Abstract
Objective
The present study aimed to evaluate if genetic variants in PAX9, MSX1, TGFα, FGF3, FGF10, FGF13, GLI2 and GLI3 are involved in TS of permanent teeth.
Materials and methods
Pretreatment dental records from orthodontic patients were assessed prior to recruitment. Patients with tooth agenesis and congenital anomalies (including oral cleft) and/or syndromes were excluded. Dental casts were used to measure the maximum crown dimensions of all fully erupted permanent teeth except second and third molars in mesiodistal direction. Teeth with caries, occlusal wear, mesiodistal restorations, and obvious deformities were not evaluated. Genomic DNA samples were used for genotyping. The allelic discrimination of 13 genetic variants was performed. The associations between TS and genotype were analyzed by linear regression, adjusted by gender at a significance level of p ≤ 0.05.
Results
Genetic polymorphisms in the tooth agenesis–related genes studied here were associated with increased and decreased TS, in both maxilla and mandible (p < 0.05).
Conclusion
This study reported associations of novel tooth agenesis–related gene variants with permanent tooth size variations.
Clinical relevance
The presence of some genetic variants could allow the prediction of permanent tooth size.
Similar content being viewed by others
References
Weston JA, Yoshida H, Robinson V, Nishikawa ST, Fraser S, Nishikawa S (2004) Neural crest and the origin of ectomesenchyme: neural fold heterogeneity suggests an alternative hypothesis. Dev Dyn 229:118–130. https://doi.org/10.1002/dvdy.10478
Arte S, Nieminen P, Apajalahti S, Haavikko K, Thesleff I, Pirinen S (2001) Characteristics of incisor-premolar hypodontia in families. J Dent Res 80:445–1450. https://doi.org/10.1177/00220345010800051201
Townsend G, Hughes T, Luciano M, Bockmann M, Brook A (2009) Genetic and environmental influences on human dental variation: a critical evaluation of studies involving twins. Arch Oral Biol 54:S45–S51. https://doi.org/10.1016/j.archoralbio.2008.06.009
Fauzi NH, Ardini YD, Zainuddin Z, Lestari W (2018) A review on non-syndromic tooth agenesis associated with PAX9 mutations. Jpn Dent Sci Rev 54:30–36. https://doi.org/10.1016/j.jdsr.2017.08.001
Thesleff I (2003) Epithelial-mesenchymal signalling regulating tooth morphogenesis. J Cell Sci 116:1647–1648. https://doi.org/10.1242/jcs.00410
Lee WC, Yamaguchi T, Watanabe C, Kawaguchi A, Takeda M, Kim YI, Park SB (2012) Association of common PAX9 variants with permanent tooth size variation in non-syndromic East Asian populations. J Hum Genet 57:654–659. https://doi.org/10.1038/jhg.2012.90
Garn SM, Lewis AB (1970) The gradient and the pattern of crown-size reduction in simple hypodontia. Angle Orthod 40:51–58. https://doi.org/10.1043/0003-3219(1970)040<0051:TGATPO>2.0.CO;2
Lavelle CLB, Ashton EH, Flinn RM (1970) Cusp pattern, tooth size and third molar agenesis in the human mandibular dentition. Arch Oral Biol 15:227–237. https://doi.org/10.1016/0003-9969(70)90081-6
Wright J, Bosio JA, Chou JC, Jiang SS (2016) Maxillary lateral incisor agenesis and its relationship to overall tooth size. J Prosthet Dent 115:209–214. https://doi.org/10.1016/j.prosdent.2015.07.010
Nakatomi M, Wang XP, Key D, Lund JJ, Turbe-Doan A, Kist R, Peters H (2010) Genetic interactions between Pax9 and Msx1 regulate lip development and several stages of tooth morphogenesis. Dev Biol 340:438–449. https://doi.org/10.1016/j.ydbio.2010.01.031
Bonczek O, Bielik P, Krejčí P, Zeman T, Izakovičová-Hollá L, Šoukalová J, Šerý O (2018) Next generation sequencing reveals a novel nonsense mutation in MSX1 gene related to oligodontia. PLoS One 13:9. https://doi.org/10.1371/journal.pone.0202989
Yin W, Bian Z (2015) The gene network underlying hypodontia. J Dent Res 94:878–885. https://doi.org/10.1177/0022034515583999
Bonczek O, Balcar VJ, Šerý O (2017) PAX9 gene mutations and tooth agenesis: a review. Clin Genet 92:467–476. https://doi.org/10.1111/cge.12986
Phan M, Conte F, Khandelwal KD, Ockeloen CW, Bartzela T, Kleefstra T, Carels CEL (2016) Tooth agenesis and orofacial clefting: genetic brothers in arms? Hum Genet 135:1299–1327. https://doi.org/10.1007/s00439-016-1733-z
