Next Article in Journal
Hylin-a1: A Pan-Inhibitor against Emerging and Re-Emerging Respiratory Viruses
Next Article in Special Issue
Single-Nucleotide Polymorphisms in Genes Maintaining the Stability of Mitochondrial DNA Affect the Occurrence, Onset, Severity and Treatment of Major Depressive Disorder
Previous Article in Journal
Assessment of Apolipoprotein(a) Isoform Size Using Phenotypic and Genotypic Methods
Previous Article in Special Issue
Report on the Effect of the Implementation of an Early Detection and Prevention of Cancer Program on Families at High Hereditary Risk—Concentrating on Patients Undergoing Genetic Diagnostics and Counseling in Central Poland
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 18
10.3390/ijms241813889
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Genetic Factors of Teeth Impaction: Polymorphic and Haplotype Variants of PAX9, MSX1, AXIN2, and IRF6 Genes

by
Grzegorz Trybek
1,2,*,
Aleksandra Jaroń
2,
Ewa Gabrysz-Trybek
3,
Monika Rutkowska
2,
Aleksandra Markowska
2,
Krzysztof Chmielowiec
4,
Jolanta Chmielowiec
4 and
Anna Grzywacz
5
1
Department of Oral Surgery, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72/18, 70-111 Szczecin, Poland
2
4th Military Clinical Hospital in Wroclaw, ul. Rudolfa Weigla 5, 50-981 Wroclaw, Poland
3
Individual Specialist Medical Practice Ewa Gabrysz-Trybek, 70-111 Szczecin, Poland
4
Department of Hygiene and Epidemiology, Collegium Medicum, University of Zielona Góra, 28 Zyty St., 65-046 Zielona Góra, Poland
5
Independent Laboratory of Health Promotion, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72 St., 70-111 Szczecin, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(18), 13889; https://doi.org/10.3390/ijms241813889
Submission received: 30 July 2023 / Revised: 3 September 2023 / Accepted: 6 September 2023 / Published: 9 September 2023
(This article belongs to the Special Issue State-of-the-Art Molecular Genetics and Genomics in Poland 2.0)
Versions Notes

Abstract

:
In recent research, there has been a growing awareness of the role of genetic factors in the positioning and eruption of teeth in the maxilla and mandible. This study aimed to evaluate the potential of specific polymorphic markers of single nucleotide polymorphisms (SNPs) located within the PAX9, MSX1, AXIN2, and IRF6 genes to determine the predisposition to tooth impaction. The study participants were divided into two groups: the first group consisted of individuals with at least one impacted secondary tooth. In contrast, the second group (control group) had no impacted teeth in their jaws. To analyze the genes, real-time PCR (polymerase chain reaction) and TaqMan probes were utilized to detect the selected polymorphisms. The findings suggest that disruptions in the structure and function of the mentioned genetic factors such as polymorphic and haplotype variants of PAX9, MSX1, AXIN2, and IRF6 genes, which play a direct role in tooth and periodontal tissue development, might be significant factors in tooth impaction in individuals with genetic variations. Therefore, it is reasonable to hypothesize that tooth impaction may be influenced, at least in part, by the presence of specific genetic markers, including different allelic variants of the PAX9, AXIN2, and IRF6 genes, and especially MSX1.

1. Introduction

Extensive research has revealed that tooth development in humans and other mammals is influenced by both genetic and environmental factors [1,2,3]. Interactions between hundreds of genes control the number, shape, and location of teeth during embryogenesis [1,2,3]. The genetic basis of tooth developmental disorders, including agenesis, extra teeth, and structural anomalies, has been extensively documented [4,5,6,7]. Specific genetic factors have also been associated with abnormalities in tooth location and eruption [7]. Additionally, the impact of genetical, pre-, peri-, and postnatal risk factors on enamel development disorders should be considered. These risk factors include severe illness or complications during pregnancy, low birth weight or premature birth, breastfeeding issues or illness, and early childhood infections [8].
Studies in animals have shown that dental defects, including impacted teeth, are often influenced by multiple genes [9,10]. Currently, an impacted tooth is defined as a fully developed tooth embedded in the jawbone or mandible, with closed and mineralized root apices. It can be categorized as complete if fully covered by bone, or partial if the crown has perforated the bone plate and remains adjacent to the soft tissues. Impacted teeth no longer exhibit growth tendencies [11,12].
Researchers are continuously delving into the intricate relationship between genetic and environmental factors in tooth development, advancing our understanding of dental defects and their underlying mechanisms. Impacted teeth are commonly found in the maxilla, specifically the canines and incisors, as well as in the mandible, including the third molars and second premolars. The prevalence of impacted teeth in the anterior region ranges from 0.9% to 4.3% of the population, with canines accounting for 70% and incisors for 11.5% of cases [13,14]. The diagnosis of lower third molar impaction varies across populations and time periods. In the 1960s, the prevalence ranged from 17% to over 70% among young Europeans, while more recent studies in the early 2000s have reported varying figures [15].
Extensive research on the genetic basis of dental disorders has identified several candidate genes, such as MSX1, PAX9, AXIN2, WNT10A, EDA, EDAR, BMP4, FGF8, IRF6, and PITX2 [16,17,18,19,20,21,22,23,24,25,26]. These genes encode proteins with diverse functions, including signaling molecules, receptors, mediators, and gene expression regulators. They participate in various signaling pathways, including WNT/β-catenin, transforming growth factor-beta (TGFβ), and BMP pathways [16]. Mutations in the MSX1 and PAX9 genes are frequently associated with tooth developmental disorders. These genes encode transcriptional regulators that play a crucial role in tooth formation and the development of other structures [1,2]. The PAX9 gene has been extensively studied in terms of its molecular structure, expression, and potential effects on tooth development processes [27,28,29,30].
The PAX9 gene, located on chromosome 14 in humans, is linked to various dental abnormalities. It consists of four exons, with the first exon acting as a start codon and exon 2 encoding a highly conserved region of the pairing domain [31]. Most mutations in the PAX9 gene have been identified in exon 2, or less frequently, in exon 4. These mutations are associated with different forms of agenesis, non-syndromic hypodontia, and oligodontia [29,32,33]. Specific alleles at polymorphic sites in exon 2 or 4, as well as the deletion of one copy of the PAX9 gene, can lead to selective tooth agenesis, particularly in molars. The observed phenotype is often seen in heterozygotes, indicating that haploinsufficiency of the PAX9 gene contributes to tooth agenesis [30,34].
The MSX1 gene, located on chromosome 4 in humans, consists of two exons, 2332 and 1229 bp in length, separated by a 2332 bp intron. It produces two distinct transcripts, resulting in two polypeptides of different lengths of 303 and 297 amino acids [35,36]. The transcription factor encoded by the MSX1 gene regulates the expression of multiple target genes and interacts with proteins involved in odontogenesis, such as PAX9, Dlx family proteins, and Tbp [37]. Genes like MSX1, which code for proteins containing a homeodomain, play a crucial role in odontogenesis, controlling various stages of tooth development and influencing the final dentition pattern [38]. The AXIN2 gene is responsible for encoding a factor in the WNT signaling pathway, which regulates the stability of beta-catenin. Disruptions in this pathway can contribute to the development of certain neoplasms [39,40,41]. The WNT pathway controls the levels and localization of beta-catenins. Activation of the WNT-dependent pathway stabilizes beta-catenin, allowing it to bind to transcription factors from the TCF family and regulate target gene expression. In the absence of WNT signals, beta-catenin undergoes phosphorylation and degradation through a multiprotein complex involving the APC protein, AXIN1, and AXIN2 proteins [42,43,44,45]. AXIN proteins, including AXIN2, facilitate the formation of beta-catenin-degrading complexes [46]. AXIN2 gene expression is induced by the WNT signaling pathway, indicating that AXIN2 acts as a negative regulator in a feedback loop [47,48]. The SHH and WNT pathways, along with proteins like MSX1 and PAX9, play crucial roles in normal tooth morphogenesis and contribute to the complex regulation of tooth development [49,50]. The IRF6 gene is associated with van der Woude syndrome (VWS) and Bartsocas–Papas congenital anomaly syndrome. VWS is characterized by cleft lip and palate, mucous cysts of the lower lip, and tooth agenesis [51]. Certain SNP mutations in the IRF6 gene have been significantly correlated with the presence of cleft lip with or without cleft palate (CL/P) in various populations [52,53,54,55,56,57]. The IRF6 gene may also contribute to tooth developmental disorders, especially when other craniofacial abnormalities are present. The development of teeth, palate, and lips is interconnected, and the severity of cleft symptoms is often associated with the number of affected teeth [58,59,60,61,62,63,64,65,66,67]. Therefore, the IRF6 gene is considered important in the study of dental development disorders due to its confirmed role in the etiology of cleft lip and palate.
This research’s main objective was to assess the usefulness of selected polymorphic markers of single nucleotide polymorphism (SNP) characters located within the PAX9, MSX1, AXIN2, and IRF6 genes in the context of their applicability to determine the predisposition to the occurrence of the tooth impaction phenomenon. The protein products of the PAX9, MSX1, AXIN2, and IRF6 genes directly participate in the processes of tooth formation. Therefore, it has been hypothesized that the polymorphism of these genes may contribute to the phenomenon of impacted teeth in humans.

2. Results

Table 1, Table 2, Table 3 and Table 4 describe the frequency of impaction of different groups of teeth in the maxilla and mandible.
Differences in the frequency of the MSX1 rs8670 gene polymorphism were found in respondents with impacted teeth between maxilla and mandible(max&man) together, and maxilla(max) and mandible(man) separately (C/Cmax&man 0.47 vs. C/Cmax 0.71 vs. C/Cman 0.34; T/Tmax&man 0.05 vs. T/Tmax 0.05 vs. T/Tman 0.14; C/Tmax&man 0.48 vs. C/Tmax 0.24 vs. C/Tman 0.24; χ2 = 15.876; p = 0.0031, Table 4).
Differences in the frequency of the MSX1 rs12532 gene polymorphism were found in respondents with impacted teeth between maxilla and mandible (max&man) together, and maxilla(max) and mandible(man) separately (A/Amax&man 0.61 vs. A/Amax 0.29 vs. A/Aman 0.58; G/Gmax&man 0.06 vs. G/Gmax 0.21 vs. G/Gman 0.08; A/Gmax&man 0.33 vs. A/Gmax 0.50 vs. A/Gman 0.34; χ2 = 15.1036; p = 0.0044) and alleles (Amax&man 0.78 vs. Amax 0.54 vs. Aman 0.75; Gmax&man 0.22 vs. Gmax 0.46 vs. Gman 0.25; χ2 = 16.3635; p = 0.0003) (Table 4).
Differences in the frequency of the AXIN2 rs2240308 gene polymorphism were found in respondents with impacted teeth between maxilla and mandible (max&man) together, and maxilla (max) and mandible(man) separately (A/Amax&man 0.30 vs. A/Amax 0.13 vs. A/Aman 0.40; G/Gmax&man 0.21 vs. G/Gmax 0.39 vs. G/Gman 0.17; A/Gmax&man 0.49 vs. A/Gmax 0.47 vs. A/Gman 0.43; χ2 = 11.2104; p = 0.0243) and alleles (Amax&man 0.55 vs. Amax 0.37 vs. Aman 0.61; Gmax&man 0.45 vs. Gmax 0.63 vs. Gman 0.39; χ2 = 11.3513; p = 0.00343) (Table 4).
The PAX9 rs4904210, AXIN2 rs7591, AXIN2 rs4904210, IRF6 rs642961, IRF6 rs861019, IRF6 rs4904210, and IRF6 rs658860 genotype and allele frequencies in the studied sample did not differ in respondents with impacted teeth between maxilla and mandible together, and maxilla and mandible separately (Table 4).
For genotypes and alleles for which statistical significances were demonstrated, a comparison of allele and genotype frequencies between the study and control groups is also presented in Table 5.

3. Discussion

When examining the phenotypic impact of mutations, certain circumstances can associate an allele reducing functional protein levels with favorable traits. For instance, the reduction in C-allele teeth at the rs4904210 locus in the PAX9 gene, primarily affecting the development of the third molars, has been observed in studies and considered not only neutral but even beneficial [68].
The shift in modern lifestyles, with a preference for highly processed and cooked foods over the raw and hard diet of our ancestors, has rendered third molars unnecessary remnants of our species’ evolutionary history [69]. In cases of impacted or abnormally erupted molars, their presence can pose health hazards, serving as sites for inflammation and bacterial impaction, leading to cavities in neighboring teeth and infections in the bone tissue, potentially weakening or even destroying them. Additionally, bacteria multiplying in these areas can spread systemically, attacking other organs and posing health risks [70].
In this context, the Ala240Pro mutation in the PAX9 gene is described by some authors as a beneficial change aimed at eliminating unnecessary third molars from the modern human population [68].
Functional analysis of the Arg196Pro polymorphism in the MSX1 gene, involved in hypodontia, showed that the structurally defective protein with reduced thermal stability resulted in impaired DNA binding and protein interactions. This mutation was associated with a higher frequency of missing second premolars and third molars, and in some cases, upper premolars and lower first molars [71].
In a study of the Chinese population, a new C662A mutation in the MSX1 gene’s homeodomain region was identified, leading to an Ala221Glu substitution. This mutation disrupts the binding to DNA and interactions with other proteins, such as those from the DLX family, hindering the initiation of epithelial–mesenchymal signal cascades during tooth development [72]. Carriers of the Ala221Glu mutation exhibited selective tooth loss, including premolars, third molars, lateral incisors, and canines [73].
Another mutation in the MSX1 gene’s homeodomain region is the T671C substitution, resulting in a Leu224Pro substitution. Predictive analysis suggests that this mutation may completely abolish the activity of the MSX1 protein, leading to the congenital absence of second premolars and third molars in carriers [74].
Bearing in mind the information presented above on the influence of various mutations in the coding area of the MSX1 gene homeodomain, it is worth emphasizing that the functional analysis of the remaining five missense mutations in the same region of the MSX1 gene, correlated with hypodontia (Met61Lys, Ala194Val, Arg196Pro, Ala219Thr, and Ala221Glu), revealed none of the previously known molecular mechanisms (such as a disturbance of the interaction of MSX1 with PAX9 or other regulatory proteins). Considering the influence of various mutations in the coding region of the MSX1 gene homeodomain, it is important to note that functional analysis of five missense mutations (Met61Lys, Ala194Val, Arg196Pro, Ala219Thr, and Ala221Glu) associated with hypodontia revealed that previously known molecular mechanisms could not fully explain the significance of these amino acid substitutions in tooth agenesis [22].
Furthermore, it was demonstrated that most of these missense mutations did not impair the crucial interaction between MSX1 and PAX9, which activates the expression of the BMP4 gene, suggesting that the role of MSX1 in tooth development is not directly linked to the interaction with PAX9 [22]. This implies that potential molecular targets responsible for dental abnormalities may lie in other regions of the MSX1 gene beyond the homeodomain.
Promising variants of the MSX1 gene, relevant to various dental development disorders, include polymorphic sites rs8670 and rs12532, located in the non-coding UTR region of exon 2 [75]. These variants were found in the Polish population and primarily associated with non-syndromic sporadic oligodontics in humans [76].
The non-coding regions of the MSX1 gene may also contribute to the development of dental disorders, independent of the homeodomain’s direct functioning. The rs8670 variant in the MSX1 gene was found to potentially correlate with non-syndromic hypodontia in the upper lateral incisors, suggesting an impact on mRNA stability, antisense RNA-mediated interactions, or translation processes [77]. However, larger studies in Brazilian patients did not show significant differences in the distribution of genotypes and alleles in the rs8670 and rs12532 sites between the agenesis group and the control group [78].
In patients with severe familial hypodontia, direct sequencing of the AXIN2 gene revealed a nonsense mutation (Arg656Stop) in exon 7, which led to premature translation termination [79]. This mutation may result in mRNA degradation through the nonsense-mediated decay mechanism, as the mRNA transcript with a premature stop codon fulfills the conditions for degradation [80,81]. The protein produced in individuals with the C1966T mutation lacks the C-terminal domain responsible for oligomerization and interaction with other proteins [42,82,83]. Consequently, individuals with this mutation experience a decrease in the function of the AXIN2 protein, leading to the accumulation of beta-catenin [84]. Sequence analysis of the AXIN2 gene in Polish patients with selective tooth agenesis identified several polymorphic sites, including two new variants in the intron region and one variant in exon 7 [85]. Statistical analysis revealed that carriers of the c.956 + 16G and c.2062T alleles had an increased risk of selective tooth agenesis, indicating a potential association [85]. The synonymous change Leu688Leu may disrupt the exonic splicing enhancer sequence, affecting the recognition of cleavage sites in splicing processes [81]. The c.956 + 16A>G mutation could also impact splicing processes, creating an additional donor site within exon 2, potentially interfering with odontogenesis [85].
In studies involving Brazilian and Turkish patients with selective tooth agenesis, three intragenic polymorphic sites (rs7591, rs11867417, and rs2240308) in the AXIN2 gene were analyzed [86]. The presence of the rs2240308 variant, either in isolation or as part of a haplotype, correlated with the absence of at least one incisor in the studied populations [86]. Although in silico analysis did not confirm this variant as a direct etiological factor, it is suggested that it may interact with another variant to contribute to the development of tooth developmental disorders [86].
Associations between selected markers (rs7802, rs861019, and rs2235371) within the IRF6 gene and preferential agenesis of premolars were confirmed in the Brazilian population [87]. The non-synonymous mutation rs2235371 (Val274Ile) was found to have an attributable fraction (AF) coefficient value of 16.4%, indicating its contribution to agenesis cases [87]. Haplotypes reconstructed for the analyzed polymorphic sites in the IRF6 gene, containing the more common allele at rs2235371, were consistently found in agenesis patients, particularly in relation to premolar agenesis [87].
However, it was suggested that the rs2235371 variant may not be an etiological factor in itself, but rather interacts with other variants that directly impact the appearance of agenesis [88]. To further investigate, additional markers within the IRF6 gene (rs4844880, rs2235371, rs2013162, rs861019, rs2073487, rs642961, and rs658860) were analyzed. The presence of rs658860 variants and the haplotype [A; T; A] reconstructed for sites [rs861019; rs2073487; rs642961] showed a correlation with abnormal development of at least one incisor [88].
In patients with impaired premolar development, the association was observed for the rs2013162 and rs642961 variants, as well as the haplotypes [G; T; A] in [rs861019; rs2073487; rs642961] and [T; AND; T] in [rs2073487; rs642961; rs658860] [88]. The presence of the rs642961 site in all statistically significant haplotype systems suggests its potential functional role. In silico analyses indicate that the rs642961 mutation may alter the AGAAT sequence near the IRF6 gene to the AGGAT sequence, which is responsible for binding to the product of the heat shock transcription factor (HSF) gene, a transcription factor activated in response to temperature stress. Additionally, the rs861019 mutation was found to cause a change in another sequence (GTTCT → ATTCT) within the HSF binding domain [88]. However, the precise mechanism by which disruption of HSF binding affects normal tooth development remains unknown.

4. Materials and Methods

4.1. Subjects

Participation in the research project was offered to a consecutive group of 392 patients who visited the Department of Oral Surgery. The inclusion criteria for the study group required the presence of at least one fully impacted tooth in either the maxillary or mandibular bone. An impacted tooth was defined as a tooth surrounded by bone in X-ray images but absent in the dental arch during eruption. The study group consisted of 204 individuals, including 82 males and 122 females, who had one to seven impacted teeth. Patients under the age of sixteen and those who were unable to undergo a panoramic radiograph or had multiple missing teeth that prevented a diagnosis of hypodontia were not eligible for the project. Relatives of the patients were also excluded.
The study participants were divided into two groups based on the presence or absence of a diagnosis of tooth/teeth impaction provided by a medical specialist:
The study group included patients with at least one permanently impacted tooth in the maxillary or mandibular bone, as well as patients with supernumerary teeth.
The control group consisted of patients who had no impacted teeth in the maxillary bones and whose permanent teeth had properly emerged and aligned in the dental arches.
All patients were fully informed about the purpose, benefits, and research methods of the study. After providing written consent to participate, they were assigned individual identification numbers to ensure anonymity.
The study group included 204 patients (82 males and 122 females) in whom one to seven impacted teeth were identified (median 3, interquartile range 2–4). A histogram of patients in the study group with a specific number of impacted teeth is shown in Table 5. The most significant number of patients in the study group were observed to have four impacted teeth, while patients with two impacted teeth were the second most numerous subgroup.
It was assumed that the size of the Phi effect would be 0.25 with a group of 204 tested people, and the power of the statistical test for the polymorphism of the tested genes would be 0.83. However, for alleles (n = 408) the Phi effect size was assumed to be 0.16 and the power of the statistical test to be 0.83. The actual results obtained for the size of the Phi effect and the power of the statistical test are presented in Table 6.

4.2. Genotyping

Genomic DNA was extracted from venous blood using standard procedures. Genotyping was conducted with the real-time PCR method.
LightCycler® 480 II System (Roche Diagnostic, Basel, Switzerland) was applied to perform the fluorescence resonance energy into the genotypic data. The data relating to the DRD2 gene polymorphism were obtained under the following conditions: PCR was performed with 50 ng DNA of each sample in a final volume of 20 µL containing 2 µL reaction mix, 0.5 mM of each primer, 0.2 mM of each hybridization probe, and 2 mM MgCl2 according to the manufacturer’s instructions with initial denaturation (95 °C for 10 min) and then 35 cycles of denaturation (95 °C for 10 s), annealing (60 °C for 10 s), and extension (72 °C for 15 s). After amplification, a melting curve was generated by holding the reaction at 40 °C for 20 s and heating slowly to a level of 95 °C. The fluorescence signal was plotted against temperature to provide melting curves for each sample.

4.3. Statistical Analysis

The frequencies of genotypes and alleles of the PAX9 rs4904210, MSX1 rs8670, MSX1 rs12532, AXIN2 rs7591, AXIN2 rs4904210, AXIN2 rs2240308, IRF6 rs642961, IRF6 rs861019, IRF6 rs4904210, and IRF6 rs658860 polymorphisms in analyzed groups were compared with the chi-square test. All analyses were performed using STATISTICA 13 (Tibco Software Inc., Palo Alto, CA, USA) for Windows (Microsoft Corporation, Redmond, WA, USA).

5. Conclusions

Abnormalities in the structure and function of the previously described genetic factors directly involved in the development of the tooth, including its hard tissues and periodontal tissues, may therefore have a role in the appearance of retained teeth in individuals with such alterations in genetic material. On the basis of this study, it can be assumed that the impaction of teeth will also depend, at least in part, on the presence of certain genetic markers, particularly AXIN2 rs2240308 and MSX1 rs12532.

Author Contributions

Conceptualization, G.T.; methodology, G.T.; software, A.J., A.G., M.R. and J.C.; validation, G.T. and A.G.; formal analysis, G.T., A.G. and K.C.; investigation, G.T.; resources, G.T. and A.J.; data curation, G.T. and A.J.; writing—original draft preparation, G.T.; writing—review and editing, G.T., A.J. and A.G.; visualization, A.J., E.G.-T. and A.M.; supervision, G.T.; project administration, G.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Ethics Committee of Pomeranian Medical University in Szczecin, Poland (Resolution No. KB-0012/39/16 of 25 April 2016).

Informed Consent Statement

Informed consent was obtained from all subjects involved in this study.

