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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 31-37

Evaluation of MSX1 gene as the common candidate gene of nonsyndromic congenital hypodontia and cleft lip and palate


1 Department of Orthodontics, Faculty of Dentistry, Ankara University, Ankara, Turkey
2 Gölbasi Oral and Dental Health Center, Ankara, Turkey
3 Intergen Genetic Diagnosis and Research Center, Ankara, Turkey

Date of Web Publication21-Nov-2017

Correspondence Address:
Ayse Tuba Altug
Department of Orthodontics, Faculty of Dentistry, Ankara University, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jclpca.jclpca_87_17

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  Abstract 

Introduction and Aim: Cleft lip and palate (CLP) is complex craniofacial deformity in which both the environmental and genetic factors play a role. Congenital hypodontia is the absence of permanent teeth. As congenitally missing maxillary lateral incisors (CMML) and CLP both occur at the suture between premaxilla and maxillary posterior segments, this finding has directed us to investigate if both anomalies could be affected by the same genetic factors. Therefore, the aim of our study is to investigate if there is a common genetic pattern between the occurrence of CLP and congenitally CMMLs. Subjects and Methods: Muscle Segment Homeobox-1 (MSX1) is one of the common candidate genes of hypodontia and CLP. In this study, the role of MSX1 for CLP and CMML was evaluated. The CLP and CMML groups were consisted of 51 and 48 participants, respectively. 3cc blood samples with EDTA were collected and genomic deoxyribonucleic acids were isolated. To screen for putative mutations, two exons of MSX1 gene as well as their exon–intron boundaries were amplified by the PCR and analyzed with Sanger sequencing method. Results: In both groups, the same SNP (c. *6C>T, rs 8670) which is localized in 3'untranslated region of MSX1 gene was detected. Minor allele frequency, heterozygosity, and Chi-square test for Hardy–Weinberg equilibrium at c. *6C>T variation were computed. The expected wild-type, heterozygous, and homozygous allele frequencies of c. *6C>T variation were % 65.61, % 30.78, and % 3.61, respectively. However, the frequencies were %47.9, %45.8, and %6.3 in CMML group and %80.4, %11.8, and % 7.8 in CLP group. These frequencies were diverted from normal for both groups, and the differences between the groups were statistically significant P < 000.1 (Chi-square test). Conclusion: The existence of common polymorphisms and diversions from the normal population in the 3'untranslated region of the MSX1 gene is supporting the hypothesis of a possible relationship between CLP and CMML incisors.

Keywords: Cleft lip and palate, congenitally missing maxillary lateral incisors, deoxyribonucleic acid, genetics, Muscle Segment Homeobox-1, tooth agenesis


How to cite this article:
Altug AT, Senol A, Ozkepir ON, Dogan H, Ceylaner S, Ozdiler E. Evaluation of MSX1 gene as the common candidate gene of nonsyndromic congenital hypodontia and cleft lip and palate. J Cleft Lip Palate Craniofac Anomal 2017;4, Suppl S1:31-7

How to cite this URL:
Altug AT, Senol A, Ozkepir ON, Dogan H, Ceylaner S, Ozdiler E. Evaluation of MSX1 gene as the common candidate gene of nonsyndromic congenital hypodontia and cleft lip and palate. J Cleft Lip Palate Craniofac Anomal [serial online] 2017 [cited 2022 Jan 27];4, Suppl S1:31-7. Available from: https://www.jclpca.org/text.asp?2017/4/3/31/218899


  Introduction Top


Cleft lip and palate (CLP) is complex craniofacial deformity, and it can occur in an isolated form and is called “nonsyndromic” or as a finding of a specific syndrome which can be Mendelian, teratogenic, or chromosomal. If CLP is a part of a syndrome, then it will be called “syndromic” [Figure 1].[1],[2],[3]
Figure 1: Bilateral complete cleft lip and palate (from Dr. A. Altuǧ archive)

