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Rethinking the Genetic Etiology of Nonsyndromic Tooth Agenesis

  • Craniofacial Skeleton (TG Chu and S Akintoye, Section Editors)
  • Published:
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Abstract

Purpose of Review

Genetic studies in humans and animal models have improved our understanding of the role of numerous genes in the etiology of nonsyndromic tooth agenesis (TA). The purpose of this review is to discuss recently identified genes potentially contributing to TA.

Recent Findings

Despite research progress, understanding the genetic factors underlying nonsyndromic TA has been challenging given the genetic heterogeneity, variable expressivity, and incomplete penetrance of putatively pathogenic variants often observed associated with the condition. Next-generation sequencing technologies have provided a platform for novel gene and variant discoveries and informed paradigm-shifting concepts in the etiology of TA.

Summary

This review summarizes the current knowledge on genes and pathways related to nonsyndromic TA with a focus on recently identified genes/variants. Evidence suggesting possible multi-locus variation in TA is also presented.

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References

  1. Thesleff I. The genetic basis of tooth development and dental defects. Am J Med Genet A. 2006;140(23):2530–5.

    Article  PubMed  Google Scholar 

  2. Yin W, Bian Z. The gene network underlying hypodontia. J Dent Res. 2015;94(7):878–85.

    Article  CAS  PubMed  Google Scholar 

  3. Williams MA, Letra A. The changing landscape in the genetic etiology of human tooth agenesis. Genes (Basel). 2018;9(5).

  4. Polder BJ, van't Hof MA, van der Linden FPGM, Kuijpers-Jagtman AM. A meta-analysis of the prevalence of dental agenesis of permanent teeth. Community Dent Oral Epidemiol. 2004;32(3):217–26.

    Article  PubMed  Google Scholar 

  5. Nieminen P. Genetic basis of tooth agenesis. J Exp Zool B Mol Dev Evol. 2009;312B(4):320–42.

    Article  CAS  PubMed  Google Scholar 

  6. Hennekam, R, Allanson J, Krantz I. Gorlin's syndromes of the head and neck. 5th ed. New York: Oxford University Press, 2010.

  7. Williams MA, Biguetti C, Romero-Bustillos M, Maheshwari K, Dinckan N, Cavalla F, Liu X, Silva R, Akyalcin S, Uyguner ZO, Vieira AR, Amendt BA, Fakhouri WD, Letra A. Colorectal cancer-associated genes are associated with tooth agenesis and may have a role in tooth development. Sci Rep. 2018;8(1):2979.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Vieira AR. Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res. 2003;82(3):162–5.

    Article  CAS  PubMed  Google Scholar 

  9. Matalova E, Fleischmannova J, Sharpe PT, Tucker AS. Tooth agenesis: from molecular genetics to molecular dentistry. J Dent Res. 2008;87(7):617–23.

    Article  CAS  PubMed  Google Scholar 

  10. Ye X, Attaie AB. Genetic basis of nonsyndromic and syndromic tooth agenesis. J Pediatr Genet. 2016;5(4):198–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vastardis H, Karimbux N, Guthua SW, Seidman JG, Seidman CE. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat Genet. 1996;13(4):417–21.

    Article  CAS  PubMed  Google Scholar 

  12. Stockton DW, das P, Goldenberg M, D'Souza RN, Patel PI. Mutation of PAX9 is associated with oligodontia. Nat Genet. 2000;24(1):18–9.

    Article  CAS  PubMed  Google Scholar 

  13. Brook AH, Elcock C, Aggarwal M, Lath DL, Russell JM, Patel PI, Smith RN. Tooth dimensions in hypodontia with a known PAX9 mutation. Arch Oral Biol. 2009;54(Suppl 1):S57–62.

    Article  CAS  PubMed  Google Scholar 

  14. Ogawa T, Kapadia H, Feng JQ, Raghow R, Peters H, D'Souza RN. Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development. J Biol Chem. 2006;281(27):18363–9.

