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SEMINAR
ROLE OF GENES IN THE
ORO-DENTAL DISEASES
INDIAN DENTAL ACADEMY
Leader in continuing Dental Education
www.indianden...
LEARNING OBJECTIVES
At the end of the seminar learner should be able to –
• Describe HOMEOBOX gene.
• Enumerate various HO...
CONTENT
• Introduction
• HOMEOBOX genes
• Genes involvement in tooth development
• Syndromes associated with oro-dental an...
INTRODUCTION
• Genetic disorders are far more common than is
widely appreciated .
• The lifetime frequency of genetic dise...
• Humans have a mere 30,000 genes and in recent
years the explosion of knowledge in this field resulted
in the evolution o...
GENES INVOLVED IN TOOTH
DEVELOPMENT
• More than 300 genes are involved in determination of
the position, number, and shape...
HOMEOBOX GENES
• A homeobox (HOX) is a DNA sequence of about 180
base pairs long, found within genes that are involved
in ...
• HOX genes are a particular cluster of homeobox
genes which function in patterning the body axis
thereby providing the id...
• Humans generally contain homeobox genes in four
clusters, called HOXA (or HOXI), HOXB, HOXC, or
HOXD, on chromosomes 2, ...
PAX 9
• PAX-9 belongs to a transcription factor family with
nine members characterized by a DNA-binding
domain called pair...
• PAX-9 gene is mapped onto 14q12-q13 and
mutations in this gene can lead to non-syndromic
tooth agenesis.
www.indiandenta...
• PAX-9-/- mice show cleft of secondary palate besides
other skeletal alterations, lack thymus and
parathyroid glands, and...
• In mouse null mutants of Pax9, tooth development
is arrested at the bud stage, the condensation of the
ectomesenchymal c...
• PAX 9 play a special role in the development of
molar teeth which shows a development distinct from
that of other perman...
MSX 1
• The MSX gene is a member of MSX homeobox gene
family, a small family of homeobox genes related to
the drosophila g...
Normal function of the MSX1 gene
• The MSX1 gene provides instructions for making a
protein that regulates the activity of...
Changes in the MSX1 gene related to health
conditions
• The MSX1 gene is often deleted in people with Wolf-
Hirschhorn syn...
• A loss of the MSX1 gene probably also causes cleft
palate and/ or cleft lip in some people with Wolf-
Hirschhorn syndrom...
• At least six MSX1 mutations are responsible for
oligodontia, a condition in which multiple teeth fail to
develop.
• Some...
• Mutations in the MSX1 gene likely reduce the
amount of functional MSX1 protein within cells,
which disrupts the early de...
• Another mutation in the MSX1 gene has been found
to cause Witkop syndrome (also known as tooth-and-
nail syndrome).
• Th...
• The MSX1 mutation responsible for Witkop
syndrome, leads to the production of an abnormally
short, nonfunctional version...
DLX GENE
• DLX (Distal less) family of homeobox genes consists
of six members (DLX 1-6) and is expressed in the
epithelium...
• Mutation in these genes results in abnormalities
affecting first four branchial arch derivatives
including mandible and ...
• Loss of function mutation of these genes apparently
results in failure of development of upper molars.
www.indiandentala...
LHX GENE
• Lim homeodomain transcription factors are expressed
in neural crest derived ectomesenchyme of first
branchial a...
• Recently a Lim homeobox gene, LHX -8, is found to
be expressed in murine embryonic palatal
mesenchyme, and targeted dele...
BARX GENE
• Telencephalon, diencephalon, mesencephalon,
hindbrain, spinalcord, cranial and dorsal root ganglia,
craniofaci...
• Improper expression of this gene results in failure of
nervous system to develop and cleft palate formation.
BARX -1 is ...
RUNX GENE
• RUNX 2 (Runt related protein) is a transcription
factor and a key regulator of osteoblast differentiation
and ...
• Epithelium-mesenchymal recombinants demonstrated
that the dental epithelium regulates mesenchymal
RUNX -2 expression dur...
TOOTH AGENESIS (NON-
SYNDROMIC AND SYNDROMIC)
• This is the most common craniofacial malformation.
Its prevalence in perma...
• Tooth agenesis could be isolated and manifested as
the only phenotypic alteration in a person (non-
syndromic) or associ...
Non-syndromic tooth agenesis
• Isolated, non-syndromic tooth agenesis can be
sporadic or familial and may be inherited as ...
• Mutations in PAX-9 gene mapped to 14q12-q13 were
found in patients affected by molar oligodontia.
• Mutations responsibl...
Syndromic tooth agenesis
• Tooth agenesis is associated with many syndromes
because many genes take part in molecular
mech...
ECTODERMAL DYSPLASIA
• Ectodermal dysplasias are a group of 192 distinct
disorders that involve anomalies in at least two ...
Hypohydrotic ectodermal
dysplasia
• This disease is produced by point
mutations, deletions, or translocations in
the EDA g...
• Hypodontia to anodontia, and conical shape of the
anterior teeth is a hallmark of HED.
• Delay in tooth eruption, and th...
Normal function of EDA gene
• Ectodysplasin plays a vital role during development
by promoting interaction between ectoder...
• The EDA gene provides instructions for producing
many slightly different versions of ectodysplasin A.
• One version, ect...
• When these two proteins are connected, they trigger a
series of chemical signals that affect cell activities
such as div...
Changes in the EDA gene
• More than 80 different mutations in the EDA gene
have been identified in people with hypohidroti...
• Mutated EDA gene leads to the production of a non-
functional version of the ectodysplasin, a protein
which in turn cann...
Hidrotic ectodermal dysplasia
(Clouston Syndrome)
• Nail dystrophy associated with hair defects and
palmoplantar dyskerato...
• Hidrotic ED (Clouston syndrome) is an autosomal
dominant disorder caused by mutations in GJB-6,
which encodes the gap ju...
• Mutations in this gene deregulate the trafficking of
the protein and are thus associated with defects like
palmar-planta...
Witkop tooth and nail syndrome
• The tooth-and-nail syndrome (Witkop syndrome) is a
rare autosomal dominant ectodermal dys...
Reiger syndrome
• This is characterized by hypodontia, malformation of the
anterior chamber of the eyes, and umbilical ano...
• The maxillary deciduous and permanent incisors and
second maxillary premolars are most commonly
missing, and cleft palat...
• Mutations responsible for this malformation have
been found in PITX-2 (paired like homeodomain
transcription factor ), a...
Amelogenesis imperfecta
• The enamel proteins include amelogenins (90%) and
non-amelogenins (10%).
• Enamelin, tuftelin, a...
• Genes that code amelogenin and enamelin are AMELX
and ENAM.
• Amelogenin gene is located on X and Y chromosome.
• Apart ...
• Mutations in the AMELX and ENAM genes are
mainly demonstrated to result in Amelogenesis
imperfecta.
• Mutations in AMELX...
Dentinogenesis imperfecta
• There are numerous non-collagenous proteins present
in dentin, some of which interact with col...
• Dentin sialophosphoprotein is a highly phosphorylated
protein that attaches to the type 1 collagen fibril and
helps in r...
Syndrome Associated Oro-Facial
Defects
Van der Woude syndrome
• Van der Woude syndrome is an autosomal dominant
syndrome t...
• Most cases of V-W syndrome are due to deletion in
chromosome 1q32-q41 and recently locus 1p34 is
reported.
• IRF-6 gene ...
The normal function of the IRF6 gene
• The IRF6 gene provides instructions for making a
protein that plays an important ro...
• The IRF6 protein is active in cells that give rise to
tissues in the head and face.
• It is also involved in the develop...
Changes in the IRF6 gene
• Mutations in the IRF6 gene that cause van der Woude
syndrome prevent one copy of the gene in ea...
APERT SYNDROME
• Apert syndrome is a genetic disorder characterized
by the premature fusion of certain skull bones
(cranio...
Normal function of the FGFR2 gene
• The FGFR2 gene provides instructions for making a
protein called fibroblast growth fac...
• This positioning allows the FGFR2 protein to interact
with specific growth factors outside the cell and to
receive signa...
• The FGFR2 protein plays an important role in bone
growth, particularly during embryonic development.
For example, this p...
Changes in the FGFR2 gene
• Mutations in the FGFR-2 gene (10q25-26) causes
Apert syndrome.
• These mutations change single...
• The other mutation replaces the amino acid proline
with the amino acid arginine .