Data Availability Statement

Data available on request due to restrictions—privacy or ethical.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Peters, H.; Balling, R. Teeth: Where and How to Make Them. Trends Genet. 1999, 15, 59–65. [Google Scholar] [CrossRef] [PubMed]
  2. Vieira, A.R. Oral Clefts and Syndromic Forms of Tooth Agenesis as Models for Genetics of Isolated Tooth Agenesis. J. Dent. Res. 2003, 82, 162–165. [Google Scholar] [CrossRef] [PubMed]
  3. Kangas, A.T.; Evans, A.R.; Thesleff, I.; Jernvall, J. Nonindependence of Mammalian Dental Characters. Nature 2004, 432, 211–214. [Google Scholar] [CrossRef] [PubMed]
  4. Kindelan, J.D.; Rysiecki, G.; Childs, W.P. Hypodontia: Genotype or Environment? A Case Report of Monozygotic Twins. Br. J. Orthod. 1998, 25, 175–178. [Google Scholar] [CrossRef]
  5. Arte, S.; Nieminen, P.; Apajalahti, S.; Haavikko, K.; Thesleff, I.; Pirinen, S. Characteristics of Incisor-Premolar Hypodontia in Families. J. Dent. Res. 2001, 80, 1445–1450. [Google Scholar] [CrossRef] [PubMed]
  6. Parkin, N.; Elcock, C.; Smith, R.N.; Griffin, R.C.; Brook, A.H. The Aetiology of Hypodontia: The Prevalence, Severity and Location of Hypodontia within Families. Arch. Oral Biol. 2009, 54 (Suppl. S1), S52–S56. [Google Scholar] [CrossRef] [PubMed]
  7. Trybek, G.; Jaroń, A.; Grzywacz, A. Association of Polymorphic and Haplotype Variants of the MSX1 Gene and the Impacted Teeth Phenomenon. Genes 2021, 12, 577. [Google Scholar] [CrossRef]
  8. Butera, A.; Maiorani, C.; Morandini, A.; Simonini, M.; Morittu, S.; Barbieri, S.; Bruni, A.; Sinesi, A.; Ricci, M.; Trombini, J.; et al. Assessment of Genetical, Pre, Peri and Post Natal Risk Factors of Deciduous Molar Hypomineralization (DMH), Hypomineralized Second Primary Molar (HSPM) and Molar Incisor Hypomineralization (MIH): A Narrative Review. Children 2021, 8, 432. [Google Scholar] [CrossRef]
  9. Aksenovich, T.I.; Zorkal’tsov, I.V.; Kniazev, S.P.; Kulikova, A.V. Inheritance of Hypodontia in Kerry Blue Terrier Dogs. Genetika 2004, 40, 658–666. [Google Scholar] [CrossRef]
  10. Aksenovich, T.I.; Kulikova, A.V.; Kniazev, S.P.; Zorkal’tseva, I.V.; Borodin, P.M. Polymorphism of dental formula and segregation of its variants in a pedigree of kerry blue terrier dogs. Genetika 2006, 42, 414–420. [Google Scholar] [CrossRef]
  11. Mead, S. Incidence of Impacted Teeth. Int. J. Orthod. Oral Surg. Radiogr. 1930, 16, 885–890. [Google Scholar] [CrossRef]
  12. Jaroń, A.; Trybek, G. The Pattern of Mandibular Third Molar Impaction and Assessment of Surgery Difficulty: A Retrospective Study of Radiographs in East Baltic Population. Int. J. Environ. Res. Public Health 2021, 18, 6016. [Google Scholar] [CrossRef] [PubMed]
  13. Haralabakis, H. Observations on the Time of Eruption, Congenital Absence, and Impaction of the Third Molar Teeth. Trans. Eur. Orthod. Soc. 1957, 33, 9. [Google Scholar]
  14. Dachi, S.F.; Howell, F.V. A Survey of 3874 Routine Full-Mouth Radiographs: II. A Study of Impacted Teeth. Oral Surg. Oral Med. Oral Pathol. 1961, 14, 1165–1169. [Google Scholar] [CrossRef]
  15. Elsey, M.J.; Rock, W.P. Influence of Orthodontic Treatment on Development of Third Molars. Br. J. Oral Maxillofac. Surg. 2000, 38, 350–353. [Google Scholar] [CrossRef]
  16. Mostowska, A.; Trzeciak, W.H. Molekularne Podłoże Wrodzonego Braku Zawiązków Zębów Stałych Na Podstawie Piśmiennictwa. Czas Stomat 2006, 59, 110–117. [Google Scholar]
  17. Chalothorn, L.A.; Beeman, C.S.; Ebersole, J.L.; Kluemper, C.T.; Hicks, E.P.; Kryscio, R.J.; DeSimone, C.P.; Modesitt, S.C. Hypodontia as a Risk Marker for Epithelial Ovarian Cancer: A Case-Controlled Study. J. Am. Dent. Assoc. 2008, 139, 163–169. [Google Scholar] [CrossRef]
  18. Goldenberg, M.; Das, P.; Messersmith, M.; Stockton, D.W.; Patel, P.I.; D’Souza, R.N. Clinical, Radiographic, and Genetic Evaluation of a Novel Form of Autosomal-Dominant Oligodontia. J. Dent. Res. 2000, 79, 1469–1475. [Google Scholar] [CrossRef]
  19. Jędryszek, A.; Kmiecik, M.; Paszkiewicz, A. Review of Modern Knowledge on Hypodontia. Dent. Med. Probl. 2009, 46, 118–125. [Google Scholar]
  20. Shafi, I.; Phillips, J.M.; Dawson, M.P.; Broad, R.D.; Hosey, M.T. A Study of Patients Attending a Multidisciplinary Hypodontia Clinic over a Five Year Period. Br. Dent. J. 2008, 205, 649–652. [Google Scholar] [CrossRef]
  21. Vieira, A.R.; Meira, R.; Modesto, A.; Murray, J.C. MSX1, PAX9, and TGFA Contribute to Tooth Agenesis in Humans. J. Dent. Res. 2004, 83, 723–727. [Google Scholar] [CrossRef] [PubMed]
  22. Wang, Y.; Kong, H.; Mues, G.; D’Souza, R. MSX1 Mutations: How Do They Cause Tooth Agenesis? J. Dent. Res. 2011, 90, 311–316. [Google Scholar] [CrossRef] [PubMed]
  23. Chhabra, N.; Goswami, M.; Chhabra, A. Genetic Basis of Dental Agenesis—Molecular Genetics Patterning Clinical Dentistry. Med. Oral Patol. Oral Cirugía Bucal 2014, 19, 112–119. [Google Scholar] [CrossRef]
  24. Mitsui, S.N.; Yasue, A.; Masuda, K.; Watanabe, K.; Horiuchi, S.; Imoto, I.; Tanaka, E. Novel PAX9 Mutations Cause Non-Syndromic Tooth Agenesis. J. Dent. Res. 2014, 93, 245–249. [Google Scholar] [CrossRef] [PubMed]
  25. van den Boogaard, M.J.; Créton, M.; Bronkhorst, Y.; van der Hout, A.; Hennekam, E.; Lindhout, D.; Cune, M.; van Amstel, H.K.P. Mutations in WNT10A Are Present in More than Half of Isolated Hypodontia Cases. J. Med. Genet. 2012, 49, 327–331. [Google Scholar] [CrossRef]
  26. Mostowska, A.; Biedziak, B.; Zadurska, M.; Dunin-Wilczynska, I.; Lianeri, M.; Jagodzinski, P. Nucleotide Variants of Genes Encoding Components of the Wnt Signalling Pathway and the Risk of Non-Syndromic Tooth Agenesis. Clin. Genet. 2013, 84, 429–440. [Google Scholar] [CrossRef]
  27. Xu, W.; Rould, M.A.; Jun, S.; Desplan, C.; Pabo, C.O. Crystal Structure of a Paired Domain-DNA Complex at 2.5 A Resolution Reveals Structural Basis for Pax Developmental Mutations. Cell 1995, 80, 639–650. [Google Scholar] [CrossRef]
  28. Neubüser, A.; Koseki, H.; Balling, R. Characterization and Developmental Expression of PAX9, a Paired-Box-Containing Gene Related to Pax1. Dev. Biol. 1995, 170, 701–716. [Google Scholar] [CrossRef]
  29. Stockton, D.W.; Das, P.; Goldenberg, M.; D’Souza, R.N.; Patel, P.I. Mutation of PAX9 Is Associated with Oligodontia. Nat. Genet. 2000, 24, 18–19. [Google Scholar] [CrossRef]
  30. Mensah, J.K.; Ogawa, T.; Kapadia, H.; Cavender, A.C.; D’Souza, R.N. Functional Analysis of a Mutation in PAX9 Associated with Familial Tooth Agenesis in Humans. J. Biol. Chem. 2004, 279, 5924–5933. [Google Scholar] [CrossRef]
  31. Paixão-Côrtes, V.R.; Meyer, D.; Pereira, T.v.; Mazières, S.; Elion, J.; Krishnamoorthy, R.; Zago, M.A.; Silva, W.A.; Salzano, F.M.; Bortolini, M.C. Genetic Variation among Major Human Geographic Groups Supports a Peculiar Evolutionary Trend in PAX9. PLoS ONE 2011, 6, e15656. [Google Scholar] [CrossRef]
  32. Frazier-Bowers, S.A.; Guo, D.C.; Cavender, A.; Xue, L.; Evans, B.; King, T.; Milewicz, D.; D’Souza, R.N. A Novel Mutation in Human PAX9 Causes Molar Oligodontia. J. Dent. Res. 2017, 81, 129–133. [Google Scholar] [CrossRef]
