Genetics in orthodontics

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Genetics in orthodontics

  1. 1. JUHI ANSAR JR-2
  2. 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. 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. 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
  5. 5. EMBRYONIC DEVELOPMENT
  6. 6. Development of the head and face comprises one ofthe most complex events during embryonicdevelopment, coordinated by a network oftranscription factors and signalling molecules
  7. 7. Disturbance of this tightly controlled cascade canresult in a facial cleft where the facial primordiaultimately fail to meet and fuse or form theappropriate structures
  8. 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. 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. 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
  11. 11. Some of the key genes required for craniofacial morphogenesis Polarizing signals Shh, Bmp2, Bmp4 and Bmp7, Wnt5a, Smad2–4 Growth factors and receptors - Egf, Egfr, Tgfa, Tgfb1–3, Fgf1, Fgf2, Fgf8, Fgfr1, Fgfr2 Transcription factors- Hoxa2, Irf6, Lhx8, Pax9, Pitx2, Prx1, Msx1, Tbx1, Tbx22 Cell adhesion molecules Pvrl1, Connexin43, E-cadherin Extracellular matrix Mmp2, Mmp3, Mmp9,Mmp13, Timp1–3, Fibronectin
  12. 12. 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
  13. 13. 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
  14. 14. Genetic control of early odontogenesis
  15. 15. Genes involved in odontogenesis Msx gene Dlx gene Barx-1 gene BMP FGF Sonic Hedgehog
  16. 16. Msx gene Related to Drosophila Muscle segment homeobox (msh) (Bell et al1993) Msx-1 Msx-2Both exhibits horse shoe shaped fields of correspondingmesenchymal 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
  17. 17. 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 .
  18. 18. 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.
  19. 19. Heritability of Malocclusion Heritability of dentofacial phenotypes Heritability of local occlusal variables
  20. 20. 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
  21. 21. 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)
  22. 22. Cont…. Genetic influence Autosomal Polygenic dominant model Ballard , Houston ,Mills – environmental factors Graber , Hotz , Markovic – Genetic Lauweryns – Masticatory Muscle Behavior
  23. 23. 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
  24. 24. Class III malocclusion Hapsburg family line Concordance in monozygotic twins is six times higher than dizygotic twins Polygenic inheritance primary cause for mandibular prognathism
  25. 25. Heredity and class III malocclusion Mode of inheritance Autosomal Autosomal polygenic dominant recessive
  26. 26. Nasal blockage(Davidov1960)Enlarged Hormonaltonsils(Angle1907) disturbances(P ascoe 1960) Environmental factors EndocrineCongenital anatomic imbalances(Downs1928)defects(Monteleone1963) Trauma /posture / premature loss of tooth(Gold1949)
  27. 27. 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)
  28. 28. 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
  29. 29. 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 molarsHelpin & Duncan 1986 siblings of affected pts likely to be affected in 18% cases High concordance in MZ twins
  30. 30. cleft lip and palate
  31. 31.  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
  32. 32. Inheritance of cleft lip and palate Causes 1. Single mutant gene 2. Chromosomal aberration 3. Specific environmental agents 4. Multi factorial inheritance model
  33. 33.  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
  34. 34.  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
  35. 35. GENETIC ANALYSIS OF CL/P
  36. 36.  TBX22 These genes play essential roles in early development and in particular mesoderm specification Human Molecular Genetics, 2004, Vol. 13, Review Issue 1
  37. 37.  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)
  38. 38.  IRF6 In the mouse, Irf6 expression is restricted to the palatal MEE immediately prior to and during fusion
  39. 39.  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
  40. 40. External apical root resorption (EARR)
  41. 41.  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
  42. 42.  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
  43. 43.  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
  44. 44.  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
  45. 45. Recent Advances in Genetics and Molecular Biology
  46. 46. Genetic testing Identification of the functions of various genes in facial development and the mutations that affect these changesBruce Havens, Sunil Wadhwa, Ravindra Nanda, 549 – 56 vol XLI Number 9,JCO/ Sep 2007
  47. 47.  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
  48. 48. 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
  49. 49. Gene TherapyInsertion 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)
  50. 50.  To promote the mandibular condylar growth the use of a promoter fragment of the collagen IIα gene and Iα1 gene is used
  51. 51. 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)
  52. 52.  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
  53. 53. Orthodontic tooth movement
  54. 54. (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)
  55. 55. 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)
  56. 56. 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
  57. 57. 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
  58. 58. 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
  59. 59.  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”
  60. 60.  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
  61. 61. 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
  62. 62.  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
  63. 63. Thank you

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