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. 2023 Mar 10;243(1):167–173. doi: 10.1111/joa.13855

Assessing the relationship between single nucleotide polymorphisms in Wingless signaling pathway genes and sella turcica morphology

João Armando Brancher 1,✉, Rodrigo Schuh 1, Maria Fernanda Pioli Torres 1, Jordanna de Melo Teixeira do Brasil 2, Maria Angélica Hueb 2, Carlos Alexandre dos Santos Haemmerle 1, Peter Proff 3, Mohammad Khursheed Alam 4, Christian Kirschneck 3, Erika Calvano Küchler 2,3,5
PMCID: PMC10273339  PMID: 36898853

Abstract

Sella turcica development involves molecular factors and genes responsible for ossification. It is possible that single nucleotide polymorphisms (SNPs) in key genes are involved in morphological variation of sella turcica. Genes belonging to the WNT signaling pathway are involved in the ossification process and are candidates of sella turcica morphology. This study aimed to evaluate if SNPs in WNT6 (rs6754599) and WNT10A (rs10177996 and rs3806557) genes are associated with the calcification and patterns of the sella turcica. Nonsyndromic individuals were included in the research. Cephalometric radiographs were examined and the sella calcification was evaluated and classified according to the calcification of the interclinoid ligament (no calcification, partial calcification, and incomplete calcification) and sella turcica pattern (normal sella turcica, bridge type A—ribbon‐like fusion, bridge type B—extension of the clinoid processes, incomplete bridge, hypertrophic posterior clinoid process, hypotrophic posterior clinoid process, irregularity in the posterior part, pyramidal shape of the dorsum, double contour of the floor, oblique anterior wall, and oblique contour of the floor). DNA samples were used to evaluate SNPs in the WNT genes (rs6754599, rs10177996, and rs3806557) using real‐time PCR. Chi‐square test or Fisher's exact test were used to compare the allele and genotype distributions according to sella turcica phenotypes. The alpha was set as 5% for all comparisons. A total of 169 individuals were included, 133 (78.7%) present sella turcica partially or completely calcified. Sella turcica anomalies were found in 131 individuals (77.5%). Sella turcica bridge type A (27.8%), posterior hypertrophic clinoid process (17.1%), and sella turcica bridge type B (11.2%) were the most prevalent morphological patterns observed. Individuals carrying the TT genotype in rs10177996 (TT vs. CT + CC) had higher chance to present a partially calcified sella turcica (p = 0.047; Odds ratio = 2.27, Confidence Interval 95% 1.01–5.13). In conclusion, the SNP in WNT10A is associated with the calcification phenotype of the sella turcica, the pleiotropic effect of this gene should be taken into consideration in future studies.

Keywords: morphology, sella turcica, single nucleotide polymorphisms, sphenoid bone, WNT gene

Sella turcica development and ossification are regulated by molecular factors that depend on genetic information. This study investigated the association between single nucleotide polymorphisms (SNPs) in the WNT signaling pathway genes and the morphology of the sella turcica. After analyses of DNA samples, WNT10A gene showed an association with the calcification phenotype of the sella turcica. The pleiotropic effect of this gene should be considered in future anatomical studies of the sella.

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1. INTRODUCTION

The human skull consists of 22 bones linked by cranial sutures designed to support and protect its inner content (Anderson et al., 2022). The complex structure of the human skull, as we know it today, is the result of physiological and environmental adaptations that occurred during the evolutionary process, and that provided a craniofacial pattern of growth and development used to identify populational groups in anthropometric and evolutionary studies (González‐José et al., 2004). In fact, the morphology of the skull allows tracing a profile of the anatomical pattern of the individuals (Fuyamada et al., 2011; Rupa et al., 2015; Sidlauskas et al., 2016). The sphenoid bone, located deep at the skull base level, is recognized as one of the most difficult bones to be studied once its anatomical configuration is intricated. It is the typical bone that can be called a polymorphous bone (Costea et al., 2018). Besides forming the middle cranial fossa floor, this bone has several anatomical details such as channels, fissures, and foramina that allow the passage of nerves, arteries, and veins across it (Ramos et al., 2021; Roomaney & Chetty, 2021). The sphenoid bone's intricate morphology can be divided into four main parts: greater wings, lesser wings, pterygoid processes, and the body (Er et al., 2020; Roomaney & Chetty, 2021).