  33. Nieminen, P.; Arte, S.; Tanner, D.; Paulin, L.; Alaluusua, S.; Thesleff, I.; Pirinen, S. Identification of a Nonsense Mutation in the PAX9 Gene in Molar Oligodontia. Eur. J. Hum. Genet. 2001, 9, 743–746. [Google Scholar] [CrossRef]
  34. Das, P.; Stockton, D.W.; Bauer, C.; Shaffer, L.G.; D’Souza, R.N.; Wright, J.T.; Patel, P.I. Haploinsufficiency of PAX9 Is Associated with Autosomal Dominant Hypodontia. Hum. Genet. 2002, 110, 371–376. [Google Scholar] [CrossRef] [PubMed]
  35. Mostowska, A.; Kobielak, A.; Trzeciak, W.H. Molecular Basis of Non-Syndromic Tooth Agenesis: Mutations of MSX1 and PAX9 Reflect Their Role in Patterning Human Dentition. Eur. J. Oral Sci. 2003, 111, 365–370. [Google Scholar] [CrossRef] [PubMed]
  36. Stoczyńska, E.; Pawłowska, E.; Popławski, T.; Szczepańska, J.; Błasiak, J. Rola Białek PAX9 i MSX1 w Rozwoju i Agenezji Zębów. J. Stomatol. 2010, 65, 310–319. [Google Scholar]
  37. Neubüser, A.; Peters, H.; Balling, R.; Martin, G.R. Antagonistic Interactions between FGF and BMP Signaling Pathways: A Mechanism for Positioning the Sites of Tooth Formation. Cell 1997, 90, 247–255. [Google Scholar] [CrossRef]
  38. Sharpe, P.T. Homeobox Genes and Orofacial Development. Connect. Tissue Res. 1995, 32, 17–25. [Google Scholar] [CrossRef]
  39. Huelsken, J.; Birchmeier, W. New Aspects of Wnt Signaling Pathways in Higher Vertebrates. Curr. Opin. Genet. Dev. 2001, 11, 547–553. [Google Scholar] [CrossRef]
  40. Lustig, B.; Behrens, J. The Wnt Signaling Pathway and Its Role in Tumor Development. J. Cancer Res. Clin. Oncol. 2003, 129, 199–221. [Google Scholar] [CrossRef]
  41. Giles, R.H.; van Es, J.H.; Clevers, H. Caught up in a Wnt Storm: Wnt Signaling in Cancer. Biochim. Biophys. Acta Rev. Cancer 2003, 1653, 1–24. [Google Scholar] [CrossRef]
  42. Seidensticker, M.J.; Behrens, J. Biochemical Interactions in the Wnt Pathway. Biochim. Biophys. Acta 2000, 1495, 168–182. [Google Scholar] [CrossRef] [PubMed]
  43. Ming, M.; Qian, C.; Yokomizo, A.; Smith, D.I.; Wanguo, L. Cloning of the Human Homolog of Conductin (AXIN2), a Gene Mapping to Chromosome 17q23-Q24. Genomics 1999, 55, 341–344. [Google Scholar] [CrossRef]
  44. Behrens, J.; Jerchow, B.A.; Würtele, M.; Grimm, J.; Asbrand, C.; Wirtz, R.; Kühl, M.; Wedlich, D.; Birchmeier, W. Functional Interaction of an Axin Homolog, Conductin, with β-Catenin, APC, and GSK3β. Science 1998, 280, 596–599. [Google Scholar] [CrossRef] [PubMed]
  45. Yamamoto, H.; Kishida, S.; Uochi, T.; Ikeda, S.; Koyama, S.; Asashima, M.; Kikuchi, A. Axil, a Member of the Axin Family, Interacts with Both Glycogen Synthase Kinase 3beta and Beta-Catenin and Inhibits Axis Formation of Xenopus Embryos. Mol. Cell. Biol. 1998, 18, 2867–2875. [Google Scholar] [CrossRef] [PubMed]
  46. Lee, E.; Salic, A.; Krüger, R.; Heinrich, R.; Kirschner, M.W. The Roles of APC and Axin Derived from Experimental and Theoretical Analysis of the Wnt Pathway. PLoS Biol. 2003, 1, e10. [Google Scholar] [CrossRef]
  47. Leung, J.Y.; Kolligs, F.T.; Wu, R.; Zhai, Y.; Kuick, R.; Hanash, S.; Cho, K.R.; Fearon, E.R. Activation of AXIN2 Expression by Beta-Catenin-T Cell Factor. A Feedback Repressor Pathway Regulating Wnt Signaling. J. Biol. Chem. 2002, 277, 21657–21665. [Google Scholar] [CrossRef]
  48. Jho, E.; Zhang, T.; Domon, C.; Joo, C.-K.; Freund, J.-N.; Costantini, F. Wnt/Beta-Catenin/Tcf Signaling Induces the Transcription of AXIN2, a Negative Regulator of the Signaling Pathway. Mol. Cell. Biol. 2002, 22, 1172–1183. [Google Scholar] [CrossRef]
  49. Jernvall, J.; Thesleff, I. Reiterative Signaling and Patterning during Mammalian Tooth Morphogenesis. Mech. Dev. 2000, 92, 19–29. [Google Scholar] [CrossRef]
  50. Thesleff, I. Epithelial-Mesenchymal Signalling Regulating Tooth Morphogenesis. J. Cell Sci. 2003, 116, 1647–1648. [Google Scholar] [CrossRef]
  51. Kondo, S.; Schutte, B.C.; Richardson, R.J.; Bjork, B.C.; Knight, A.S.; Watanabe, Y.; Howard, E.; de Lima, R.L.L.F.; Daack-Hirsch, S.; Sander, A.; et al. Mutations in IRF6 Cause Van Der Woude and Popliteal Pterygium Syndromes. Nat. Genet. 2002, 32, 285–289. [Google Scholar] [CrossRef]
  52. Mossey, P.A.; Modell, B. Epidemiology of Oral Clefts 2012: An International Perspective. In Cleft Lip and Palate: Epidemiology, Aetiology and Treatment; Karger Medical and Scientific Publishers: Basel, Switzerland, 2012; Volume 16, pp. 1–18. [Google Scholar] [CrossRef]
  53. Zucchero, T.M.; Cooper, M.E.; Maher, B.S.; Daack-Hirsch, S.; Nepomuceno, B.; Ribeiro, L.; Caprau, D.; Christensen, K.; Suzuki, Y.; Machida, J.; et al. Interferon Regulatory Factor 6 (IRF6) Gene Variants and the Risk of Isolated Cleft Lip or Palate. N. Engl. J. Med. 2004, 351, 769–780. [Google Scholar] [CrossRef] [PubMed]
  54. Blanton, S.H.; Cortez, A.; Stal, S.; Mulliken, J.B.; Finnell, R.H.; Hecht, J.T. Variation in IRF6 Contributes to Nonsyndromic Cleft Lip and Palate. Am. J. Med. Genet. A 2005, 137A, 259–262. [Google Scholar] [CrossRef] [PubMed]
  55. Ghassibé, M.; Bayet, B.; Revencu, N.; Verellen-Dumoulin, C.; Gillerot, Y.; Vanwijck, R.; Vikkula, M. Interferon Regulatory Factor-6: A Gene Predisposing to Isolated Cleft Lip with or without Cleft Palate in the Belgian Population. Eur. J. Hum. Genet. 2005, 13, 1239–1242. [Google Scholar] [CrossRef] [PubMed]
  56. Scapoli, L.; Palmieri, A.; Martinelli, M.; Pezzetti, F.; Carinci, P.; Tognon, M.; Carinci, F. Strong Evidence of Linkage Disequilibrium between Polymorphisms at the IRF6 Locus and Non-syndromic Cleft Lip with or without Cleft Palate, in an Italian Population. Am. J. Hum. Genet. 2005, 76, 180–183. [Google Scholar] [CrossRef]
  57. Srichomthong, C.; Siriwan, P.; Shotelersuk, V. Significant Association between IRF6 820G->A and Non-Syndromic Cleft Lip with or without Cleft Palate in the Thai Population. J. Med. Genet. 2005, 42, e46. [Google Scholar] [CrossRef]
  58. Slayton, R.L.; Williams, L.; Murray, J.C.; Wheeler, J.J.; Lidral, A.C.; Nishimura, C.J. Genetic Association Studies of Cleft Lip and/or Palate with Hypodontia Outside the Cleft Region. Cleft Palate Craniofacial J. 2003, 40, 274–279. [Google Scholar] [CrossRef]
  59. Dewinter, G.; Quirynen, M.; Heidbüchel, K.; Verdonck, A.; Willems, G.; Carels, C. Dental Abnormalities, Bone Graft Quality, and Periodontal Conditions in Patients with Unilateral Cleft Lip and Palate at Different Phases of Orthodontic Treatment. Cleft Palate Craniofacial J. 2003, 40, 343–350. [Google Scholar] [CrossRef]
  60. Vichi, L.M. Franchi Abnormalities of the Maxillary Incisors in Children with Cleft Lip and Palate. ASDC J. Dent. Child. 1995, 62, 412–417. [Google Scholar]
  61. Roth, P.; Hirschfelder, U. Frequency of Tooth Agenesis in CLP Patients with Eruption of All Four Third Molars. Dtsch. Zahnarztl. Z. 1991, 46, 734–736. [Google Scholar]
  62. Lopes, L.D.; Mattos, B.S.; André, M. Anomalies in Number of Teeth in Patients with Lip and/or Palate Clefts. Braz. Dent. J. 1991, 2, 9–17. [Google Scholar] [PubMed]
  63. Carretero Quezada, M.G.; Hoeksma, J.B.; van de Velde, J.P.; Prahl-Andersen, B.; Kuijpers-Jagtman, A.M. Dental Anomalies in Patients with Familial and Sporadic Cleft Lip and Palate. J. Biol. Buccale 1988, 16, 185–190. [Google Scholar] [PubMed]
