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Oral Clefts and Syndromic Forms of Tooth Agenesis as Models for Genetics of Isolated Tooth AgenesisDepartment of Pediatrics ML 2182, The University of Iowa, Iowa City, IA 52242; alexandre-vieira{at}uiowa.edu
Genetic defects responsible for tooth agenesis are only now beginning to be uncovered. MSX1 and PAX9 have been associated with tooth agenesis in mice and humans, but interestingly for humans, these genes are associated with specific missing teeth. Mouse models also show that specific genes contribute to the development of specific types of teeth. A precise description of the phenotype specifying which teeth are missing has become fundamental. Mendelian segregation can be identified in families with tooth agenesis, but heterogenous or multiple genes may be responsible for the development of specific types of teeth agenesis in humans. Data from animal models are still very complex, and the human embryology is still poorly understood. Oral clefts and syndromic forms of tooth agenesis may be the best models for isolated tooth agenesis. In the future, a precise description of the missing teeth in syndromes involving tooth agenesis may be useful.
Key Words: missing teeth • hypodontia • cleft lip and palate • Van der Woude syndrome • orofacial clefts
Tooth agenesis occurs more frequently among a few specific teeth (lateral incisors, second premolars, and third molars). Familial tooth agenesis is transmitted as an autosomal-dominant, autosomal-recessive, or X-linked condition, but can also show no clear segregation pattern. Affected members within a family often exhibit significant variability with regard to the location, symmetry, and number of teeth involved. Residual teeth can vary in size, shape, or rate of development. The permanent dentition is more affected than the primary dentition. Genetic defects responsible for tooth agenesis are only now beginning to be uncovered. In the last few years, mutations in MSX1 and PAX9 have been associated with tooth agenesis in humans, but those mutations probably cause only a very few cases. To date, the number of genes identified as having a role in tooth development exceeds 100, and all those genes are potential candidates for tooth agenesis in humans (http://bite-it.helsinki.fi/).
MSX1 is a transcription factor expressed in several embryonic structures (reviewed by Davidson, 1995), including the dental mesenchyme (MacKenzie et al., 1991a,b; Jowett et al., 1993). Mice lacking Msx1 function manifest cleft palate, deficient mandibular and maxillary alveolar bones, and failure of tooth development (Satokata and Maas, 1994). A missense mutation (arg196pro) in the homeodomain of MSX1 is responsible for an autosomal-dominant agenesis of second premolars and third molars in a White family (Vastardis et al., 1996). Another mutation in the homeodomain of MSX1 was associated with Witkop tooth-and-nail syndrome (Jumlongras et al., 2001). A heterozygous nonsense mutation (ser202stop) co-segregated with the phenotype. Remarkably, affected individuals showed several types of teeth missing, but preferentially premolars and first and third molars. A third mutation in MSX1 was found in a Dutch family which was associated with orofacial clefting and tooth agenesis segregating in an autosomal-dominant fashion (van den Boogard et al., 2000). A nonsense mutation in exon 1 and outside the homeodomain region (ser105stop) was detected in all affected individuals. The 12 affected-family members studied showed various combinations of cleft lip, cleft palate, and tooth agenesis. Predominantly, they had missing second premolars and third molars. This phenotype is similar to that of the Msx1-mutant mouse. Also, it suggests that tooth agenesis, cleft lip and palate, and cleft palate share only mechanisms that involve MSX1. These three MSX1 mutations show that this gene might be closely related to agenesis of premolars and third molars. Most recently, a fourth mutation in MSX1 (met61lys) was found (Lidral and Reising, 2002). This mutation also segregated in an autosomal-dominant manner, and the five affected-family members more often were missing the second premolars and the third molars, such as the previously reported MSX1 mutations. Interestingly, the existing teeth of the two affected individuals that showed the MSX1 met61lys mutation could be studied. The maxillary second molars did not present a distal lingual cusp, and the mandibular first molars had only 4 cusps, missing the distal buccal cusp. Previous studies that reported negative results for MSX1 (Nieminen et al., 1995; Scarel et al., 2000; Lidral and Reising, 2002) included individuals with predominantly missing second premolars and third molars, and the negative results further support our belief that MSX1 mutations are not a common cause of tooth agenesis. PAX9 also has been described as a contributor to one specific type of tooth agenesis. Pax gene products are thought to function primarily by binding the enhancer DNA sequences and by modifying transcriptional activity of downstream genes (reviewed by Chi and Epstein, 2002). Pax9 homozygous null mice lack derivatives of the third and fourth pharyngeal arches (thymus, parathyroid gland, ultimobranchial bodies), have craniofacial and limb anomalies, and fail to form teeth beyond the bud stage (Peters et al., 1998). Three mutations were described in the second exon of PAX9 in families who predominantly presented missing molars along with other types of teeth (Stockton et al., 2000; Nieminen et al., 2001; Frazier-Bowers et al., 2002). Also, PAX9, as with MSX1, might explain only a few cases of tooth agenesis. Interestingly, molar agenesis appears to be associated with a defective PAX9 gene.