On the superior surface of the sphenoid body appears a depression similar to the saddle used by Turkish knights, hence the name sella turcica where the pituitary gland is found (Tekiner et al., 2015). The pituitary gland produces a range of hormones and is associated with a variety of conditions (Stratakis, 2022; Tudor & Thompson, 2019). Sella turcica morphology includes four clinoid processes, two anterior and two posterior, tuberculum, dorsum sellae and, in some cases, sella bridging that is a partial or total calcification of the interclinoid ligaments. In addition, sella morphology depends on the development of the pituitary gland and the pattern of sella development is responsible for its size and shape (Kjaer, 2015). In fact, these alterations reflect different patterns of sella calcification that, in previous studies, have been associated with dental aspects (Dadgar et al., 2021; Scribante et al., 2017), craniofacial growth variations (Kucia et al., 2014; Roomaney & Chetty, 2021), and genetic syndromes (Axelsson et al., 2004). The fact that patients with genetic syndromes present differences in the sella turcica morphology (Axelsson et al., 2004; Roomaney & Chetty, 2021) clearly indicates that genetic factors play a pivotal role in sella turcica development and pattern.

It is well‐known that molecular factors are responsible for endochondral ossification of the skull base, including the sphenoid bone (Jin et al., 2016). This ossification process depends on inductive epithelial–mesenchymal cell interactions during embryogenesis (Hay, 2005). WNT (Wingless) signaling pathway genes are fundamental to almost every aspect of embryogenesis, once they codify proteins that act in formation, adhesion, cell–cell communication (Krawetz & Kelly, 2008), and bone morphogenesis (Doolan et al., 2021). Studies in animal models demonstrated that WNT signaling is critical in the development of the craniofacial structures, including head, brain, and face (Mani et al., 2010; Marchini et al., 2021). Besides the regulation of bone development during embryogenesis, WNT signaling is also well known due to its role in bone turnover and remodeling (Baron & Hesse, 2012; Kobayashi et al., 2008). Therefore, in this study, we evaluated, if single nucleotide polymorphisms (SNPs) in WNT6 (rs6754599) and WNT10A (rs10177996 and rs3806557) genes are associated with the calcification pattern of sella turcica in a sample of nonsyndromic individuals. Furthermore, we also investigated the genotype frequency between these individuals according to sella turcica patterns.

2. MATERIALS AND METHODS

2.1. Study design

This is a nested case–control study which was approved by the Ethics Committee from the University of Regensburg (# 19–1549‐101, revised and accepted in 2019) and was prepared according to the Strengthening the Reporting of Genetic Association (STREGA) (Little et al., 2009). Appropriate written informed consent was obtained from all patients. Also, assent was obtained from patients younger than 18 years. Inclusion criteria were nonsyndromic German individuals of both genders. In order to minimize genetic confounders, self‐reported information regarding the family members were collected during the anamnesis and only patients that have Central‐European ancestry (who reported at maximum one grandparent not from Central Europe) were included. Also, only one patient per nuclear family was included to avoid biologically related individuals in the sample. Patients with syndromes, oral cleft, bone disease, and endocrine alterations were excluded.

2.2. Sample

This is a preliminary study that aimed to explore the genetic contribution of the sella turcica morphology. Due to the novelty of the study, a convenience sample was used, and the size was decided based on previous studies that revised sella turcica phenotype prevalence (do Brasil et al., 2022). The study sample was composed of individuals, aged 12 to 35 years old, undergoing orthodontic treatment at the University of Regensburg and private orthodontic practices in Regensburg, Germany. As part of the initial screening, all patients included in the research had lateral cephalometric radiographs that were performed for orthodontic treatment purposes. This exam was taken in Frankfurt horizontal plane parallel to the floor in a rigid cephalostat. Only pre‐orthodontic treatment cephalometric radiographs of good quality (clear visualization of the sella turcica) were included in this study. The sella calcification was evaluated in three aspects: (i) no calcification, (ii) partial calcification, and (iii) complete calcification of the interclinoid ligament (Leonardi et al., 2006). The pattern of the sella turcica was evaluated according to the protocol described by Kucia et al. (2014) and is shown in Figure 1. All cephalometric radiographs were examined by only one trained and calibrated examiner. For interexaminer reliability, 10% of the sample were randomly chosen for a second analysis in a 2‐week interval. The Kappa statistics showed perfect agreement (Kappa = 1) for sella calcification and for sella turcica pattern. All individuals included in this study were recruited from 2020 to 2021.