  64. Ranta, R.; Tulensalo, T. Symmetry and Combinations of Hypodontia in Non-Cleft and Cleft Palate Children. Scand. J. Dent. Res. 1988, 96, 1–8. [Google Scholar] [CrossRef] [PubMed]
  65. Ranta, R. Numeric Anomalies of Teeth in Concomitant Hypodontia and Hyperdontia. J. Craniofacial Genet. Dev. Biol. 1988, 8, 245–251. [Google Scholar]
  66. Ranta, R. Associations of Some Variables to Tooth Formation in Children with Isolated Cleft Palate. Scand. J. Dent. Res. 1984, 92, 496–502. [Google Scholar] [CrossRef] [PubMed]
  67. van den Boogaard, M.J.H.; Dorland, M.; Beemer, F.A.; van Amstel, H.K.P. MSX1 Mutation Is Associated with Orofacial Clefting and Tooth Agenesis in Humans. Nat. Genet. 2000, 24, 342–343. [Google Scholar] [CrossRef]
  68. Pereira, T.v.; Salzano, F.M.; Mostowska, A.; Trzeciak, W.H.; Ruiz-Linares, A.; Chies, J.A.B.; Saavedra, C.; Nagamachi, C.; Hurtado, A.M.; Hill, K.; et al. Natural Selection and Molecular Evolution in Primate PAX9 Gene, a Major Determinant of Tooth Development. Proc. Natl. Acad. Sci. USA 2006, 103, 5676–5681. [Google Scholar] [CrossRef]
  69. Silvestri, A.R.; Singh, I. The Unresolved Problem of the Third Molar: Would People Be Better off without It? J. Am. Dent. Assoc. 2003, 134, 450–455. [Google Scholar] [CrossRef]
  70. Song, F.; O’Meara, S.; Wilson, P.; Golder, S.; Kleijnen, J. The Effectiveness and Cost-Effectiveness of the Prophylactic Removal of Wisdom Teeth. Health Technol. Assess. 2000, 4, 1–55. [Google Scholar] [CrossRef]
  71. Vastardis, H.; Karimbux, N.; Guthua, S.W.; Seidman, J.G.; Seidman, C.E. A Human MSX1 Homeodomain Missense Mutation Causes Selective Tooth Agenesis. Nat. Genet. 1996, 13, 417–421. [Google Scholar] [CrossRef]
  72. Xuan, K.; Jin, F.; Liu, Y.L.; Yuan, L.T.; Wen, L.Y.; Yang, F.S.; Wang, X.J.; Wang, G.H.; Jin, Y. Identification of a Novel Missense Mutation of MSX1 Gene in Chinese Family with Autosomal-Dominant Oligodontia. Arch. Oral Biol. 2008, 53, 773–779. [Google Scholar] [CrossRef] [PubMed]
  73. Zhang, H.; Hu, G.; Wang, H.; Sciavolino, P.; Iler, N.; Shen, M.M.; Abate-Shen, C. Heterodimerization of Msx and Dlx Homeoproteins Results in Functional Antagonism. Mol. Cell. Biol. 1997, 17, 2920–2932. [Google Scholar] [CrossRef]
  74. Mostowska, A.; Biedziak, B.; Jagodzinski, P.P. Novel MSX1 Mutation in a Family with Autosomal-Dominant Hypodontia of Second Premolars and Third Molars. Arch. Oral Biol. 2012, 57, 790–795. [Google Scholar] [CrossRef]
  75. Zhang, M.Q. Statistical Features of Human Exons and Their Flanking Regions. Hum. Mol. Genet. 1998, 7, 919–932. [Google Scholar] [CrossRef] [PubMed]
  76. Pawlowska, E.; Janik-Papis, K.; Wisniewska-Jarosinska, M.; Szczepanska, J.; Blasiak, J. Mutations in the Human Homeobox MSX1 Gene in the Congenital Lack of Permanent Teeth. Tohoku J. Exp. Med. 2009, 217, 307–312. [Google Scholar] [CrossRef]
  77. Boeira Junior, B.R.; Echeverrigaray, S. Polymorphism in the MSX1 Gene in a Family with Upper Lateral Incisor Agenesis. Arch. Oral Biol. 2012, 57, 1423–1428. [Google Scholar] [CrossRef] [PubMed]
  78. Paixão-Côrtes, V.R.; Braga, T.; Salzano, F.M.; Mundstock, K.; Mundstock, C.A.; Bortolini, M.C. PAX9 and MSX1 Transcription Factor Genes in Non-Syndromic Dental Agenesis. Arch. Oral Biol. 2011, 56, 337–344. [Google Scholar] [CrossRef] [PubMed]
  79. Lammi, L.; Arte, S.; Somer, M.; Järvinen, H.; Lahermo, P.; Thesleff, I.; Pirinen, S.; Nieminen, P. Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer. Am. J. Hum. Genet. 2004, 74, 1043–1050. [Google Scholar] [CrossRef]
  80. Wilusz, C.J.; Wang, W.; Peltz, S.W. Curbing the Nonsense: The Activation and Regulation of MRNA Surveillance. Genes Dev. 2001, 15, 2781–2785. [Google Scholar] [CrossRef]
  81. Cartegni, L.; Chew, S.L.; Krainer, A.R. Listening to Silence and Understanding Nonsense: Exonic Mutations That Affect Splicing. Nat. Rev. Genet. 2002, 3, 285–298. [Google Scholar] [CrossRef] [PubMed]
  82. Hsu, W.; Zeng, L.; Costantini, F. Identification of a Domain of Axin That Binds to the Serine/Threonine Protein Phosphatase 2A and a Self-Binding Domain. J. Biol. Chem. 1999, 274, 3439–3445. [Google Scholar] [CrossRef]
  83. Mao, J.; Wang, J.; Liu, B.; Pan, W.; Farr, G.H.; Flynn, C.; Yuan, H.; Takada, S.; Kimelman, D.; Li, L.; et al. Low-Density Lipoprotein Receptor-Related Protein-5 Binds to Axin and Regulates the Canonical Wnt Signaling Pathway. Mol. Cell 2001, 7, 801–809. [Google Scholar] [CrossRef] [PubMed]
  84. Liu, W.; Dong, X.; Mai, M.; Seelan, R.S.; Taniguchi, K.; Krishnadath, K.K.; Halling, K.C.; Cunningham, J.M.; Qian, C.; Christensen, E.; et al. Mutations in AXIN2 Cause Colorectal Cancer with Defective Mismatch Repair by Activating Beta-Catenin/TCF Signalling. Nat. Genet. 2000, 26, 146–147. [Google Scholar] [CrossRef] [PubMed]
  85. Mostowska, A.; Biedziak, B.; Jagodzinski, P.P. Axis Inhibition Protein 2 (AXIN2) Polymorphisms May Be a Risk Factor for Selective Tooth Agenesis. J. Hum. Genet. 2006, 51, 262–266. [Google Scholar] [CrossRef]
  86. Callahan, N.; Modesto, A.; Meira, R.; Seymen, F.; Patir, A.; Vieira, A.R. Axis Inhibition Protein 2 (AXIN2) Polymorphisms and Tooth Agenesis. Arch. Oral Biol. 2009, 54, 45–49. [Google Scholar] [CrossRef]
  87. Vieira, A.R.; Modesto, A.; Meira, R.; Barbosa, A.R.S.; Lidral, A.C.; Murray, J.C. Interferon Regulatory Factor 6 (IRF6) and Fibroblast Growth Factor Receptor 1 (FGFR1) Contribute to Human Tooth Agenesis. Am. J. Med. Genet. A 2007, 143A, 538–545. [Google Scholar] [CrossRef]
  88. Vieira, A.R.; Seymen, F.; Patir, A.; Menezes, R. Evidence of Linkage Disequilibrium between Polymorphisms at the IRF6 Locus and Isolate Tooth Agenesis, in a Turkish Population. Arch. Oral Biol. 2008, 53, 780–784. [Google Scholar] [CrossRef] [PubMed]
Table 1. Number of impacted molars in maxilla and mandible together, and in maxilla and mandible separately in respondents with impacted teeth.
Table 1. Number of impacted molars in maxilla and mandible together, and in maxilla and mandible separately in respondents with impacted teeth.
Location of Impacted TeethImpacted Molars—0
n (%)		Impacted Molars—1
n (%)		Impacted Molars—2
n (%)		Impacted Molars—3
n (%)		Impacted Molars—4
n (%)		Impacted Molars—5
n (%)		Ʃ
Maxilla and mandible1
(0.01)		1
(0.01)		15
(0.14)		24
(0.23)		64
(0.60)		1
(0.01)		106
Maxilla10
(0.26)		13
(0.34)		5
(0.13)		2
(0.05)		8
(0.21)		0
(0.00)		38
Mandible3
(0.05)		17
(0.28)		37
(0.62)		0
(0.00)		3
(0.05)		0
(0.00)		60
Ʃ14315726751204
Table 2. Number of impacted premolars in maxilla and mandible together, and in maxilla and mandible separately in respondents with impacted teeth.
Table 2. Number of impacted premolars in maxilla and mandible together, and in maxilla and mandible separately in respondents with impacted teeth.
Location of
Impacted Teeth		Impacted
Premolars—0
n (%)		Impacted
Premolars—1
n (%)		Impacted
Premolars—2
n (%)		Impacted
Premolars—5
n (%)		Ʃ
Maxilla and mandible103
(0.97)		2
(0.02)		0
(0.00)		1
(0.01)		106
Maxilla37
(0.97)		0
(0.00)		1
(0.03)		0
(0.00)		38
Mandible57
(0.95)		3
(0.05)		0
(0.00)		0
(0.00)		60
Ʃ197511204
Table 3. Number of impacted canines in maxilla and mandible together, and in maxilla and mandible separately in respondents with impacted teeth.
