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Genetics and Genetic Derangements in Dentistry

Introduction

 

Genetics is the study of genes, heredity, and genetic variation in living organisms. Genetic processes work in combination with an organism's environment and experiences to influence the development and behavior of the organism. Recent research has revealed that a patient’s genetic background can have a significant impact on their dental health and that dentists can leverage genetics as a powerful tool in the treatment of dental disorders.
 
 
At its most fundamental level, a gene is a portion (or sequence) of DNA that codes for a known cellular function or process typically involving protein synthesis. Genes contain the nucleotide bases cytosine, guanine, adenine, and thymine, arranged in specific order. The cell transcribes a sequence of nucleotide bases within a gene to produce a chain of amino acids that in turn creates a protein. The order of amino acids in a protein corresponds to the order of nucleotides in the gene. (See Figure 1.)
 
 
Inheritance in organisms occurs by passing discrete genes from parent to offspring. When a sperm and egg fuse, genes intermingle before pairing off, creating a unique individual. Genes can be dominant, recessive, have incomplete dominance, or be codominant, and different genes activate at different times based on the needs of the cell and environmental influences.

Inheritance Patterns
 
 
Genes can be dominant, recessive, have incomplete dominance, or be codominant. Dominant genes have an effect on an organism’s phenotype, masking the contribution of a second allele at the same locus. The other allele is termed recessive. When a dominant allele is on an autosome, it is termed autosomal dominant. In contrast, when in the presence of a dominant allele (heterozygous), recessive alleles are repressed. However, in the presence of another recessive allele (homozygous), that phenotype expresses itself. (See Figure 2.)
 
 
Incomplete dominance occurs when a dominant allele partially expresses itself. The opposing gene partially mitigates Its impact. This results in a third phenotype in which the expressed physical trait is a combination of the dominant and recessive phenotypes. Codominance occurs when there is complete expression of genes from both alleles. This results in a third phenotype being produced. The classic example is ABO blood type expression in which alleles for type A and type B are expressed to form combinations such as type A, B, AB, or O. (See Figure 3.)
 
 
Genetic expression may be sex-linked. There are many more genes on X chromosomes than on Y chromosomes, and a gene present on X chromosome is referred to as X linked. An X linked recessive gene is unopposed in male offspring and is expressed while an X linked recessive gene in females will only be expressed if she has another recessive gene from the other parent. An example of this is hemophilia, an X linked recessive trait. Hemophilia is much more common in males since a female must inherit the hemophilia gene from both parents to have hemophilia. (See Figure 4.)
 

Chromosomal Abnormalities
 
 
Abnormalities in chromosomes typically lead to heritable genetic abnormalities. Genetics clinics typically see diseases such as chromosomal rearrangements, Down syndrome, DiGeorge syndrome, fragile X syndrome, Marfan’s syndrome, neurofibromatosis, and Turner syndrome. Inborn errors of metabolism include enzymatic deficiencies that interfere with biochemical pathways involved in metabolism of carbohydrates, amino acids, and lipids. The field of molecular genetics involves the discovery of DNA mutations that underlie many single gene disorders such as cystic fibrosis, Duchenne muscular dystrophy, hereditary breast cancer (BRCA1/2), and Huntington disease.
 
 
Some genetic abnormalities develop over time as acquired molecular changes and mutations. During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, or mutations, can have an impact on the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Replication errors are uncommon and increase by exposure to mutagens (chemicals, UV radiation). Since the majority of these mutations are not advantageous for the cell, natural selection tends to weed out most mutations. Some mutations interfere with a cell’s growth and replication control, allowing the cell to grow without limits often to the detriment of the organism. In this sense, cancer is a genetic disease caused by an accumulation of mutations within cells.
 

Implications in Dentistry
 
 
According to a seminal 2008 panel report on the importance of genetics education in dental school, “knowing the molecular biology of bone, periodontal structures, salivary gland, and tooth development will lead to innovative treatment approaches that will differ greatly from dentistry’s current surgically based techniques”.1 Studies have found many genetic influences on oral health including malocclusion, abnormal numbers of teeth, abnormally shaped teeth, abnormal dentin, enamel, or cementum, abnormal salivary gland function, and impaired defense against infection. The susceptibility to caries genetically determined.2-4 Likewise, the susceptibility to aggressive periodontitis is inherited.5 Certain dental anomalies are related to genetic inheritance including malocclusion, Lelis syndrome, dentinogenesis imperfecta (see Figure 5), and cleft lip and palate. Recent studies have focused on inheritance patterns of temporomandibular joint disorders (TMJD).6 As mentioned above, cancer is the result of an accumulation of genetic errors resulting in the loss of control from normal cellular feedback loops, uncontrolled growth, and damage to underlying structures.7,8 (See Figure 5.)
 
 
Genetic traits determine the eruption, shape, and location of teeth. In this sense, malocclusion, supernumerary teeth, anodontia, and hypodontia are genetic disorders. Since genetics play a role in dentin thickness, immune response, and overall susceptibility to caries and periodontitis, a patient’s genetic profile may ultimately determine the frequency of follow-up and timing of interventions.9,10 A clinical analogy would be inquiring about a patient’s family history of early childhood caries, rampant caries, and acute periodontitis, then determining appropriate follow-up and intervention strategies based on those risk factors. In many cases, fluoride treatment mitigates the effects of genetics on caries risk and periodontitis to some extent.11

 
Stem Cells and Gene Therapy
 
 
Dental pulp is a rich source of pluripotent stem cells. Researchers use dental pulp stem cells in tissue engineering to rebuild bone and cartilage for repair of bony defects in facial reconstructive surgery and alveolar bone augmentation.12-14 Scientists have studied the use of gene therapy in the treatment of aggressive periodontitis.15 Gene therapy involves injecting active DNA nucleotide fragments into a diseased cell. (See Figure 6) After injection, some nucleotide fragments express a specific protein, some fragments suppress the expression on an unwanted protein, and some fragments insert themselves into genetic sequence to correct mutation. (See Figure 6.)

 
Conclusion
 
 
The basic science field of genetics has deep implications for dentists. The genetic variability in dental structure, enamel thickness, TMJ function, and immune system responsiveness translate to an individual patient’s susceptibility to disease and need for intervention. By definition, cancer is a disease that results from genetic mutations. Researchers are investigating use of genetics as a therapeutic modality including stem cell-based tissue engineering and gene therapy.

 
References
1. Johnson L, Genco RJ, Damsky C, et al. Genetics and its implications for clinical dental practice and education: report of panel 3 of the Macy study. J Dent Educ. Feb 2008;72(2 Suppl):86-94.
 
2. Abbasoğlu Z, Tanboğa İ, Calvano Küchler E, et al. Early Childhood Caries Is Associated with Genetic Variants in Enamel Formation and Immune Response Genes. Caries research. 2015;49(1):70-77.
 
3. Halusic AM, Sepich VR, Shirley DC, et al. Calcium and magnesium levels in primary tooth enamel and genetic variation in enamel formation genes. Pediatric dentistry. Sep-Oct 2014;36(5):384-388.
 
4. Stanley BO, Feingold E, Cooper M, et al. Genetic Association of MPPED2 and ACTN2 with Dental Caries. J Dent Res. May 8 2014;93(7):626-632.
 
5. Vieira AR, Albandar JM. Role of genetic factors in the pathogenesis of aggressive periodontitis. Periodontol 2000. Jun 2014;65(1):92-106.
 
6. Westlund KN, McIlwrath SL, Oz HS. Combined genetic polymorphisms and environmental factors in the etiology of a chronic TMJD murine model. Molecular Pain. 2014;10(1):1-2.
 
7. Banno K, Kisu I, Yanokura M, et al. Epimutation and cancer: a new carcinogenic mechanism of Lynch syndrome (Review). Int J Oncol. Sep 2012;41(3):793-797.
 
8. Bernstein C, Prasad AR, Nfonsam V, Bernstein H, Chen C. DNA damage, DNA repair and cancer. New Research Directions in DNA Repair; Chen, C., Ed.; InTech: Rijeka, Croatia. 2013.
9. Opal S, Garg S, Jain J, Walia I. Genetic factors affecting dental caries risk. Aust Dent J. Mar 2015;60(1):2-11.
 
10. Shaffer JR, Wang X, McNeil DW, Weyant RJ, Crout R, Marazita ML. Genetic Susceptibility to Dental Caries Differs between the Sexes: A Family-Based Study. Caries Research. 2015;49(2):133-140.
 
11. Shaffer JR, Carlson JC, Stanley BO, et al. Effects of enamel matrix genes on dental caries are moderated by fluoride exposures. Hum Genet. Feb 2015;134(2):159-167.
 
12. Padial-Molina M, Rios HF. Stem Cells, Scaffolds and Gene Therapy for Periodontal Engineering. Current Oral Health Reports. 2014;1(1):16-25.
 
13. Rosa V, Della Bona A, Cavalcanti BN, Nor JE. Tissue engineering: from research to dental clinics. Dental materials : official publication of the Academy of Dental Materials. Apr 2012;28(4):341-348.
 
14. Lin Z, Rios HF, Cochran DL. Emerging regenerative approaches for periodontal reconstruction: a systematic review from the AAP Regeneration Workshop. J Periodontol. Feb 2015;86(2 Suppl):S134-152.
 
15. Sugano M, Negishi Y, Endo‐Takahashi Y, et al. Gene delivery to periodontal tissue using Bubble liposomes and ultrasound. Journal of periodontal research. 2014;49(3):398-404.

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