FIGURE 1.

FIGURE 1

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Evaluated patterns of the sella turcica. (a) Normal sella turcica. (b) Sella turcica bridge type A—ribbon‐like fusion. (c) Sella turcica bridge type B—extension of the clinoid processes. (d) Incomplete bridge. (e) Hypertrophic posterior clinoid process. (f) Hypotrophic posterior clinoid process. (g) Irregularity (notching) in the posterior part of the sella turcica. (h) Pyramidal shape of the dorsum sellae. (i) Double contour of the floor. (j) Oblique anterior wall. (k) Oblique contour of the floor. Adapted from Kucia et al. (2014).

2.3. DNA extraction and genotyping

Potentially functional SNPs in WNT10A and WNT6 genes previously associated with craniofacial phenotypes (He et al., 2013; Kimura et al., 2015; Magruder et al., 2018) were screened from the dbSNP database (http://www.ncbi.nlm.nih.gov/snp/) and SNPinfo (http://snpinfo.niehs.nih.gov/), based on the following criteria: MAF (minor allele frequency) ≥ 10% in the global population. In addition, SNP selection considered linkage disequilibrium measures. The characteristics of the selected SNPs are presented in Table 1.

TABLE 1.

Description of genes and polymorphisms studied.

Gene Position Rs MAF Reference allele Polymorphic allele Functional consequence
WNT6 chr2:218867420 rs6754599 0.250 C G Intron_variant
WNT10A chr2:218881839 rs10177996 0.210 T C Upstream transcript variant
chr2:218879152 rs3806557 0.223 G A Upstream transcript variant
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Note: Obtained from database: ncbi.nlm.nih.gov.

Abbreviation: MAF, mean minor allele frequency.

For the genotyping analysis 4 ng of genomic DNA of each included patient was used. The DNA was isolated from buccal epithelial cells collected with cytobrushes using extraction solution (Tris–HCl 10 mmol/L, pH 7.8; EDTA 5 mmol/L; SDS 0.5%, 1 mL, all reagents from Merck™) and proteinase K (100 ng/mL, Invitrogen™) and ammonium acetate to remove nondigested proteins. Then, the DNA was precipitated with isopropanol and resuspended to be quantified by spectrophotometry (Nanodrop 1000; Thermo Scientific) (Küchler et al., 2012).

The selected SNPs were blindly genotyped via real‐time polymerase chain reaction (PCR) using the Mastercycler® ep realplex‐S thermocycler (Eppendorf AG, Hamburg, Germany). The TaqMan technology, which uses extremely sensitive allele‐specific probes (VIC™ and FAM™ dyes were used for the alleles) (Ranade et al., 2000), was used in this study. A negative control template was included in each reaction plate and 10% of the samples were randomly selected for repeated analysis (presented 100% concordance). DNA samples that failed to be genotyped (samples that failed to produce signal twice) were considered missing data and was excluded from the statistical analysis.

2.4. Statistical analysis

The Hardy–Weinberg Equilibrium was assessed for each genetic polymorphism by Chi‐square test (wpcalc.com/en/equilibrium‐hardy‐weinberg). Epi Info™ (Centers for Disease Control and Prevention) was used for statistical analysis. In order to evaluate the influence of age and gender in the sella turcica morphology, comparisons of gender and age distributions among phenotypes were performed. Chi‐square test or Fisher's exact test were used to compare gender, and allele and genotype in 3 models (additive: AA vs. Aa vs. aa; recessive: aa vs. Aa + AA; and dominant: aa + Aa vs. AA) distribution according to sella turcica morphology. T test was used to compare age according to sella turcica morphology groups. The significance level was set as p < 0.05 for all comparisons.