    Article  CAS  PubMed  Google Scholar 

  15. Jia S, Zhou J, Fanelli C, Wee Y, Bonds J, Schneider P, Mues G, D'Souza RN. Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero. Development. 2017;144(20):3819–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Arte S, Parmanen S, Pirinen S, Alaluusua S, Nieminen P. Candidate gene analysis of tooth agenesis identifies novel mutations in six genes and suggests significant role for WNT and EDA signaling and Allele Combinations. PLoS ONE. 2013;8(8):e73705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fan H, Ye X, Shi L, Yin W, Hua B, Song G, Shi B, Bian Z. Mutations in the EDA gene are responsible for X-linked hypohidrotic ectodermal dysplasia and hypodontia in Chinese kindreds. Eur J Oral Sci. 2008;116(5):412–7.

    Article  CAS  PubMed  Google Scholar 

  18. Deshmukh S, Prashanth S. Ectodermal dysplasia: a genetic review. Int J Clin Pediatr Dent. 2012;5(3):197–202.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Song S, Han D, Qu H, Gong Y, Wu H, Zhang X, Zhong N, Feng H. EDA gene mutations underlie non-syndromic oligodontia. J Dent Res. 2009;88(2):126–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mues G, Tardivel A, Willen L, Kapadia H, Seaman R, Frazier-Bowers S, Schneider P, D'Souza RN. Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis. Eur J Hum Genet. 2010;18(1):19–25.

    Article  CAS  PubMed  Google Scholar 

  21. Han D, Gong Y, Wu H, Zhang X, Yan M, Wang X, Qu H, Feng H, Song S. Novel EDA mutation resulting in X-linked non-syndromic hypodontia and the pattern of EDA-associated isolated tooth agenesis. Eur J Med Genet. 2008;51(6):536–46.

    Article  PubMed  Google Scholar 

  22. Thesleff I. Current understanding of the process of tooth formation: transfer from the laboratory to the clinic. Aust Dent J. 2014;59(Suppl 1):48–54.

    Article  PubMed  Google Scholar 

  23. 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(5):1043–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Callahan N, Modesto A, Meira R, Seymen F, Patir A, Vieira AR. Axis inhibition protein 2 (AXIN2) polymorphisms and tooth agenesis. Arch Oral Biol. 2009;54(1):45–9.

    Article  CAS  PubMed  Google Scholar 

  25. Letra A, Menezes R, Granjeiro JM, Vieira AR. AXIN2 and CDH1 polymorphisms, tooth agenesis, and oral clefts. Birth Defects Res A Clin Mol Teratol. 2009;85(2):169–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Davidson G. LRPs in WNT Signalling. Handb Exp Pharmacol. 2021;269:45–73.

    Article  PubMed  Google Scholar 

  27. Yu M, Fan Z, Wong SW, Sun K, Zhang L, Liu H, Feng H, Liu Y, Han D. Lrp6 dynamic expression in tooth development and mutations in oligodontia. J Dent Res. 2021;100(4):415–22.

    Article  CAS  PubMed  Google Scholar 

  28. Dinckan N, du R, Petty LE, Coban-Akdemir Z, Jhangiani SN, Paine I, Baugh EH, Erdem AP, Kayserili H, Doddapaneni H, Hu J, Muzny DM, Boerwinkle E, Gibbs RA, Lupski JR, Uyguner ZO, Below JE, Letra A. Whole-exome sequencing identifies novel variants for tooth agenesis. J Dent Res. 2018;97(1):49–59.

    Article  CAS  PubMed  Google Scholar 

  29. Ockeloen CW, Khandelwal KD, Dreesen K, Ludwig KU, Sullivan R, van Rooij IALM, Thonissen M, Swinnen S, Phan M, Conte F, Ishorst N, Gilissen C, Roa Fuentes L, van de Vorst M, Henkes A, Steehouwer M, van Beusekom E, Bloemen M, Vankeirsbilck B, et al. Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. Genet Med. 2016;18(11):1158–62.

  30. Wang H, Liu Y, Zheng Y, Zhao X, Lin S, Zhang Q, Zhang X. A novel missense mutation of LRP6 identified by whole-exome sequencing in a Chinese family with non-syndromic tooth agenesis. