2. contents
Introduction
Terminology
Molecular genetics in oral and craniofacial
dysmorphology
Molecular genetics in dental development
Genetics of malocclusion
External apical root resorption (EARR)
Cleft lip and palate
Recent Advances in Genetics and Molecular Biology
conclusion
3. Genetics, Principles and Terminology
The science of genetics is concerned with the inheritance
of traits, whether normal or abnormal, and with the
interaction of genes and the environment
Genotype is defined as the genetic constitution of an
individual
Phenotype may refer to a specified character or to all the
observable characteristics of the individual
4. Phenotype = genotype + environment
Any trait is the ultimate product of genetic &
environmental interaction
The craniofacial complex is a result of chains of
biochemical reactions catalyzed presumably by
genes
6. Development of the head and face comprises one of
the most complex events during embryonic
development, coordinated by a network of
transcription factors and signalling molecules
7. Disturbance of this tightly controlled cascade can
result in a facial cleft where the facial primordia
ultimately fail to meet and fuse or form the
appropriate structures
8. Development of the human face begins in the fourth
week of gestation when migrating neural crest cells
combine with mesodermal cells to establish the
facial primordia
The maxillary prominences enlarge and grow
towards each other and the nasal prominences
9. During the sixth to seventh weeks, the nasal
prominences merge to form the intermaxillary
segment resulting in both the filtrum and primary
palate
This region then fuses to the maxillary prominences,
which form the lateral parts of the upper lip
10. 4th week
64 genes (homeobox D9, zinc finger 197, transcription
factor 3, and homeobox D1 genes) are upregulated
5th week
26 genes are upregulated in the frontonasal prominence
6th week
Lateral nasal prominence expresses 45 genes
The medial nasal prominence exhibits 36
upregulated genes
14. Cont…
The palatal shelves first appear at 6 weeks post
conception in human and rapidly grow in a vertical
plane flanking the developing tongue
Due to rapidly proliferating mesenchymal cells
Several genes have been implicated in palatal
mesenchymal proliferation such as msx1 and lhx8
15. Cont…
Epidermal growth factor (EGF) stimulates
glycosaminoglycan production within the palatal
Shelves
While TGFA, expressed throughout the palatal
mesenchyme and epithelia, stimulates extracellular
matrix biosynthesis
The TGFB family is particularly interesting in palate
development and isoforms 1, 2 and 3 are all
expressed during this process
18. Msx gene
Related to Drosophila Muscle segment homeobox (msh)
(Bell et al1993)
Msx-1 Msx-2
Both exhibits horse shoe shaped fields of corresponding
mesenchymal expression in anterior regions of first arch
(MacKenzie et al ,1992)
Corresponds to future epithelial thickening
Msx-1 → Dental papilla & dental follicle
Msx-2 → Dental papilla, follicle and enamel organ
19. Sonic Hedgehog (Shh)
Homologue of Drosophila Hedgehog (hh)
In vertebrates it encodes a signal peptide that
mediates a long and short range patterning in number
of well known developmental signaling centers
(Hammerscmidt et al ,1997)
Expressed strongly in the tooth forming regions and in
the enamel knot region in the later stages of tooth
development .
20. Epithelial mesenchymal interaction
Bone morphogentic protein (BMP)
BMP 2 & 4 are homologous with the Drosophila
decapentaplegic (DPP gene) have important role in
the ectodermal –mesodermal interaction.
BMP 2,4&7 are expressed in the dental epithelium in
early odontogenesis.
22. Class II Div 1 Malocclusion
Harris (1973)
Class II Div 1 Malocclusion
Reduced mandibular length
Higher correlation between individual
and his family
↓
Polygenic
Inheritance
Role of environmental factors
23. Heredity and class II div 2
malocclusion
Class II div 2 – a syndrome rather than
malocclusion
Familial occurrence documented by several
authors
Twin /
- Quinne & Yoshikava (1985) triplets
- Markovic (1992)
family
- Peck et Al (1998)
25. Heredity and class II div 2 malocclusion
Markovic (1992)
114 samples
48 pairs of twins , 6 sets of triplets
Documentation of familial occurrence
Monozygotic twins → 100% concordance
Dizygotic twins → 90% Discordant
26. Class III malocclusion
Hapsburg family line
Concordance in monozygotic twins
is six times higher than dizygotic twins
Polygenic inheritance primary cause for mandibular
prognathism
27. Heredity and class III malocclusion
Mode of inheritance
Autosomal Autosomal
polygenic
dominant recessive
29. Heritability of local occlusal factors
Harris & Smith 1982 environment >genetic
Lundstrom 1984 – genetics important role
- width & length of dental arch
- Crowding & spacing
- degree of overbite
King 1993 – 104 sibling pairs
Displacements,rotations,cross bites (high)
30. Heritability of local occlusal factors
Hypodontia
Spence - hypodontia and reduction in tooth size are
controll by same gene or related gene loci
supernumerary tooth (mesiodens)
commonly present in parents & siblings of of patients
Inheritance does not follow simple Mendelian pattern
31. Cont…
1. Abnormal tooth shape
Abnormalities in lateral incisor region –
polygenic etiology
2. cusp of Carabelli – strong genetic influence
(Townsend & Martin)
3. Ectopic maxillary canines
Zilberman , Peck
Submerged primary molars
Helpin & Duncan 1986 siblings of affected pts likely to
be affected in 18% cases High concordance in MZ
twins
33. Collectively, craniofacial abnormalities are
among the most common features of all birth
defects
The most frequent of these are the orofacial
clefts, cleft lip and/or cleft palate (CL/P)
As a general model, it is thought that both genes
and environmental factors, acting either
independently or in combination, are responsible
for facial clefting
34. Inheritance of cleft lip and palate
Causes
1. Single mutant gene
2. Chromosomal aberration
3. Specific environmental agents
4. Multi factorial inheritance model
35. Sibling risk for cleft lip & palate is app. 30%
Concordance rate in monoyzogatic twins is 24-25%
Concordance rate in dioyzogatic twins is 3-6%
This illustrate the importance of environmental factor
in etiology of disease
36. While numerous non-genetic risk factors have been
identified such as use of anti-epileptic drugs,
maternal alcohol or cigarette use much effort has
been concentrated on identifying the genetic
contribution
38. TBX22
These genes play essential roles in early
development and in particular mesoderm
specification
Human Molecular Genetics, 2004, Vol. 13, Review
Issue 1
39. PVRL1
mutations were identified in the cell adhesion
molecule PVRL1 (Nectin-1), which is expressed in
the developing face and palate
Autosomal recessive CLP with ectodermal dysplasia
(CLPED1)
40. IRF6
In the mouse, Irf6 expression is restricted to the
palatal MEE immediately prior to and during
fusion
41. MSX1
MSX1 first came to prominence as a candidate for
CL/P following the generation of a gene knockout
with cleft palate and oligodontia
Jezewski et al analysed a large cohort of CL/P
patients from a variety of different ethnic origins and
demonstrated that up to 2% of patients,
predominantly with CLP, carried MSX1 mutations
Human Molecular Genetics, 2004, Vol. 13, Review Issue 1
43. External apical root resorption (EARR) is a common
outcome following orthodontic treatment
Although EARR may occur in any or all teeth, it most
often involves the maxillary incisors
7 to 13% of individuals who have not had orthodontic
treatment show 1 to 3 mm of EARR on radiographs
Severe EARR, which is root loss of more than 5
mm, has been reported to occur in 2% to 5% of
patient treated with orthodontics
44. There is a significant variability for EARR
susceptibility among individuals
EARR, however, is a complex disease, with multiple
genetic and environmental factors contributing to its
occurrence and severity
45. There is evidence of linkage between EARR of maxillary
central incisors and a polymorphic marker D18S64
This polymorphic marker lies close to the TNFRSF11A
gene suggesting that this locus or a closely linked one
contributes to the susceptibility to EARR
The TNFRSF11A gene codes for RANK, an essential
signaling molecule in osteoclasts differentiation and
function
46. Al-Qawasmi studied 35 families indicated that the
IL-1B polymorphism accounts for 15% of the total
variation seen for EARR seen in the maxillary central
incisor in the sample studied
Al-Qawasmi RA, Hartsfield JK Jr, Everett ET, et al: Genetic predisposition to external apical
root resorption in orthodontic patients: linkage of chromosome-18 marker. J Dent Res 82:356-
360, 2003
48. Genetic testing
Identification of the functions of various genes