• The altered FGFR2 protein appears to...
CROUZON SYNDROME
• Crouzon syndrome is a genetic disorder
characterized by the premature fusion of certain
skull bones (cr...
• Abnormal growth of these bones leads to wide-set,
bulging eyes and vision problems caused by shallow
eye sockets; eyes t...
• Mutations in the FGFR-2 gene, located on 10q24,
cause Crouzon syndrome.
• Most of these mutations substitute one DNA bui...
TREACHER COLLIN
SYNDROME
• Treacher Collins syndrome is characterized by
defects of structures derived from the first and ...
• 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 prote...
• Treacle is involved in the production of a molecule
called ribosomal RNA (rRNA) within cells.
• Ribosomal RNA, a chemica...
Changes in the TCOF1 gene
• About 150 mutations in the TCOF gene have been
identified in people with Treacher Collins synd...
• A loss of treacle may reduce the production of rRNA
in cells that contribute to the development of facial
bones and tiss...
DOWN SYNDROME
Down syndrome is
characterized by single
transverse palmar crease,
epicanthic folds, upslanting
palpebral fi...
• Trisomy 21, mosaicism, and tranlocation are the
various genetic events that result in Down syndrome.
• 95% of Down syndr...
• Most cases of Down syndrome result from trisomy
21, which means each cell in the body has three
copies of chromosome 21 ...
• Although uncommon, Down syndrome can also occur
when part of chromosome 21 becomes attached
(translocated) to another ch...
CONCLUSION
GENE DISORDER
PAX 9 SEVERE AGENESIS( ESPECIALLY MOLARS)
MSX 1 SEVERE AGENESIS( SECOND PREMOLARS AND
THIRD MOLAR...
GENE DISORDER
PITX 2 REIGER SYNDROME
AMELX and ENAM AMELOGENESIS IMPERFECTA
DSPP DENTINOGENESIS IMPERFECTA
IRF 6 VANDERWOU...
REFERENCES
• Thesleff I. The genetic basis of tooth development and
dental defects. Am J Med Genet A 2006;140:2530-5.
• Mc...
www.indiandentalacademy.com
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Genes in the orodental disease/certified fixed orthodontic courses by Indian dental academy

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The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit 
www.indiandentalacademy.com

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Genes in the orodental disease/certified fixed orthodontic courses by Indian dental academy

  1. 1. SEMINAR ROLE OF GENES IN THE ORO-DENTAL DISEASES INDIAN DENTAL ACADEMY Leader in continuing Dental Education www.indiandentalacademy.com
  2. 2. LEARNING OBJECTIVES At the end of the seminar learner should be able to – • Describe HOMEOBOX gene. • Enumerate various HOMEOBOX genes. • Describe the genes involved in tooth development. • Enumerate various oro-dental syndromes associated with genetic alterations. www.indiandentalacademy.com
  3. 3. CONTENT • Introduction • HOMEOBOX genes • Genes involvement in tooth development • Syndromes associated with oro-dental and orofacial defets. • Conclusion www.indiandentalacademy.com
  4. 4. INTRODUCTION • Genetic disorders are far more common than is widely appreciated . • The lifetime frequency of genetic diseases is estimated to be 670 per 1000. www.indiandentalacademy.com
  5. 5. • 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. www.indiandentalacademy.com
  6. 6. 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 www.indiandentalacademy.com
  7. 7. 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. www.indiandentalacademy.com
  8. 8. • 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. www.indiandentalacademy.com
  9. 9. • 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 www.indiandentalacademy.com
  10. 10. 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. www.indiandentalacademy.com
  11. 11. • PAX-9 gene is mapped onto 14q12-q13 and mutations in this gene can lead to non-syndromic tooth agenesis. www.indiandentalacademy.com
  12. 12. • 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. www.indiandentalacademy.com
  13. 13. • 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. www.indiandentalacademy.com
  14. 14. • 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. www.indiandentalacademy.com
  15. 15. 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. www.indiandentalacademy.com
  16. 16. 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. www.indiandentalacademy.com
  17. 17. 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. www.indiandentalacademy.com
  18. 18. • 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. www.indiandentalacademy.com
  19. 19. • 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. www.indiandentalacademy.com
  20. 20. • 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. www.indiandentalacademy.com
  21. 21. • 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. www.indiandentalacademy.com
  22. 22. • 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. www.indiandentalacademy.com
  23. 23. 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. www.indiandentalacademy.com
  24. 24. • 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. www.indiandentalacademy.com
  25. 25. • Loss of function mutation of these genes apparently results in failure of development of upper molars. www.indiandentalacademy.com
  26. 26. 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. www.indiandentalacademy.com
  27. 27. • 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 . www.indiandentalacademy.com
  28. 28. BARX GENE • Telencephalon, diencephalon, mesencephalon, hindbrain, spinalcord, cranial and dorsal root ganglia, craniofacial structures, and palate are the expression sites for Barx gene. www.indiandentalacademy.com
  29. 29. • 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 www.indiandentalacademy.com
  30. 30. 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. www.indiandentalacademy.com
  31. 31. • Epithelium-mesenchymal recombinants demonstrated that the dental epithelium regulates mesenchymal RUNX -2 expression during the bud and cap stages. www.indiandentalacademy.com
  32. 32. 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. www.indiandentalacademy.com
  33. 33. • 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). www.indiandentalacademy.com
  34. 34. 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. www.indiandentalacademy.com
  35. 35. • 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. www.indiandentalacademy.com
  36. 36. 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. www.indiandentalacademy.com
  37. 37. 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). www.indiandentalacademy.com
  38. 38. 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. www.indiandentalacademy.com
  39. 39. • 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. www.indiandentalacademy.com
  40. 40. 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. www.indiandentalacademy.com
  41. 41. • 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. www.indiandentalacademy.com
  42. 42. • 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. www.indiandentalacademy.com
  43. 43. 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. www.indiandentalacademy.com
  44. 44. • 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. www.indiandentalacademy.com
  45. 45. 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. www.indiandentalacademy.com
  46. 46. • 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. www.indiandentalacademy.com
  47. 47. • 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. www.indiandentalacademy.com
  48. 48. 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. www.indiandentalacademy.com
  49. 49. Reiger syndrome • This is characterized by hypodontia, malformation of the anterior chamber of the eyes, and umbilical anomalies. www.indiandentalacademy.com
  50. 50. • 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. www.indiandentalacademy.com
  51. 51. • 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. www.indiandentalacademy.com
  52. 52. Amelogenesis imperfecta • The enamel proteins include amelogenins (90%) and non-amelogenins (10%). • Enamelin, tuftelin, and ameloblastin are the non- amelogenin proteins. www.indiandentalacademy.com
  53. 53. • 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
  54. 54. • 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. www.indiandentalacademy.com
  55. 55. 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. www.indiandentalacademy.com
  56. 56. • 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. www.indiandentalacademy.com
  57. 57. 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. www.indiandentalacademy.com
  58. 58. • 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. www.indiandentalacademy.com
  59. 59. 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. www.indiandentalacademy.com
  60. 60. • 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. www.indiandentalacademy.com
  61. 61. 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
  62. 62. 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
  63. 63. 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. www.indiandentalacademy.com
  64. 64. • 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
  65. 65. • 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. www.indiandentalacademy.com
  66. 66. 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. www.indiandentalacademy.com
  67. 67. • 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. www.indiandentalacademy.com
  68. 68. 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. www.indiandentalacademy.com
  69. 69. • 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. www.indiandentalacademy.com
  70. 70. • 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
  71. 71. 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. www.indiandentalacademy.com
  72. 72. • Mutations in the TCOF-1, “Treacher Collins-Franceschetti syndrome 1” (5q32 - q33.1) gene cause Treacher Collins syndrome. www.indiandentalacademy.com
  73. 73. 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
  74. 74. • 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. www.indiandentalacademy.com
  75. 75. 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 www.indiandentalacademy.com
  76. 76. • 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. www.indiandentalacademy.com
  77. 77. 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
  78. 78. • 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. www.indiandentalacademy.com
  79. 79. • 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.. www.indiandentalacademy.com
  80. 80. • 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 www.indiandentalacademy.com
  81. 81. 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 www.indiandentalacademy.com
  82. 82. 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 www.indiandentalacademy.com
  83. 83. 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. • Burkit’s Oral Medicine11th edition. Page549 • 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.www.indiandentalacademy.com
  84. 84. www.indiandentalacademy.com

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