Animal models also suggest that specific genetic factors might be involved with specific types of teeth during development. Mice with targeted null mutations of both Dlx-1 and Dlx-2 homeobox genes do not develop maxillary molar teeth, but the incisors and mandibular molars are normal (Thomas et al., 1997). In contrast, activin βA [a member of the transforming growth factor (TGF) β superfamily] mutant mice have incisors and mandibular molar teeth failing to develop beyond a rudimentary bud, whereas maxillary molar teeth develop normally (Ferguson et al., 1998). The mice lack whiskers and have defects in their secondary palates, including cleft palate (Matzuk et al., 1995b). Also, analysis of tooth development in activin receptor IIA and IIB mutants and Smad2 mutants (both playing a role in the activin βA pathway) shows that a tooth phenotype similar to activin βA mutants can be observed (Ferguson et al., 2001). The combination of all this information suggests a parallel independent genetic pathway for maxillary molars, one that may possibly involve Dlx genes, compared with the process of mandibular molar and incisor development in mice. A common factor between these two pathways, apart from the fact that they are involved in odontogenesis, is that they share an upstream activator: Fgf8. Fgf8 has been shown to be upstream of Dlx and activin βA genes (Ferguson et al., 1998, 2000; Thomas et al., 2000) and may have a different kind of influence over the cranial neural crest cells that populate the mandibular and maxillary arches (Ferguson et al., 2000). Newborn Fgf8 mutants lack most first branchial arch-derived structures except those that develop from the distal-most region of the first branchial arch, including lower incisors. However, lacking Fgf8 did not change patterns of expression in some of the Dlx family members (Trumpp et al., 1999). This finding argues against FGF8 as an upstream regulator of the DLX family of transcription factors, but still supports an independent genetic pathway for different types of teeth. Dlx proteins have been shown to interact with Msx proteins in an antagonistic mechanism, with Dlx proteins being transcriptional activators, and Msx proteins being transcriptional repressors (Zhang et al., 1997). The human MSX1 mutations described to date have caused different patterns of upper molar agenesis. The Witkop syndrome nonsense mutation caused agenesis of first maxillary molars in seven of eight affected-family members; however, the missense mutations met61lys and arg196pro did not cause any maxillary molar agenesis. The autosomal-dominant orofacial clefting and tooth agenesis nonsense mutation caused one missing maxillary first molar and two missing second molars in two of twelve affected-family members. The Witkop syndrome mutation is more downstream than the orofacial clefting and tooth agenesis mutation. Missing the C terminal of the homeodomain disrupts teeth and nail formation, and the complete absence of the MSX1 homeodomain causes orofacial clefts along with tooth agenesis, but is less severe in the first maxillary molar region. Whether these mutations disrupt the DLX-MSX interactions remains to be studied. When targeted mutations in the individual activin receptor genes (IIA and IIB) have been produced, mice with mutations in activin receptor IIA have a more altered head phenotype than do mice with mutations in activin receptor IIB (Matzuk et al., 1995a). Activin receptor IIA-deficient mice show anterior head defects such as hypoplastic mandible (22% penetrance), which can result in secondary defects such as a lack of incisors. Activin receptor IIB-deficient mice have no mandibular or tooth defects but exhibit cleft palate at low penetrance (Oh and Li, 1997). Activins also bind to other receptors, such as type II activin receptor. A few type II activin receptor-deficient mice present skeletal and facial abnormalities reminiscent of the Robin sequence in humans (Matzuk et al., 1995a). Again, these experiments suggest that tooth development and palate formation share mechanisms.