Vieira AR, Meira R, Modesto A, Murray JC (2004) MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. J Dent Res 83:723–727. https://doi.org/10.1177/154405910408300913
Xiong X, Li S, Cai Y, Chen F (2017) Targeted sequencing in FGF/FGFR genes and association analysis of variants for mandibular prognathism. Medicine 96. https://doi.org/10.1097/MD.0000000000007240
Ornitz DM, Marie PJ (2002) FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16:1446–1465. https://doi.org/10.1101/gad.990702
Küchler EC, Lips A, Tannure PN, Ho B, Costa MC, Granjeiro JM, Vieira AR (2013) Tooth agenesis association with self-reported family history of cancer. J Dent Res 92:149–155. https://doi.org/10.1177/0022034512468750
Liu H, Han D, Wong S, Nan X, Zhao H, Feng H (2013) rs929387 of GLI3 is involved in tooth agenesis in Chinese Han population. PloS One 8. https://doi.org/10.1371/journal.pone.0080860
Vieira AR, D’Souza RN, Mues G, Deeley K, Hsin HY, Küchler EC, Costa MC (2013) Candidate gene studies in hypodontia suggest role for FGF3. Eur Arch Paediatr Dent 14:405–410. https://doi.org/10.1007/s40368-013-0010-2
Vortkamp A, Gessler M, Grzeschik KH (1995) Identification of optimized target sequences for the GLI3 zinc finger protein. DNA Cell Biol 14:629–634. https://doi.org/10.1089/dna.1995.14.629
Little J, Higgins JP, Loannidis JP, Moher D, Gagnon F, Von Elm E et al (2009) STrengthening the REporting of genetic association studies (STREGA)—an extension of the STROBE statement. Genet Epidemiol 33(7):581–598. https://doi.org/10.1002/gepi.20410
Fess EE (1995) Guidelines for evaluating assessment instruments. J Hand Ther 8(2):144–148. https://doi.org/10.1016/S0894-1130(12)80312-7
Küchler EC, Tannure PN, Falagan-Lotsch P, Lopes TS, Granjeiro JM, Amorim LMF (2012) Buccal cells DNA extraction to obtain high quality human genomic DNA suitable for polymorphism genotyping by PCR-RFLP and real-time PCR. J Appl Oral Sci 20:467–471. https://doi.org/10.1590/S1678-77572012000400013
Ranade K, Chang MS, Ting CT, Pei D, Hsiao CF, Olivier M, Curb D (2001) High-throughput genotyping with single nucleotide polymorphisms. Genome Res 11:1262–1268. https://doi.org/10.1101/gr.157801
Chattopadhyay A, Srinivas K (1996) Transposition of teeth and genetic etiology. Angle Orthod 66:147–152. https://doi.org/10.1043/0003-3219(1996)066<0147:TOTAGE>2.3.CO;2
Peck L, Peck S, Attia Y (1993) Maxillary canine-first premolar transposition, associated dental anomalies and genetic basis. Angle Orthod 63:99–109. https://doi.org/10.1043/00033219(1993)063<0099:MCFPTA>2.0.CO;2
Antunes LS, Küchler EC, Tannure PN, Dias JB, Ribeiro VN, Lips A, Granjeiro JM (2013) Genetic variations in MMP9 and MMP13 contribute to tooth agenesis in a Brazilian population. J Oral Sci 55:281–286. https://doi.org/10.2334/josnusd.55.281
Brook AH, Elcock C, Al-Sharood MH, McKeown HF, Khalaf K, Smith RN (2002) Further studies of a model for the etiology of anomalies of tooth number and size in humans. Connect Tissue Res 43:289–295. https://doi.org/10.1080/03008200290000718
Schalk-Van der Weide Y, Steen WHA, Beemer FA, Bosman F (1994) Reductions in size and left-right asymmetry of teeth in human oligodontia. Arch Oral Biol 39:935–939. https://doi.org/10.1016/0003-9969(94)90076-0
Brook AH, Elcock C, Aggarwal M, Lath DL, Russell JM, Patel PI, Smith RN (2009) Tooth dimensions in hypodontia with a known PAX9 mutation. Arch Oral Biol 54:S57–S62. https://doi.org/10.1016/j.archoralbio.2008.05.017
Kirac D, Eraydin F, Avcilar T, Ulucan K, Özdemir F, Guney AI, Isbir T (2016) Effects of PAX9 and MSX1 gene variants to hypodontia, tooth size and the type of congenitally missing teeth. Cellular and Molecular Biology 62:78–84. https://doi.org/10.14715/cmb/2016.62.13.14
Nieminen P, Arte S, Tanner D, Paulin L, Alaluusua S, Thesleff I, Pirinen S (2001) Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. Eur J Hum Genet 9:743–746. https://doi.org/10.1038/sj.ejhg.5200715
Ogawa T, Kapadia H, Feng JQ, Raghow R, Peters H, D'Souza RN (2006) Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development. J Biol Chem 281:18363–18369. https://doi.org/10.1074/jbc.M601543200