Table 3. Number of impacted canines in maxilla and mandible together, and in maxilla and mandible separately in respondents with impacted teeth.
Location of
Impacted Teeth		Impacted
Canines—0
n (%)		Impacted
Canines—1
n (%)		Impacted
Canines—2
n (%)		Ʃ
Maxilla and mandible103
(0.97)		3
(0.03)		0
(0.00)		106
Maxilla26
(0.68)		11
(0.29)		1
(0.03)		38
Mandible59
(0.98)		1
(0.02)		0
(0.00)		60
Ʃ188151204
Table 4. Frequency of genotypes and alleles of the PAX9 rs4904210, MSX1 rs8670, MSX1 rs12532, AXIN2 rs7591, AXIN2 rs4904210, AXIN2 rs2240308, IRF6 rs642961, IRF6 rs861019, IRF6 rs4904210, and IRF6 rs658860 polymorphisms in respondents with impacted teeth in maxilla and mandible together, and maxilla and mandible separately.
Table 4. Frequency of genotypes and alleles of the PAX9 rs4904210, MSX1 rs8670, MSX1 rs12532, AXIN2 rs7591, AXIN2 rs4904210, AXIN2 rs2240308, IRF6 rs642961, IRF6 rs861019, IRF6 rs4904210, and IRF6 rs658860 polymorphisms in respondents with impacted teeth in maxilla and mandible together, and maxilla and mandible separately.
Location of Impacted TeethGenotypesAlleles
PAX9 rs4904210
GG
n (%)		CC
n (%)		GC
n (%)		G
n (%) 		C
n (%)
Maxilla and mandible
n = 106		42
(0.40)		15
(0.14)		49
(0.46)		133
(0.63)		79
(0.37)
Maxilla
n = 38		19
(0.50)		7
(0.18)		12
(0.32)		50
(0.66)		26
(0.34)
Mandible
n = 58		20
(0.34)		11
(0.19)		27
(0.47)		67
(0.58)		49
(0.42)
χ2
p-value
φ
Statistical test power		3.592
0.4640
0.13
0.28		1.394
0.4982
0.06
0.17
MSX1 rs8670
CC
n (%)		TT
n (%)		CT
n (%)		C
n (%) 		T
n (%)
Maxilla and mandible
n = 106		50
(0.47)		5
(0.05)		51
(0.48)		151
(0.71)		61
(0.29)
Maxilla
n = 38		27
(0.71)		2
(0.05)		9
(0.24)		63
(0.83)		13
(0.17)
Mandible
n = 58		36
(0.62)		8
(0.14)		14
(0.24)		86
(0.74)		30
(0.26)
χ2
p-value
φ
Statistical test power		15.876 *
0.0031
0.28
0.91		3.986.
0.1363
0.10
0.42
MSX1 rs12532
AA
n (%)		GG
n (%)		AG
n (%)		A
n (%) 		G
n (%)
Maxilla and mandible
n = 106		65
(0.61)		6
(0.06)		35
(0.33)		165
(0.78)		47
(0.22)
Maxilla
n = 38		11
(0.29)		8
(0.21)		19
(0.50)		41
(0.54)		35
(0.46)
Mandible
n = 59		34
(0.58)		5
(0.08)		20
(0.34)		88
(0.75)		30
(0.25)
χ2
p-value
φ
Statistical test power		15.104 *
0.0044
0.27
0.89		16.364 *
0.0003
0.20
0.96
AXIN2 rs7591
TT
n (%)		AA
n (%)		TA
n (%)		T
n (%) 		A
n (%)
Maxilla and mandible
n = 106		44
(0.42)		19
(0.18)		43
(0.41)		131
(0.62)		81
(0.38)
Maxilla
n = 38		7
(0.18)		9
(0.24)		22
(0.58)		36
(0.47)		40
(0.53)
Mandible
n = 59		20
(0.33)		14
(0.23)		26
(0.43)		66
(0.56)		52
(0.44)
χ2
p-value
φ
Statistical test power		7.013
0.1352
0.185
0.54		4.904
0.0861
0.11
0.50
AXIN2 rs4904210
CC
n (%)		TT
n (%)		CT
n (%)		C
n (%) 		T
n (%)
Maxilla and mandible
n = 106		55
(0.52)		11
(0.10)		40
(0.38)		150
(0.71)		62
(0.29)
Maxilla
n = 38		13
(0.34)		8
(0.21)		17
(0.45)		43
(0.57)		33
(0.43)
Mandible
n = 60		30
(0.50)		7
(0.12)		23
(0.38)		83
(0.69)		37
(0.31)
χ2
p-value
φ
Statistical test power		4.833
0.3050
0.15
0.36		5.316
0.0701
0.11
0.50
AXIN2 rs2240308
AA
n (%)		GG
n (%)		AG
n (%)		A
n (%) 		G
n (%)
Maxilla and mandible
n = 106		32
(0.30)		22
(0.21)		52
(0.49)		116
(0.55)		96
(0.45)
Maxilla
n = 38		5
(0.13)		15
(0.39)		18
(0.47)		28
(0.37)		48
(0.63)
Mandible
n = 58		23
(0.40)		10
(0.17)		25
(0.43)		71
(0.61)		45
(0.39)
χ2
p-value
φ
Statistical test power		11.210 *
0.0243
0.235
0.77		11.351 *
0.0034
0.17
0.87
IRF6 rs642961
GG
n (%)		AA
n (%)		GA
n (%)		G
n (%) 		A
n (%)
Maxilla and mandible
n = 106		74
(0.70)		3
(0.03)		29
(0.27)		177
(0.83)		35
(0.17)
Maxilla
n = 38		26
(0.68)		0
(0.00)		12
(0.32)		64
(0.84)		12
(0.16)
Mandible
n = 59		41
(0.69)		2
(0.03)		16
(0. 27)		98
(0.83)		20
(0.17)
χ2
p-value
φ
Statistical test power		1.412
0.8420
0.08
0.12		0.072
0.9648
0.01
0.05
IRF6 rs861019
AA
n (%)		GG
n (%)		AG
n (%)		A
n (%) 		G
n (%)
Maxilla and mandible
n = 106		25
(0.24)		18
(0.17)		63
(0.59)		113
(0.53)		99
(0.47)
Maxilla
n = 38		8
(0.21)		5
(0.13)		25
(0.66)		41
(0.54)		35
(0.46)
Mandible
n = 59		18
(0.51)		10
(0.17)		31
(0.53)		67
(057)		51
(0.43)
χ2
p-value
φ
Statistical test power		2.025
0.7312
0.10
0.17		0.379
0.8276
0.03
0.08
IRF6 rs4904210
TT
n (%)		CC
n (%)		TC
n (%)		T
n (%) 		C
n (%)
Maxilla and mandible
n = 106		43
(0.41)		13
(0.12)		50
(0.47)		136
(0.64)		76
(0.36)
Maxilla
n = 38		12
(0.32)		5
(0.13)		21
(0.55)		45
(0.59)		31
(0.41)
Mandible
n = 58		23
(0.40)		9
(0.16)		26
(0.45)		72
(0.62)		44
(0.38)
χ2
p-value
φ
Statistical test power		1.461
0.8336
0.085
0.13		0.605
0.7391
0.04
0.10
IRF6 rs658860
TT
n (%)		CC
n (%)		TC
n (%)		T
n (%) 		C
n (%)
Maxilla and mandible
n = 106		74
(0.70)		3
(0.03)		29
(0.27)		177
(0.83)		35
(0.17)
Maxilla
n = 37		26
(0.70)		0
(0.00)		11
(0.30)		63
(0.85)		11
(0.15)
Mandible
n = 57		39
(0.68)		1
(0.02)		17
(0.30)		95
(0.83)		19
(0.17)
χ2
p-value
φ
Statistical test power		1.240
0.8715
0.08
0.12		0.129
0.9374
0.02
0.06
p—statistical significance, χ2—Chi2 test result, n—number of subjects, *—significant statistical differences, φ—effect size.
Table 5. Comparison of allele and genotype frequencies for MSX1 NM_002448.3:c.*6C>T (rs8670) and NM_002448.3:c.*276A>G (rs12532), and AXIN2 NM_004655.3:c.148C>T (rs2240308) variants between study and control groups.
Table 5. Comparison of allele and genotype frequencies for MSX1 NM_002448.3:c.*6C>T (rs8670) and NM_002448.3:c.*276A>G (rs12532), and AXIN2 NM_004655.3:c.148C>T (rs2240308) variants between study and control groups.
MSX1 rs8670Control Group (n = 186)Study Group (n = 202)pa
CC (n = 228)115 (61.8%)113 (55.9%)0.487 (χ² 1.44)
CT (n = 134)60 (32.3%)74 (36.6%)
TT (n = 26)11 (5.9%)15 (7.4%)
C 0.760.780.740.228 (χ² 1.46)
T 0.240.220.26
HWE
χ² = 1.07; pb = 0.301χ² = 0.7; pc = 0.403χ² = 0.35; pd = 0.554
MSX1 rs12532Control group (n = 186)Study group (n = 202)pa
AA (n = 209)99 (53.2%)110 (54.2%)0.925 (χ² 0.16)
AG (n = 145)71 (38.2%)74 (36.5%)
GG (n = 35)16 (8.6%)19 (9.4%)
A 0.720.720.720.975 (χ² 0.001)
G 0.280.280.28
HWE
χ² = 1.8; pb = 0.180χ² = 0.41; pc = 0.522χ² = 1.56; pd = 0.212
AXIN2 rs2240308Control group (n = 186)Study group (n = 202)pa
AA (n = 113)53 (28.5%)60 (29.7%)0.695 (χ² 0.73)
AG (n = 190)95 (51.1%)95 (47.0%)
GG (n = 85)38 (20.4%)47 (23.3%)
A 0.540.540.530.820 (χ² 0.05)
G 0.460.460.47
HWE
χ² = 0.09; pb = 0.764χ² = 0.15; pc = 0.699χ² = 0.62; pd = 0.431
pa—values calculated for allele and genotype frequency comparisons between control and study groups; pb—values calculated for genotype Hardy–Weinberg proportions in all participants (control and study groups analyzed together); pc—values calculated for genotype Hardy–Weinberg proportions in control group; pd—values calculated for genotype Hardy–Weinberg proportions in study group; HWE—Hardy–Weinberg equilibrium.
Table 6. Number of impacted teeth in study group patients.
Table 6. Number of impacted teeth in study group patients.
Number of Impacted Teethn%
14421.6
25527.0
32813.7
4 and more7737.7
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Trybek, G.; Jaroń, A.; Gabrysz-Trybek, E.; Rutkowska, M.; Markowska, A.; Chmielowiec, K.; Chmielowiec, J.; Grzywacz, A. Genetic Factors of Teeth Impaction: Polymorphic and Haplotype Variants of PAX9, MSX1, AXIN2, and IRF6 Genes. Int. J. Mol. Sci. 2023, 24, 13889. https://doi.org/10.3390/ijms241813889