3. RESULTS

A total of 169 individuals were included, of which 83 (49.1%) were men and 86 (50.9%) were women. The characteristics of the sella turcica are presented in Table 2. Regarding sella turcica calcification, 133 (78.7%) presented a partially or completely calcified sella turcica, followed by no calcification (21.3%). The calcification phenotype was not associated with the gender (p = 0.536), nor age (p = 0.479). Sella turcica anomalies were found in 131 individuals (77.5%), in which sella turcica bridge type A (27.8%), posterior hypertrophic clinoid process (17.1%), and sella turcica bridge type B (11.2%) were the most prevalent morphological anomalies observed. The prevalence of other morphologies was less than 10.0% altogether. The sella turcica pattern distribution was not associated with the gender (p = 0.525), nor age (p = 0.511).

TABLE 2.

Frequency distribution of the characteristics of the sella turcica in the studied population.

Sella turcica calcification N (%)
No calcification 36 (21.3)
Partially calcified 113 (66.9)
Completely calcified 20 (11.8)
Sella turcica pattern N (%)
Normal sella turcica 38 (22.5)
Sella turcica bridge type A 47 (27.8)
Sella turcica bridge type B 19 (11.2)
Incomplete bridge 14 (8.3)
Hypertrophic posterior clinoid process 29 (17.1)
Hypotrophic posterior clinoid process 1 (0.6)
Irregularity in the posterior part of the sella turcica 4 (2.4)
Pyramidal shape of the dorsum of the sella turcica 3 (1.8)
Double contour of the floor 1 (0.6)
Oblique anterior wall 9 (5.3)
Oblique contour of the floor 4 (2.4)
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Genotype distributions for studied polymorphisms were consistent with the Hardy–Weinberg equilibrium (p = 0.150 for rs6754599; p = 0.327 for rs10177996; p = 0.245 for rs3806557). Table 3 shows the calcification pattern according to the genotypes. A statistical significance was observed for the SNP rs10177996 in WNT10A, in which individuals carrying two copies of the wild allele (TT vs. CT + CC) had a higher chance to present a partially calcified sella turcica (p = 0.047; Odds ratio = 2.2, Confidence Interval 95% 1.0–5.1), suggesting that TT genotype is a risk factor for sella turcica calcification. When the comparison is performed between a sella turcica with no calcification and sella turcica with calcification (partially calcified + completely calcified), a statistical significance was also observed in the dominant model, in which individuals carrying the TT genotype (TT vs. CT + CC) also had higher chance to present calcification (p = 0.05; Odds ratio = 2.1, Confidence Interval 95% 1.0–4.8). The rs6754599 in WNT6 and the rs3860557 in WNT10A were not statistically associated with the type of calcification (p > 0.05). Table 4 shows the genotype distribution for the sella turcica patterns. A statistical significance difference was not observed in none of the SNPs (p > 0.05).

TABLE 3.

Genotype frequency distribution and comparison between the degree of calcification in the allele, additive, dominant, and recessive models.

rs6754599 (WNT6) GG CG CC p‐Value additive p‐Value dominant p‐Value recessive p‐value allele
No calcification 2 (6.3) 8 (25.0) 22 (68.7) Reference Reference Reference Reference
Partially calcified 1 (1.0) 25 (24.8) 75 (74.2) 0.241 0.541 0.080 0.288
Completely calcified 1 (5.3) 5 (26.3) 13 (68.4) 0.986 0.980 0.885 0.967
rs10177996 (WNT10A) CC CT TT p‐Value additive p‐Value dominant p‐Value recessive p‐Value allele
No calcification 3 (8.6) 22 (68.9) 10 (28.5) Reference Reference Reference Reference
Partially calcified 9 (8.4) 47 (43.9) 51 (47.7) 0.123 0.047* 0.976 0.136
Completely calcified 1 (5.0) 11 (55.0) 8 (40.0) 0.645 0.385 0.623 0.434
rs3806557 (WNT10A) AA AG GG p‐Value additive p‐Value dominant p‐Value recessive p‐Value allele
No calcification 3 (9.7) 9 (29.3) 19 (61.3) Reference Reference eference Reference
Partially calcified 7 (7.1) 34 (34.3) 58 (58.6) 0.342 0.561 0.682 0.428
Completely calcified 2 (10.3) 6 (31.6) 11 (57.9) 0.886 0.990 0.834 0.954
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Note: *Means statistically significant difference (p < 0.05).

TABLE 4.

Genotype frequency distribution and comparison (in the additive model) between sella turcica patterns.

Sella turcica pattern rs6754599 (WNT6) CC/CG/GG p‐value rs10177996 (WNT10A) CC/CT/TT p‐value rs3806557 (WNT10A) AA/AG/GG p‐value
Normal ST 24/9/1 0.999 2/21/14 0.774 2/12/19 0.855
ST bridge type A 30/10/1 7/19/19 3/13/24
ST bridge type B 11/5/1 1/7/10 1/7/9
Incomplete bridge 10/3/0 1/5/7 1/6/5
Hypertrophic posterior clinoid process 21/7/1 2/13/14 3/8/17
Hypotrophic posterior clinoid process 1/0/0 0/1/0 0/0/1
Irregularity in the posterior part 2/1/0 0/2/1 0/0/3
Pyramidal shape of the dorsum 3/0/0 0/3/0 0/0/3
Double contour of the floor 1/0/0 0/1/0 0/0/1
Oblique anterior wall 5/2/0 0/5/3 2/2/3
Oblique contour of the floor 2/1/0 0/3/1 0/1/3
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Note: p‐value for genotype distribution in the additive model.

Abbreviation: ST, sella turcica.

4. DISCUSSION

In this study we hypothesized that SNPs of genes encoding components of the WNT signaling pathway might be associated with sella turcica phenotypes in humans, such as sella turcica calcification and sella turcica patterns. To explore this hypothesis, we evaluated DNA samples from 169 German individuals and selected SNPs in WNT6 (rs6754599) and WNT10A (rs10177996 and rs3806557). It is important to emphasize that the three selected SNPs have already been investigated in previous genome‐wide association studies, and were associated with multiple dental or craniofacial traits, such as maxillary length and crown size (He et al., 2013; Kimura et al., 2015; Magruder et al., 2018) but, to the best of our knowledge, this is the first study that investigates the association of these genes with the sella turcica phenotypes. A limitation of our study is the sample, which is a convenience sample. A sample size calculation was not possible as this is the first study to explore the role of SNPs in sella turcica phenotypes. Therefore, multiple test correction was not performed since this could increase the type II error. Also, all included individuals are patients seeking orthodontic treatment and they have a variety of malocclusions. Although this is also a limitation of our study, since the sample represents orthodontic patients (and not the general population), it is important to mention that orthodontic patients already have cephalometric exams and additional radiographs were not necessary for this study. If the study was performed in a sample representative of the population, the individuals would be exposed to radiograph exams only to be included in the study.

The WNT ligand genes are responsible for encoding glycoproteins that play a decisive action in signaling cell fate, cell movement, and tissue polarity. In humans, these genes encode at least 19 WNT glycoproteins that are identified and classified according to the intracellular signaling pathway. In this sense, these glycoproteins could be classified according to singling pathways in (i) glycoprotein that depends on the canonical β‐catenin pathway, and (ii) glycoproteins that used noncanonical pathways that include planar cell polarity and Ca2+/WNT pathway (Komiya & Habas, 2008; Niehrs, 2012). Both pathways, in different forms, result in transcriptional activation of target genes that allow correct cell–cell communication (Krawetz & Kelly, 2008) and bone morphogenesis (Doolan et al., 2021). In this sense, disturbances in the WNT pathway signaling have been investigated and associated with skeletal defects, bone‐related disorders, and bone mass and turnover (Baron & Hesse, 2012). These characteristics make WNT genes natural candidates to be studied in bone formation variation phenotype.

Our analyses revealed no significant association between sella turcica phenotypes, rs6754599 in WTN6, and rs3806557 in WNT10A. However, the rs10177996 in WNT10A showed a significant association with phenotypes related to sella turcica calcification. It appears that individuals carrying the TT genotype had two times the odds of presenting a partially calcified and calcified sella turcica. It is possible that SNPs in WNT10A could be a biomarker for sella turcica calcification or calcification in other structures in the human body. WNT10A codified glycoproteins that depend on the canonical WNT β‐catenin pathway. This pathway depends on the interaction between the WNT encoding glycoproteins and frizzled membrane receptor plus low‐density lipoprotein receptor‐related protein resulting in the synthesis of an intracellular protein that prevents β‐catenin phosphorylation. As the protein is not phosphorylated, it is sequestered to the cell nucleus, where it initiates transcriptional activation of genes important for osteoblast function, consequently bone formation (Baron & Hesse, 2012). Hence there is interest in this signaling pathway in studies that investigate bone metabolism and pathological calcification, future studies in this field should consider rs10177996 as a candidate.

We chose two SNPs in WNT10A: rs10177996 and rs3806557. Our results support that rs10177996 is involved in sella turcica calcification. WNT10A is involved in osteoblastogenesis (Cawthorn et al., 2012) and are associated with craniofacial phenotypes (He et al., 2013; Kimura et al., 2015; Magruder et al., 2018). The rs10177996 is an intronic SNP, it is plausible that it does not affect any protein structure, that modifies the three‐dimensional conformation of the protein to the point of preventing interaction between the WNT glycoproteins and their membrane receptors. Maybe the other possible explanation is that it may be involved in binding transcription factors due to its intronic position and, affecting other pathways, causing calcification between the anterior and posterior clinoid processes. So, to understand how these transcription factors contribute to the activity of WNT in Wnt/β‐catenin signaling and bone homeostasis, further research should be designed specifically to address this issue.

WTN6 codifies glycoproteins that act in Ca2+/WNT noncanonical pathway. In our study, we observed a relatively homogeneous distribution of the genotypes among studied individuals, suggesting that this SNP is not involved with sella turcica phenotypes. A similar result was observed for the rs3806557, in which genotype distribution was similar among phenotypes. Overall, this study provides evidence that genes may play an important role on sella turcica morphological variation in humans. Our results demonstrated an association between an intronic SNP in WNT10A gene with sella turcica calcification pattern, however, additional studies are needed to confirm our findings, additionally, future studies covering more SNPs in WNT10A would be recommended to investigate the role of this gene in sella turcica morphology.

5. CONCLUSIONS

Considering the limitations of this study, the main results indicate that the single nucleotide polymorphism rs10177996 in WNT10A was associated with calcification phenotypes of the sella turcica.

AUTHOR CONTRIBUTIONS

Erika Calvano Küchler, Christian Kirschneck, Mohammad Khursheed Alam, and Peter Proff wrote the study proposal. João Armando Brancher, Rodrigo Schuh, Maria Fernanda Pioli Torres, Maria Angélica Hueb, and Carlos Alexandre dos Santos Haemmerle performed the study under supervision of JB. João Armando Brancher, MFPT, and Rodrigo Schuh collected the data, and Carlos Alexandre dos Santos Haemmerle and Maria Angélica Hueb conducted the data analysis. João Armando Brancher, Rodrigo Schuh, Maria Fernanda Pioli Torres, and Carlos Alexandre dos Santos Haemmerle wrote the primary version of the manuscript. Erika Calvano Küchler, Christian Kirschneck, Mohammad Khursheed Alam, and Peter Proff supervised the data analysis, contributed to the interpretation of the results, and reviewed and revised the manuscript.

ACKNOWLEDGMENTS

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES) ‐ Finance Code 001 and Alexander‐von‐Humboldt‐Foundation (Küchler/Kirschneck accepted on July 4th, 2019).

Brancher, J.A. , Schuh, R. , Torres, M.F.P. , Brasil, J. , Hueb, M.A. , dos Santos Haemmerle, C.A. et al. (2023) Assessing the relationship between single nucleotide polymorphisms in Wingless signaling pathway genes and sella turcica morphology. Journal of Anatomy, 243, 167–173. Available from: 10.1111/joa.13855

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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