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Congenitally missing teeth (hypodontia) can be simply defined as a condition in which the number of the teeth in the mouth is less than it has to be as a result of the failure of development of the teeth. Hypodontia can also occur as an isolated anomaly (nonsyndromic hypodontia) or occur in association with syndromes (syndromic hypodontia) such as CLP. Both CLP and tooth agenesis are complex disorders, and genetic and environmental factors play a role in their etiology.[4],[5],[6]

The most frequently missing teeth are maxillary lateral incisors, and they are most likely missing bilaterally [Figure 2].[5],[6] Or, if one of the maxillary lateral incisors is missing on one side, its reciprocal may show morphological disorders [Figure 3]. CLP can also be seen as uni- or bilaterally. And interesting enough, both conditions are seen on the left side more than on the right side.[1],[2],[7],[8] In addition, both clefts of lip and alveoli and the lateral incisor agenesis occur at the same region which is the sutures between premaxilla and maxillary posterior segments [Figure 4]. These similarities brought a question whether both anomalies are being affected by the similar genetic factors.
Figure 2: Bilateral missing maxillary lateral incisor (from Dr. A. Altuǧ's archive)

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Figure 3: Missing maxillary lateral incisor on the right side, shape anomaly on the left maxillary lateral incisor (from Dr. A. Altuǧ's archive)

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Figure 4: The sutural region where both cleft lip and palate and also missing maxillary lateral incisors or deformity of the same are seen (Gray's Anatomy of the Human Body. 20th Ed. Lea and Febiger Publishers, Philadelphia and New York.)[36]

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Therefore, the aim of our study is to investigate if there is a common genetic pattern between the occurrence of CLP and congenitally missing maxillary lateral (CMML) incisors.

Genetic terminology

The amazing order of our genes is our identity what makes us “one” and differs from each other. Genetic data are stored on deoxyribonucleic acid (DNA). DNA is a nucleic acid that carries the genetic instructions needed for life functions and biological development of all organisms and some viruses. Genetic code is written by an alphabet consisting of A (adenine), T (thymine), G (guanine), C (cytosine) nucleotides (nucleobases), meaning genetic letters.

The final product of gene expression is specific proteins. The reason to define a protein “specific” is based on the reality that it is made of 20 different amino acids. As soon as the proteins are made, due to their activity or the location in the cell, phenotypic characters are formed. In a case like a mutation that will cause a gene to alter, the chemical structure of the DNA changes. When the mutation is in the gamete cells, it is inherited to the following generations and spreads in the population. This genetic diversity is the raw material of the evolution.[8],[9]

Polymorphisms are single nucleotide changes in the different sequence alternated (alleles) DNAs, which are common in normal individuals. These polymorphisms are usually dependent on other polymorphisms or some other environmental factors to develop a disorder or finding.[8] Polymorphisms have a considerably important role not only in the development of disorders but also in the occurrence of individual differences. Sometimes, they do not cause disorders but reduce or increase the symptoms of the disorder. Some of the differences defined as polymorphisms earlier are found out to be mutations with mild effects that cause future disorders. In summary, there is no clear borderline between mutation and polymorphism.

DNA analyses are the directly used molecular approaches for defining such genetic differences between individuals in a population. These methods are important tools to determine and evaluate genetic variations between and within populations.[9]

Except organisms such as bacteria, virus, and yeast, in nearly all organisms, the chromosomes appear in pairs and members in each pair are named as homologous chromosomes. Each chromosome forming the homologous chromosome pair shows a high-degree genetic similarity with the other. They have same gene regions called “locus” among their length. One of the members of the homologous chromosomes comes from the female parent and other from the male parent. Each pair of gene pairs, while affecting the same property, can be different from each other. There can be many different alternatives of the same gene, called allele, among the individuals of the same species. Two alleles being same or one being dominant over the other plays an effective role in the formation of physical properties, characteristics. Having two alleles with same properties in the loci of the chromosomes is called homozygosis. These two alleles affect the formation of the characteristic in the same direction (Example: AA or aa). Having two alleles with different properties in reciprocal areas (loci) of a chromosome is called heterozygosis. In this situation, these two alleles affect the formation of the characteristic in opposite directions (Example: Aa).[9]

