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REVIEW ARTICLE
Year : 2011  |  Volume : 29  |  Issue : 2  |  Page : 84-89
 

The genetic basis of tooth agenesis: Basic concepts and genes involved


Department of Pediatric Dentistry, Riyadh Colleges of Dentistry and Pharmacy, Riyadh, Saudi Arabia

Date of Web Publication9-Sep-2011

Correspondence Address:
Sharat Chandra Pani
Department of Pediatric Dentistry, Riyadh Colleges of Dentistry and Pharmacy, PO Box 84891 Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-4388.84677

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   Abstract 

Tooth agenesis is the most prevalent craniofacial congenital malformation in humans. While tooth agenesis may be associated with several syndromes, non-syndromic hypodontia refers to the congenital absence of a few teeth in the absence of any other deformity. Recent advances in molecular genetics have made it possible to identify the exact genes responsible for the development of teeth and trace the mutations that cause hypodontia. This paper reviews the literature regarding the genetic basis of non-syndromic tooth agenesis, methods used to study it, and the genes that have been definitively implicated in the agenesis of human dentition.


Keywords: Genetics, hypodontia, oligodontia


How to cite this article:
Pani SC. The genetic basis of tooth agenesis: Basic concepts and genes involved. J Indian Soc Pedod Prev Dent 2011;29:84-9

How to cite this URL:
Pani SC. The genetic basis of tooth agenesis: Basic concepts and genes involved. J Indian Soc Pedod Prev Dent [serial online] 2011 [cited 2019 Aug 19];29:84-9. Available from: http://www.jisppd.com/text.asp?2011/29/2/84/84677



   Introduction Top


Tooth agenesis is the most prevalent craniofacial congenital malformation in humans. [1] Up to 25% of the population may lose at least one-third molar. [1] Agenesis of other permanent teeth ranges from 1.6% to 9.6% depending upon the population studied. [2] Traditionally, tooth agenesis is classified depending on the number of missing teeth as either hypodontia [3] (up to six missing teeth) or oligodontia [4],[5] (more than six missing teeth). While tooth agenesis may be associated with several syndromes, non-syndromic hypodontia refers to the congenital absence of a few teeth in the absence of any other deformity.

The genetic basis of hypodontia has been a topic that has been keenly studied by investigators ever since early studies showed that hypodontia tended to run in families. [6] However, identifying the exact genes responsible for the development of teeth and tracing the mutations that cause hypodontia has only been made possible with the recent advances in molecular genetics. The aim of this paper is to review the genetic basis of hypodontia, the methods used to study it, and identify the genes that have been definitively implicated in the agenesis of human dentition.

Early studies: The use of gene locus models to explain inheritance

The inheritance patterns of genes was first described by Gregor Mendel in 1865 [7] and extensively studied in the early part of the 20th century. [8] While the traditional Mendelian model of inheritance is extremely useful in studying traits caused due to a single gene, it does not give an accurate description of traits caused by multiple genes. [9] This was the reason that early investigators found that hypodontia could be either an autosomal dominant, [10] autosomal recessive, [11] or X-linked trait. [12] The limitations of the Mendelian model also meant that the genetic studies often focused on groups with a limited gene pool, such as groups with a history of consanguineous marriage [13] or isolated island populations. [11]

By the 1970s, researchers had understood that all diseases had some component of genetic risk, leading to the advent of Genome Wide Association Studies (GWAS) and the use of complex mathematical models to predict genetic risk and transmission patterns. [14] Using these models it was shown that hypodontia fit the multiple locus model rather than a single locus model proving that the initiation of tooth development was controlled by more than one gene. [6]

Experimental studies: The use of mouse models to identify the genes

In 1913, Bridges showed that genes were located on chromosomes, [15] but it was not until the early 1970s that a variety of cytogenetic methods were discovered that produced distinct bands on each chromosome [16],[17] making it possible to give each gene a specific "genetic address." [18] Even though the first draft of the entire human genome was completed only in 2001, [19] by the 1990s researchers in oral biology were studying the dental implications of the decoding of the human genome. At the forefront of research into the genetics of tooth development were the homeobox genes. [20]

Homeobox (Hox) genes are a set of genes that determine an organizational pattern in vertebrates. [21] First isolated in the fly Drosophila melanogaster, the temporal and spatial control of Hox gene expression is essential for correct patterning of many animals. [22] In mammals, 38 Hox genes have been identified which reside in four main chromosomal clusters, termed Hoxa, Hoxb, Hoxc, and Hoxd, and define 13 paralogous groups. Other vertebrate genes, such as the Msx gene family, also contain homeoboxes, but since these are dispersed to different chromosomal locations in the genome, they are referred to as "homeobox genes" rather than "Hox genes." [23] Remarkably, the relative order of mammalian Hox genes in each cluster parallels the order of the related genes in the Drosophila HOM-C, a paralogous relationship which permits the mammalian Hox genes to be grouped into the 13 discrete groups. [20] The relative similarity of the homeobox system in all mammals meant that research into human odontogenesis could be carried out on animal models. Due to its suitability for both genetic and embryologic studies, the mouse emerged as the predominant system for contemporary experimental studies on tooth development. [20] Most of the early genetic analyses of tooth development, which have formed the basis of our understanding of the genetics of hypodontia, were done by the use of mouse mutations. [24] These could be accomplished by the use of the following methods:

  • Knockout mice
  • Transgenic Mice


Knockout mice

In knockout technology, a known gene is selectively targeted for disruption in embryonic stem (ES) cells by the principle of homologous recombination. [25] Reconstitution of ES cells in chimeric mice and germline transmission results in mice which carry a loss-of-function, typically recessive, mutation in a known gene. These mice can then be bred to homozygosity and the phenotypic consequences of the mutation assessed during embryogenesis. [20] The disadvantage of knockout mutations was that the gene that is knocked out may have growth implications beyond the development of the tooth resulting in the failure of the embryo to form, a problem that was overcome by the development of conditional knockout systems. [26]

Transgenic mice

In transgenic technology, mutations of the genes responsible for tooth development are chosen and extracted. Next they are injected into fertilized mouse eggs. Embryos are implanted in the uterus of a surrogate mother. The selected genes will be expressed by some of the offspring allowing investigators to study the effects of the gene. [27]

Using mouse models, by late 1990s researchers had managed to identify the genes responsible for mammalian tooth formation. [28] In 1998, Thomas and Sharpe proposed that the patterning of murine dentition was regulated by a complex interaction of the homeobox genes and termed it the "Odontogenic Homeobox Code." [29] It was found that the genes responsible for tooth formation comprised of transcription factors, growth factors, and receptors. [30]

A transcription factor (sometimes called a sequence-specific DNA binding factor) is a protein that binds to specific DNA sequences and thereby controls the transfer (or transcription) of genetic information from DNA to mRNA. [31] The Msx [32] and Dlx [33] families of homeobox genes are examples of transcription factors that control tooth genesis. A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation, and cellular differentiation, matrix metalo proteinase (MMP) [34] and fibroblast growth factor (FGF) being an examples of such factors. [35] Receptors are protein molecules, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signaling molecules may attach. The epithelial growth factor receptor (EGFR) being an example of such a receptor. [3]

Using these mouse models Vieira in 2003 proposed that, "Specific genes were responsible for specific missing teeth" in mice [Table 1]. [36] In order to know which of these genes to look for in humans and ascertain the location of these genes, oral clefts and syndromic forms of tooth agenesis were proposed as suitable genetic models. [36]
Table 1: Genes and the type of tooth agenesis seen in mice[36]

Click here to view


The association between syndromic and non-syndromic hypodontia

Teeth develop in the context of the whole craniofacial region and recruit conserved developmental cascades common to the morphogenesis of other oro-facial structures and ectodermal derivatives. Hence, several syndromes involving hypodontia as a primary feature display various dysplasias and syndromic clefts. [1]

It has long been known that individuals with cleft lip and palate (CLAP) often have missing teeth. While some of these missing teeth may be a result of the cleft itself or the associated surgery, it has been shown that the more severe the cleft the greater the number of missing teeth. [37] The MSX 1 gene was the first gene to be studied for mutations linked to both CLAP and tooth agenesis. [38],.[39],[40] Further evidence for the possible association of MSX1 as a cause of tooth agenesis came when it was shown that a nonsense mutation in MSX1 causes the tooth agenesis and nail dysgenesis associated with the Witkop tooth and nail syndrome. [41] The locus of the MSX1 gene is located on the short arm of chromosome 4 (4p) the absence of which is manifested as the Wolf-Hirschhorn syndrome. [42] The knowledge of genetic contribution to tooth agenesis was further enhanced with the discovery of the RIEG gene. The RIEG gene causes Rieger syndrome, an autosomal dominant condition associated with missing teeth and anomalies of the eyes and the umbilicus. [43] While these mutations explained the autosomal forms of tooth agenesis, they did not explain X-linked tooth agenesis.

The association between ectodermal dysplasia and tooth agenesis is a well-established one. Hypohydrotic/anhydrotic ectodermal dysplasia is an X-linked recessive disorder that is caused by mutations on the EDA gene. [44] Virtually all persons with hypohydrotic ectodermal dysplasia express hypodontia. [45] However, mutations of the EDA gene may cause hypodontia without other syndromic features. [46] This suggests that genes involved in hypodontia associated with other syndromic features may be promising candidates for non-syndromic hypodontia. [1]

Gene mapping and familial studies: finding the genes responsible for non-syndromic tooth agenesis

In order to locate a gene, it has to first be localized to a chromosome a technique that is popularly referred to as gene mapping. The method that has been extensively used in oral biology research is the genetic linkage analysis. Genetic linkage analysis relies on the investigator's ability to detect recombinations that occur during meiosis due to independent assortment and crossings-over of homologous chromosomes. If two loci are located close to each other in the same chromosome, the chance of a recombination between them is low, and they are said to be linked. [3] The genetic distance of a disease locus and a marker can be evaluated by the amount of recombinations between them in a pedigree. The use of this technique was greatly facilitated by the by the identification of highly polymorphic microsatellite markers that could be easily analyzed by a polymerase chain-reaction (PCR). [3] Using gene mapping techniques on families known to have hypodontia and/or oligodontia investigators have been able to definitively link several gene mutations with tooth agenesis [Table 2].
Table 2: Genes and the type of tooth agenesis seen in humans


Click here to view


MSX1, initially called homeobox 7 (HOX7), is a non-clustered homeobox protein which is located on the small arm of chromosome 4 with the genetic address 4p16.3-p16.1. [47] This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. [48] The gene has been shown to have a considerable role in tooth development. [49] It was the first gene to be definitively associated with human tooth agenesis. [38] While MSX1 mutations have generally been associated with autosomal dominant inheritance of hypodontia [38] as well as oligodontia, [50] recently an autosomal recessive type of hypodontia was shown to be associated with an MSX1 mutation [51] [Table 2].

PAX9 is a member of the paired box (PAX) family of transcription factors. The PAX 9 gene is located on the long arm of chromosome 14 and has the genetic address 14q12-q13. [52] These genes play critical roles during fetal development and cancer growth. [53] The PAX9 gene was first shown to be associated with autosomal dominant, non-syndromic, familial oligodontia. [5] Since then several novel mutations in the gene have been discovered in families around the world [54],[55],[56],[57] [Table 2]. In addition, a recent study has also found that families with affected benign hereditary chorea show a deletion of the PAX9 gene resulting in oligodontia. [58] Peg-shaped lateral incisors and other forms of microdontia have long been known to be mild forms of hypodontia. [59],[60] PAX9 mutations have been associated with both hypodontia and a generalized reduction of the size of the teeth. [61]

AXIN2 or axis inhibitor protein 2 is a gene located on the long arm of chromosome 17 with a genetic address of 17q23-q24. [62] The association of the gene to tooth agenesis was first found in a Finnish family with a predisposition for colorectal cancer. [63] It has been shown that the AXIN2 mutations may also be responsible for sporadic forms of incisor agenesis. [64] The mode of transmission of hypodontia due to defects in the AXIN2 gene has not been definitively proved.

LTBP3 (latent transforming growth factor beta binding protein 3) is a gene that modulates the bioavailability of TGF-beta. [65] Located on the long arm of chromosome 11, it has the genetic address 11q12. [66] A study on a Pakistani family with a history of consanguineous marriage found that a mutation in the LTBP3 gene causes an autosomal recessive form of familial oligodontia. [67]

EDA (ectodysplasin 1) is a gene located at Xq12-q13.1 that has been linked to X-linked recessive ectodermal dysplasia. [44] A study of Chinese families with non syndromic X-linked hypodontia showed that a Thr338Met mutation of the EDA gene was responsible for the congenital absence of maxillary and mandibular central incisors, lateral incisors, and canines, with the high possibility of persistence of maxillary and mandibular first permanent molars. [46]

Clinical implications for pediatric dentistry

Missing permanent teeth in a child are a matter of concern to most parents. The ability to rebuild a tooth that is congenitally missing or lost due to disease is therefore a great boon to the pediatric dentist. Although the dream of genetically engineering teeth still remains a distant one, the study of tooth agenesis and genes producing the molecules involved in tooth agenesis have led to the development of experimental tooth regeneration techniques such as tissue scaffolding [68] and tooth engineering. [69] In addition, the association of genes such as AXIN2 and PAX9 to both tooth agenesis and colorectal cancer has shown the potential of using tooth agenesis as a genetic marker for the diagnosis of cancer. [63],[64],[70],[71]

While this paper has reviewed the genes and their mutations, most likely to cause tooth agenesis the list is far from complete. Several forms of tooth agenesis remain unexplained. Research into tooth agenesis today is increasingly relying on familial studies to locate mutations in the genes. [38] As the person who first detects the problem the pediatric dentist is in the best position to chart the pedigree of the family and determine the type of inheritance pattern. An understanding of the basic concepts of genetics will enable pediatric dentists to contribute greatly to future research into the emerging fields of tooth regeneration and molecular dentistry.

 
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