encodes the gap junction beta protein connexin
30, a component of intercellular gap junctions.
• Connexon mediates the direction of diffusion of ions
and metabolites between the cytoplasm of adjacent
cells.

• Mutations in this gene deregulate the trafficking of
the protein and are thus associated with defects like
palmar-plantar hyperkeratosis, generalized alopecia,
and nail defects.

Witkop tooth and nail syndrome
• The tooth-and-nail syndrome (Witkop syndrome) is a
rare autosomal dominant ectodermal dysplasia
manifested by defects of the nail plates of the fingers
and toes and hypodontia with normal hair and sweat
gland function.
• A nonsense mutation within MSXI homeobox has
been responsible for this disorder.

Reiger syndrome
• This is characterized by hypodontia, malformation of the
anterior chamber of the eyes, and umbilical anomalies.

• The maxillary deciduous and permanent incisors and
second maxillary premolars are most commonly
missing, and cleft palate may be present.
• The mandibular anterior teeth have usually conical
crowns.

• Mutations responsible for this malformation have
been found in PITX-2 (paired like homeodomain
transcription factor ), a gene mapped to 4q25-q26.
• PITX -2 is a gene involved in tooth development and
is more restricted to dental lamina.

Amelogenesis imperfecta
• The enamel proteins include amelogenins (90%) and
non-amelogenins (10%).
• Enamelin, tuftelin, and ameloblastin are the non-
amelogenin proteins.

• Genes that code amelogenin and enamelin are AMELX
and ENAM.
• Amelogenin gene is located on X and Y chromosome.
• Apart from tooth enamel, amelogenin is found in bone,
bone marrow, and brain cells.
• AMELX gene located on X-chromosome has a major
role in enamel formation, whereas AMELY gene
located on Y-chromosome is not needed for enamel
formation. www.indiandentalacademy.com

• Mutations in the AMELX and ENAM genes are
mainly demonstrated to result in Amelogenesis
imperfecta.
• Mutations in AMELX gene cause X-linked AI,
whereas mutations in ENAM gene cause autosomal
inherited forms of AI.

Dentinogenesis imperfecta
• There are numerous non-collagenous proteins present
in dentin, some of which interact with collagen to
initiate and/or regulate mineralization.
• The most abundant non-collagenous
protein is dentin sialophosphoprotein.

• Dentin sialophosphoprotein is a highly phosphorylated
protein that attaches to the type 1 collagen fibril and
helps in regulation of mineralization at specific sites
within the collagen.
• Mutations in either COL or DSPP genes can alter this
interaction resulting in abnormal mineralization and a
Dentinogenesis imperfecta phenotype.

Syndrome Associated Oro-Facial
Defects
Van der Woude syndrome
• Van der Woude syndrome is an autosomal dominant
syndrome typically consisting of a cleft lip or palate
and distinct pits of the lower lip.

• Most cases of V-W syndrome are due to deletion in
chromosome 1q32-q41 and recently locus 1p34 is
reported.
• IRF-6 gene (interferon regulatory factor) mutations
are responsible for this disorder.

The normal function of the IRF6 gene
• The IRF6 gene provides instructions for making a
protein that plays an important role in early
development.
• This protein is a transcription factor, which means
that it attaches (binds) to specific regions of DNA and
helps control the activity of particular genes.

• The IRF6 protein is active in cells that give rise to
tissues in the head and face.
• It is also involved in the development of other parts
of the body, including the skin and genitals.

Changes in the IRF6 gene
• Mutations in the IRF6 gene that cause van der Woude
syndrome prevent one copy of the gene in each cell from
making any functional protein.
• A shortage of the IRF6 protein affects the development
and maturation of tissues in the skull and face.
• These abnormalities underlie the signs and symptoms of
van der Woude syndrome, including cleft lip, cleft palate
and pits in the lower lip.www.indiandentalacademy.com

APERT SYNDROME
• Apert syndrome is a genetic disorder characterized
by the premature fusion of certain skull bones
(craniosynostosis).
• This early fusion prevents the skull from growing
normally and affects the shape of
the head and face. In addition,
a varied number of fingers and
toes are fused together (syndactyly).www.indiandentalacademy.com

Normal function of the FGFR2 gene
• The FGFR2 gene provides instructions for making a
protein called fibroblast growth factor receptor 2.
• The FGFR2 protein spans the cell membrane, so that
one end of the protein remains inside the cell and the
other end projects from the outer surface of the cell.
hands, and feet.

• This positioning allows the FGFR2 protein to interact
with specific growth factors outside the cell and to
receive signals that help the cell respond to its
environment.
• When growth factors attach to the FGFR2 protein, the
receptor triggers a cascade of chemical reactions
inside the cell that instruct the cell to undergo certain
changes, such as maturing to take on specialized
functions., www.indiandentalacademy.com

• The FGFR2 protein plays an important role in bone
growth, particularly during embryonic development.
For example, this protein signals certain immature
cells in the developing embryo to become bone cells
in the head, hands and feet.

Changes in the FGFR2 gene
• Mutations in the FGFR-2 gene (10q25-26) causes
Apert syndrome.
• These mutations change single protein building
blocks (amino acids) in the FGFR2 protein, which
alters the protein's 3-dimensional shape.
• One mutation replaces the amino acid serine with the
amino acid tryptophan.

• The other mutation replaces the amino acid proline
with the amino acid arginine .
• The altered FGFR2 protein appears to cause
prolonged signaling, which promotes the premature
fusion of bones in the skull, hands, and feet.

CROUZON SYNDROME
• Crouzon syndrome is a genetic disorder
characterized by the premature fusion of certain
skull bones (craniosynostosis).
• This early fusion prevents the skull from growing
normally and affects the shape of the head and face.

• Abnormal growth of these bones leads to wide-set,
bulging eyes and vision problems caused by shallow
eye sockets; eyes that do not point in the same
direction (strabismus); a beaked nose;
and an underdeveloped upper jaw.

• Mutations in the FGFR-2 gene, located on 10q24,
cause Crouzon syndrome.
• Most of these mutations substitute one DNA building
block (nucleotide) for another in the FGFR2 gene.
Insertions and deletions of a small number of
nucleotides are also known to cause the disorder.
• These mutations in FGFR2 appear to overstimulate
signaling by the FGFR2 protein, which promotes
premature fusion of bones in the skull.www.indiandentalacademy.com

TREACHER COLLIN
SYNDROME
• Treacher Collins syndrome is characterized by
defects of structures derived from the first and second
branchial arches.
• Hypoplastic zygomas and
mandible, coloboma, ear defects,
lateral facial clefting, and cleft
palate are seen in these patients.

• Mutations in the TCOF-1, “Treacher
Collins-Franceschetti syndrome 1”
(5q32 - q33.1) gene cause Treacher
Collins syndrome.

Normal function of the TCOF1 gene
• The TCOF1 gene provides instructions for making a
protein called treacle.
• This protein is active during early embryonic
development in structures that become bones and other
tissues in the face.
• Although the precise function of this protein is
unknown, but it is believed that it plays a critical role in
the development of facial bones and related structures.www.indiandentalacademy.com

• Treacle is involved in the production of a molecule
called ribosomal RNA (rRNA) within cells.
• Ribosomal RNA, a chemical cousin of DNA, helps
assemble protein building blocks (amino acids) into
functioning proteins.
• Treacle is active in the nucleolus, which is a small
region inside the nucleus where rRNA is produced.

Changes in the TCOF1 gene
• About 150 mutations in the TCOF gene have been
identified in people with Treacher Collins syndrome.
• Most of these mutations insert or delete a small
number of DNA building blocks (base pairs) in the
TCOF1 gene, which leads to a reduction in the
amount of treacle in cells

• A loss of treacle may reduce the production of rRNA
in cells that contribute to the development of facial
bones and tissues, signaling those cells to self-
destruct (undergo apoptosis).
• It is believed that this abnormal cell death may lead to
the specific problems with facial development found
in Treacher Collins syndrome.

DOWN SYNDROME
Down syndrome is
characterized by single
transverse palmar crease,
epicanthic folds, upslanting
palpebral fissures, shorter
limbs, hypotonic muscles,
learning disabilities, and
physical growth retardation.www.indiandentalacademy.com

• Trisomy 21, mosaicism, and tranlocation are the
various genetic events that result in Down syndrome.
• 95% of Down syndrome results from trisomy 21
• 3-4% of cases from translocation
• 1-2% by mosaicism.

• Most cases of Down syndrome result from trisomy
21, which means each cell in the body has three
copies of chromosome 21 instead of the usual two.
• When only few of the body's cells have an extra copy
of chromosome 21, these cases are called mosaic
Down syndrome..

• Although uncommon, Down syndrome can also occur
when part of chromosome 21 becomes attached
(translocated) to another chromosome before or at
conception.
• Affected people have two copies of chromosome 21,
plus extra material from chromosome 21 attached to
another chromosome. These cases are called
translocation Down syndrome

CONCLUSION
GENE DISORDER
PAX 9 SEVERE AGENESIS( ESPECIALLY MOLARS)
MSX 1 SEVERE AGENESIS( SECOND PREMOLARS AND
THIRD MOLARS), WITKOP SYNDROME
DLX ABSENCE OF UPPER MOLARS
LHX TOOTH AGENESIS AND CLEFT PALATE
BARX FAILURE OF NERVOUS SYSTEM TO DEVELOP AND
CLEFT PALATE
RUNX SUPERNUMERARY TOOTH
EDA ECTODERMAL DYSPLASIA

GENE DISORDER
PITX 2 REIGER SYNDROME
AMELX and ENAM AMELOGENESIS IMPERFECTA
DSPP DENTINOGENESIS IMPERFECTA
IRF 6 VANDERWOUD SYNDROME
FGFR2 APERT SYNDROME and CROUZON SYNDROME
TCOF1 TREACHER COLLIN SYNDROME

Genes Involved in Orofacial Development and Dental Defects

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