Polymerase chain reaction (PCR) is the foundation of many of the genetic analyses today and is used to amplify a single copy or a few copies of a piece of DNA across several orders of magnitude and generate thousands to millions of copies of a particular DNA sequence. PCR is a cost-effective method that enables to copy, in other words, clones the gene region many times that is planned to be worked on. Dr. Kary Banks Mullis won the Chemistry Nobel Prize with the PCR technique which he developed in 1993.[10]

Muscle segment homeobox-1 gene and craniofacial development

Hundreds of candidate genes were identified that considered to be related to odontogenesis and cleft lip and palate formation. However, the most important genes that are thought to have major effects in craniofacial development are in MSX gene family. Thus, in our research, a member of this family Muscle Segment Homeobox-1 (MSX1) gene was decided as a candidate gene to be researched. MSX1 resides on the short arm of the 4- chromosome (locus 4p16) and regulates the activity of other genes [Figure 5].[11] MSX1 gene was reported to code transcription factors function in various phases of teeth development.[12] The mutation of this gene is also correlated with the nonsyndromic cleft lip and palate, Witkop syndrome, Wolf–Hirschhorn syndrome, and autosomal dominant hypodontia.
Figure 5: MSX1 gene and genes it is related with (http://string-db.org/cgi/network.pl?taskId=PyG1GyfCxhfJ)[37]

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In expression studies, MSX1 was detected to be expressed in various tissues during embryonic development. The frequently expressed regions for MSX1 are the regions in which ectodermal-mesenchymal interactions occur during craniofacial bone and dental development.[13] Therefore, MSX1 being especially effective in craniofacial and dental development was shown with many studies. In mice with MSX1 gene knockout, craniofacial defects were seen including secondary palate clefts, facial bone deformities, malleus deformities that reside in the middle ear, and teeth agenesis.[14] MSX1 gene also is on the center of the signalization network in the frontal palate region. Thus, in many experimental CLP studies, mice lacking MSX1 function (MSX1-/-, MSX1 knockout) were used.[15] MSX1 inactivation caused cleft palate and teeth agenesis in mice and shortened the maxillary phenotype. Furthermore, in many human linkage and linkage disequilibrium studies, MSX1 mutations are shown to be effective in formation of nonsyndromic CLP.[16],[17] Studies showed that DNA variations in MSX1 are related with CLP, and the MSX1 mutations are found in 2% of cases of nonsyndromic clefting; MSX1 is reported to be active in both primary and secondary palatogenesis.[17],[18]

Hypothesis of the study

Ozkepir reported that the missing teeth are most frequently seen in maxillary lateral incisors, generally bilateral [Figure 2] or even without being missing, there is a form anomaly in the symmetrical tooth [Figure 3].[19] In addition, cytosine-thymine alteration at the noncoding (UTR) 3' end of the second exon (MSX1-c. *6C>T) of MSX1 gene is shown to be possibly effective in missing maxillary lateral incisor.[19] This alteration is registered in dbSNP database as “rs8670” polymorphism. The detection of this polymorphism is a very important finding because this polymorphism is a variation that was correlated with CLP previously. Modesto et al., in their study on individuals with CLP, reported that MSX1 gene c. *6C>T variant is correlated with oral clefts.[20] Therefore, results of both studies reinforce a possible relationship specifically between missing maxillary lateral incisors and CLP. The clefts on lips and alveoli and the congenitally missing upper lateral incisor teeth being on the same region (sutura between premaxilla and maxillary posterior segments) intensify the hypothesis that both anomalies can be affected by the similar genetic factors [Figure 4]. Furthermore, in the conducted studies, the data on both incisors with atypical form and cleft lip and palate being more commonly seen on the left side, bring out a possible relation between CLP and missing teeth.

In previous studies, the genetic studies related to CLP and maxillary lateral incisors were limited to familial evaluation or candidate gene studies. There was no study found that evaluate these two anomalies together. In the light of this data, the aim of our research is to search whether there is a relationship due to similar genetic mechanisms and common genes in between individuals with nonsyndromic cleft lip and palate and individuals with CMML teeth without “a cleft lip and palate” or not. This study is planned to investigate the hypothesis that was suggested by Ozkepir if “missing maxillary lateral incisors is a mild form of CLP.”[19]


  Subjects and Methods Top


Hundreds of candidate genes were identified regarding odontogenesis and CLP formation. In our research, MSX1 gene was investigated. A total of 99 individuals were included in our study; 51 individuals (22 females, 29 males; ages: 0–24) with nonsyndromic cleft lip and palate and 48 individuals (39 females, 9 males; ages: 9–22) with CMML teeth among patients who were referred to Ankara University, Faculty of Dentistry, Department of Orthodontics [Table 1]. Control group data for genetic evaluation were obtained from the data pool of healthy individuals (Intergen Genetic Diagnosis and Research Center, Ankara). As the evaluations of the study were carried on blood samples at DNA level, individuals being at a specific age category have not been demanded. The individuals to be included in our study were differentiated by medical anamnesis and genetic consultations whether they have a syndromic background or not. Ethical board approval was taken and informed consent forms were signed.
Table 1: Chronological ages of cleft lip-palate and congenitally missing lateral incisor participants

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Genetic testing

The peripheral blood samples were taken from the individuals; DNAs required for genetic analyzer were amplified by PCR. DNA extractions were done using QIAamp DNA Blood Mini Kit from peripheral blood samples, and collected DNAs were kept at −20°C until PCR. Both forward and reverse PCR primers were designed for 2 protein-coding exons of MSX1 gene and sequence analysis was made. Nucleotide sequence analysis was performed by the Sanger dideoxynucleotide procedure. Obtained sequence modifications were searched in HGMD, dbSNP, 1000 genomes, and EXAC databases, and the modifications that were not in these databases were evaluated functionally by the help of in silico evaluation tools (such as Mutation taster, SIFT, SIFT provean, Polyphen2, and Human Splicing Finder).


  Results Top


The focused variation for this study was MSX1-c. *6C>T as it was named as a risk factor for CLP and CMML incisors.[19],[20]

CLP, maxillary lateral missing patients' data and Turkish control group, and Asia, Europe, and World population data from 1000 genome studies[21] were given comparatively in [Table 2].
Table 2: Examining differences between groups regarding the msx1-c.*6 C > T variable, control group and 1000 genome study data comparison

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When differences between groups regarding this variable are examined, both CLP and missing lateral groups had deviations from normal. The result showed that T allele carriers, both in heterozygote and homozygote status, were more than control group and 1000 genome studies' population data (The 1000 Genomes Project Consortium).[21] Especially homozygote individuals were 4–5 times more in both patient groups compared to control group (TT; 7.8 in CLP, 6.3 in missing lateral, and 1.6 in Turkish controls). Heterozygote individuals were seven times more in maxillary missing lateral group compared to control group (CT; 45.8 in missing lateral and 6.4 in Turkish controls), whereas it was two times more in CLP group compared to control group (CT; 11.8 in CLP and 6.4 in Turkish controls).

These results suggest that the risk of cleft lip and palate is higher in thymine-thymine homozygote individuals while both homozygote or heterozygote thymine-cytosine changes increase the risk for missing lateral incisors [Table 3].
Table 3: The risk incidences for cleft lip and palate and congenitally missing maxillary lateral incisors

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  Discussion Top


Cleft lip and palate and congenital missing teeth are congenital anomalies that are frequently seen in our clinics. The etiology of both problems is considerably complicated.[1],[22],[23],[24]

In living beings with cleft lip and palate, the occurrence of CMML incisors was frequently reported both in animal[13],[25] and human studies.[25],[26] van den Boogaard et al. (2000) investigated 12 affected family members with various combinations of cleft lip, cleft palate, and tooth agenesis.[25] In cleft lip and palate and congenitally missing teeth cases, another family member is almost always affected by the same reasons. This is an unclear but an interesting and common fact about these two clinical situations.[19],[26],[27],[28],[29],[30]

Furthermore, in other studies performed, it is emphasized that if an individual has a CMML tooth, the symmetrical tooth is also missing or it has a morphological anomaly.[5],[19],[31] This finding suggests the question whether both conditions are the result of same genetic factor or not. Furthermore, Hua et al. reported in their meta-analysis study that atypical maxillary lateral incisors are more frequently seen on the left side.[31] Agreeing with this result but in a matter of cleft lip and palate situations, Gundlach and Maus and Zhou et al. again mentioned the left side.[32],[33]

Apart from the studies summarized above, Ozkepir examined the genetic background for CMML incisors and examined two candidate genes (MSX1 and PAX9).[19] She reported that the cytosine-thymine alteration at the noncoding (UTR) 3' end of the second exon (MSX1-c. *6C>T) is evident in most of the missing lateral participants. Boeira and Echeverrigaray also examined a family showing maxillary lateral teeth agenesis in their study and showed homozygote MSX1-c. *6C>T polymorphism in three individuals with agenesis.[34] A previous study by Modesto et al. specifically mentioned about MSX1-c. *6C>T alteration for CLP participants.[20] van den Boogaard et al. also mentioned about the CLP brother of a sister with hypodontia and suggested if teeth agenesis could turn into CLP in future generations for this family.[29] Those studies arise a question in our minds as “Could cleft lip and palate and missing of maxillary lateral incisors have similar genetic background?”

Nonsyndromic forms of the congenital anomalies such as CLP and hypodontia are assumed to be the result of both genetic and environmental factors. Clinically determined phenotype occurs when the effect of these factors raise over a certain threshold. This situation is also called the multifactorial threshold model. However, lately, the studies using segregation analysis methods linked the occurrence of the disorder not to the total of the effects of many factors with low-degree effects to be able to raise over a threshold but to fewer genetic factors with major effects to raise the disorder risk.[35]

The data gathered in our study suggest that MSX1-c. *6C>T alteration is not the only factor, however, one of the major factors in occurrence of CLP and missing maxillary lateral incisors. Our results suggest that homozygous polymorphism (thymine-thymine) is more precarious for CLP while both homozygous (thymine-thymine) and heterozygous (cytosine-thymine) alterations could be considered to be effective for lateral incisor agenesis. Even if in the heterozygote genotype (CT), T allele increases the risk of missing of maxillary lateral incisors significantly. However, homozygote genotype (TT) seems to be significantly more risky for the occurrence of clefts. Those results support our hypothesis that the missing maxillary lateral could be a mild form of CLP.


  Conclusion and Clinical Implication Top


As a result of our pilot study, the MSX1-c. *6C>T alteration was found to be different from normal population in both cleft lip and palate and also in teeth missing individuals.

This study shows that MSX1-c. *6C>T alteration is one of the major etiological factors for both cleft lip and palate and congenital missing of maxillary lateral incisors.

The detected mutation which occurs in the untranslated promoter region of MSX1 (c. *6C>T) gene and deviations from normal support that there is a connection between both conditions and they may have a common etiological background.

These results can enlighten new research projects that can prevent the occurrence of cleft lip and palate and improve potential gene therapies.

To understand the role and contribution of the other factors in the total effect, the second study with these patients should be carried out by “exon sequencing” that enables to scan all the gene coding regions that belong to an individual.

In summary, these findings, in fact, support our hypothesis that the missing maxillary lateral could be a mild form of CLP.

Acknowledgment

This pilot study was carried out on the data from projects that was supported by Ankara University Scientific Research Projects Coordination (“Evaluation of the Individuals with Non-Syndromic Isolated or Complete Lip-Palate Clefts by Genetic Analyzer” [Project No: 11B3334009] and “Evaluation of gene polymorphisms in nonsyndromic hypodontia cases” [Project No: 13 L3334001]). We would like to thank Intergen Genetic Diagnosis Research and Application Center which gave us scientific support in both projects.

The part related with CMML incisors was presented at the 14th International Congress of the Turkish Orthodontic Society (October 25–29, 2014, Ankara, Turkey) as an oral presentation and was awarded Best Research on Orthognathic Surgery. The part related with CLP is nominated for the best research and will be presented at the 15th International Symposium of the Turkish Orthodontics Society (November 5–7, 2017, Ankara, Turkey).

This recent study was presented at the International Cleft Congress 2017, Chennai, India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.[37]

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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