in facial development and the mutations that
affect these changes
Bruce Havens, Sunil Wadhwa, Ravindra Nanda, 549 – 56 vol XLI Number 9,
JCO/ Sep 2007
49. The size of the mandible (as well as that of the
maxilla) is partially regulated by the number of neural
crest cells that migrate successfully into the first
pharyngeal arch
Mutations in genes such as TREACLE may be
responsible for the milder cases of mandibular
retrognathia commonly seen in orthodontic practice
(Orthodontics in the year 2047: genetically driven treatment plans, Bruce Havens,
Sunil Wadhwa, Ravindra Nanda, 549 – 56 vol XLI Number 9, JCO/ Sep
50. Mandibular prognathism
Mandibular prognathism has recently been mapped
to regions on chromosomes 1, 6, and 19
orthodontists will be able to use software that detects
mutations in a patient’s genomic sequence and
provides a genetic growth prediction based on these
variations
51. Gene Therapy
Insertion of the genes into an individual’s cells or tissue to
treat a disease
Sutural growth disturbances
Mandibular growth
Orthodontic tooth movement
(Orthodontics in the year 2047: genetically driven treatment plans, Bruce Havens, Sunil
Wadhwa, Ravindra Nanda, 549 – 56 vol XLI Number 9, JCO/ Sep 2007)
52. To promote the mandibular condylar growth the use
of a promoter fragment of the collagen IIα gene and
Iα1 gene is used
53. Mandibular growth
Use of functionalappliances
↓
Up regulation of the genes
( PTHrP, Indian Hedgehog,
Collagen typeX and VEGF)
in the mandibular
condylar cartilage
(Orthodontics in the year 2047: genetically driven treatment plans, Bruce
Havens, Sunil Wadhwa, Ravindra Nanda, 549 – 56 vol XLI Number 9,
JCO/ Sep 2007)
54. Successful gene transfer to the TMJ with the
use of recombinant adeno-associated virus and
lentivirus has been reported in animal models
If the next 40 years bring a clearer understanding of
the genes responsible for mandibular growth and
safe methods of transducing genes into tissues,
gene therapy may become the standard of care for
the treatment of mandibular-deficient malocclusions
57. (Kanzaki and colleagues)
Gene therapy with OPG and RANKL
Local RANKL gene transfer to the periodontal tissue
accelerated orthodontic tooth movement by
approximately 150% after 21 days, without eliciting any
systemic effects
With OPG gene transfer , there is inhibition of the
tooth movement by 50% after 21 days
(Orthodontics in the year 2047: genetically driven treatment plans, Bruce Havens, Sunil Wadhwa, Ravindra Nanda, 549 – 56 vol XLI Number 9, JCO/
Sep 2007)
58. Pharmacogenomics
Study of how an individual’s genetic composition
affects the body’s response to drugs
Enhanced tooth movement
Anchorage control
(Orthodontics in the year 2047: genetically driven treatment plans, Bruce Havens,
Sunil Wadhwa, Ravindra Nanda, 549 – 56 vol XLI Number 9, JCO/ Sep 2007)
59. Enhance tooth movement
Prostaglandins
Prostaglandins bind to specific receptors on the
cell surface
Nine such receptors have recently been
Identified, along with their specific agonists and
antagonists
60. anchorage control
Various pharmacological therapies for orthodontic
anchorage control have been explored in animal
studies
arginine-glycineaspartic acid peptides
bisphosphonates
If pharmacogenomics can help identify the small
population of patients susceptible to the associated
side effect of osteonecrosis, the clinician would be
able to administer bisphosphonates to help maintain
anchorage control during orthodontic treatment
61. Stem Cells and Tissue Engineering
Stem cells have several characteristics that other
cells in the developing embryo or adult do not have
They can divide for long periods of time
They remain undifferentiated, without assuming the
phenotypic characteristics of any differentiated cell
type
And they can give rise to multiple (or all) cell types
found in an adult
62. Tremendous strides have been made in the field
of “tissue engineering” with respect to
regeneration of craniofacial structures
As Mao and colleagues have recently suggested,
“Craniofacial tissue engineering is an opportunity
that dentistry cannot afford to miss”
63. It seems likely that stem cell biology and tissue
engineering will produce viable biological
alternatives for the treatment of missing teeth
In the future, a patient diagnosed with congenitally
missing teeth in the early mixed dentition could be
referred for biological tooth replacement
Tissue from the developing third molars could be
harvested, and the cells could be expanded in vitro
and seeded onto appropriate scaffolds for
implantation into the desired sites
64. Conclusion
A permanent interaction between genetic and
environmental factors, both of a continually
altering nature, determine the dentofacial
morphology
We know now, that the underlying biology of an
individual may be just as important as the
malocclusion in the development of a treatment
plan
65. The influence of genetic factors on treatment
outcome must be studied and understood in
quantitative terms
Genome-wide association studies are necessary to
further the evidence base for the practice of
orthodontics