The Table
Several molecules are expressed in early (initiation stage) dental epithelium, such as Bmp2, Bmp4, Bmp7, Dlx2, Dlx5, Fgf1, Fgf2, Fgf4, Fgf8, Fgf9, Lef1, Gli2, and Gli3, among others (http://bite-it.helsinki.fi/). All these genes are potential candidates for tooth agenesis in humans. There is evidence that children with cleft palate have a higher incidence of congenitally missing teeth outside the area of the cleft. Also, the more severe the cleft, the greater the number of teeth missing (Larson et al., 1998). Therefore, studies of the genetics of non-syndromic cleft lip and palate may offer good clues for tooth agenesis. Not only MSX1- but also TGFB3-deficient mutant mice display cleft palate (Satokata and Maas, 1994; Kaartinen et al., 1995; Proetzel et al., 1995), and linkage and linkage disequilibrium studies have shown association between oral clefts and both MSX1 and TGFB3 (Lidral et al., 1998; Beaty et al., 2001). Following the same idea, MSX1 and PAX9 are obvious candidates for tooth agenesis in humans, based on their animal models. Genes for rare developmental syndromes might also play roles in common birth defects and may provide an important source of candidate genes for disorders that are not amenable to standard genome-wide mapping approaches. Homozygous loss-of-function mutations of PVRL1, which encodes a cell-cell adhesion molecule expressed in the developing face and palate, is the cause of an autosomal-recessive clefting syndrome on Margarita Island (cleft lip and palate-ectodermal dysplasia syndrome, CLPED1) (Suzuki et al., 2000). An association between heterozygosity for this mutation and sporadic, non-syndromic cleft lip and palate in northern Venezuela was later described (Sözen et al., 2001). Although further evidence is needed to confirm this finding, searches for the disease alleles of other genes known to be responsible for clefting syndromes may provide more interesting candidate genes for the isolated forms. Another example is the identification of mutations in the gene for a T-box transcription factor (TBX22) as the cause of the rare X-linked syndrome cleft palate with ankyloglossia (CPX) (Braybrook et al., 2001). TBX22 became an interesting candidate for isolated forms of cleft palate and isolated ankyloglossia. Therefore, the identification of the genetic cause of syndromes that have teeth abnormalities could be a tool for selecting candidate genes for teeth defects. Tooth agenesis is associated with at least 45 syndromes (http://www.ncbi.nlm.nih.gov/Omim/), but very few describe what types of teeth are missing. This has become very important due to the evidence that different types of teeth may have independent developmental mechanisms, and different genetic factors may be involved in the agenesis of specific types of teeth. One example is the van der Woude syndrome, which has been described as presenting missing central and lateral incisors, canines, and/or premolars in 20 to 40% of the cases, besides the typical lower-lip pits with oral clefts (Schinzel and Klausler, 1986; Jones, 1997). The disclosure of the defective gene that causes van der Woude syndrome, mapped in 1q (Murray et al., 1990), would offer a good candidate gene for isolated tooth agenesis of a more anterior segment of the arches, whereas MSX1 and PAX9 would remain as the strongest candidates for posterior tooth agenesis.
During the past decade, considerable effort and expense have been expended to detect genetic loci contributing to the susceptibility for complex human diseases (Altmüller et al., 2001). However, the success in such genetic identification attempts has been limited, and most of the fundamental questions relating to the genetic epidemiology of complex human disease remain unanswered. In contrast to what has been found for monogenic traits, the results related to complex traits have often been disappointing or even inconsistent (Terwilliger and Goring, 2000; Rao, 2001). A study design taking into account the unique characteristics of both the sample and the phenotypes studied has been suggested as a way to improve the quality of future investigations (Terwilliger and Goring, 2000). For tooth agenesis, it might require a very careful description of the teeth that are missing and of the malformations found on the teeth present, as a possible extension of the phenotype in both syndromic and isolated forms. Human tooth agenesis is probably caused by several independent defective genes, acting alone or in combination with other genes, leading to a specific phenotypic pattern. Data from animal models are still very complex, and the human embryology is still poorly understood. Oral clefts and syndromic forms of tooth agenesis may be the best models for isolated tooth agenesis. In the future, a precise description of the missing teeth in syndromes involving tooth agenesis may be useful.
Thanks to Jeff Murray for many helpful discussions and to Jill Harrington and Ryan Grady for helping with the manuscript. This work is supported by NIH grant 5 D43 TW05503. Received for publication May 20, 2002. Revision received August 29, 2002. Accepted for publication November 26, 2002.
Journal of Dental Research, Vol. 82, No. 3,
162-165 (2003) This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