Seo YJ, Park JW, Kim YH, Baek SH (2013) Associations between the risk of tooth agenesis and single-nucleotide polymorphisms of MSX1 and PAX9 genes in nonsyndromic cleft patients. Angle Orthod 83:1036–1042. https://doi.org/10.2319/020513-104.1
De Sabóia TM, Küchler EC, Tannure PN, Rey AC, Granjeiro JM, de Castro CM, Vieira AR (2013) Mesio-distal and buccal-lingual tooth dimensions are part of the cleft spectrum: a pilot for future genetic studies. Cleft Palate Craniofac J 50:678–683. https://doi.org/10.1597/11-228
Letra A, Fakhouri W, Fonseca RF, Menezes R, Kempa I, Prasad JL, Daack-Hirsch S (2012) Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate. PLoS One 7:e45441. https://doi.org/10.1371/journal.pone.0045441
Zeiger JS, Beaty TH, Liang KY (2005) Oral clefts, maternal smoking, and TGFA: a meta-analysis of gene-environment interaction. Cleft Palate Craniofac J 42:58–63. https://doi.org/10.1597/02-128.1
Jugessur A, Lie RT, Wilcox AJ, Murray JC, Taylor JA, Saugstad OD, Åbyholm F (2003) Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: a case-parent triad analysis. Genet Epidemiol 24:230–239. https://doi.org/10.1002/gepi.10223
Tucker A, Sharpe P (2004) The cutting-edge of mammalian development; how the embryo makes teeth. Nat Rev Genet 5:499–508. https://doi.org/10.1038/nrg1380
Tucker A, Sharpe P (2004) The cutting-edge of mammalian development; how the embryo makes teeth. Nat Rev Genet 5:499–508. https://doi.org/10.1038/nrg1380
Hosokawa R, Deng X, Takamori K, Xu X, Urata M, Bringas P Jr, Chai Y (2009) Epithelial-specific requirement of FGFR2 signaling during tooth and palate development. J Exp Zool B Mol Dev Evol 312:343–350. https://doi.org/10.1002/jez.b.21274
Harada H, Toyono T, Toyoshima K, Yamasaki M, Itoh N, Kato S, Ohuchi H (2002) FGF10 maintains stem cell compartment in developing mouse incisors. Development 129:1533–1541
Marañón-Vásquez GA, Dantas B, Kirschneck C, Arid J, Cunha A, de Carvalho Ramos AG et al (2019) Tooth agenesis-related GLI2 and GLI3 genes may contribute to craniofacial skeletal morphology in humans. Arch Oral Biol 103:12–18. https://doi.org/10.1016/j.archoralbio.2019.05.008
Hardcastle Z, Mo R, Hui CC, Sharpe PT (1998) The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development 125:2803–2811
Sabóia TM, Tannure PN, Luiz RR, de Castro CM, Granjeiro JM, Küchler EC, Antunes LS (2013) Sexual dimorphism involved in the mesiodistal and buccolingual dimensions of permanent teeth. Dentistry 3000(1):2–6. https://doi.org/10.5195/d3000.2013.10
Lippold C, Kirschneck C, Schreiber K, Abukiress S, Tahvildari A, Moiseenko T, Danesh G (2015) Methodological accuracy of digital and manual model analysis in orthodontics–a retrospective clinical study. Comput Biol Med 62:103–109. https://doi.org/10.1016/j.compbiomed.2015.04.012
Funding
This work was supported by the São Paulo Research Foundation (FAPESP) (funding number: 2015/06866-5) and individual scholarships (FAPESP 2018/03533-3, 2017/16990-0 and 2016/08149-1, and CAPES).
Author information
Authors and Affiliations
Contributions
ASC performed the genotype analysis and wrote the manuscript.
LVS performed the tooth measurements.
GAMV performed the DNA extraction and wrote the manuscript.
CK conceptualized and designed the study and wrote the manuscript.
JTSG performed the statistical analysis and wrote the results.
MBS designed the clinical part of the study and calibrated the operator to tooth measurements.
MANM patients’ recruitment, organized the sample and the data.
ARV provided funding support and led the PCR analysis.
RS designed and performed the statistical analysis.
ECK managed the funding resource, conceptualized and designed the study, mentored the students, and wrote the manuscript. All the authors read, corrected, and approved the final version of the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Supplementary Table 1
(DOCX 34 kb)
Supplementary Table 2
(DOCX 26 kb)
Supplementary Table 3
(DOCX 233 kb)
Rights and permissions
About this article
Cite this article
Cunha, A.S., dos Santos, L.V., Marañón-Vásquez, G.A. et al. Genetic variants in tooth agenesis–related genes might be also involved in tooth size variations. Clin Oral Invest 25, 1307–1318 (2021). https://doi.org/10.1007/s00784-020-03437-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00784-020-03437-8