AMA Style

Trybek G, Jaroń A, Gabrysz-Trybek E, Rutkowska M, Markowska A, Chmielowiec K, Chmielowiec J, Grzywacz A. Genetic Factors of Teeth Impaction: Polymorphic and Haplotype Variants of PAX9, MSX1, AXIN2, and IRF6 Genes. International Journal of Molecular Sciences. 2023; 24(18):13889. https://doi.org/10.3390/ijms241813889

Chicago/Turabian Style

Trybek, Grzegorz, Aleksandra Jaroń, Ewa Gabrysz-Trybek, Monika Rutkowska, Aleksandra Markowska, Krzysztof Chmielowiec, Jolanta Chmielowiec, and Anna Grzywacz. 2023. "Genetic Factors of Teeth Impaction: Polymorphic and Haplotype Variants of PAX9, MSX1, AXIN2, and IRF6 Genes" International Journal of Molecular Sciences 24, no. 18: 13889. https://doi.org/10.3390/ijms241813889

APA Style

Trybek, G., Jaroń, A., Gabrysz-Trybek, E., Rutkowska, M., Markowska, A., Chmielowiec, K., Chmielowiec, J., & Grzywacz, A. (2023). Genetic Factors of Teeth Impaction: Polymorphic and Haplotype Variants of PAX9, MSX1, AXIN2, and IRF6 Genes. International Journal of Molecular Sciences, 24(18), 13889. https://doi.org/10.3390/ijms241813889

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop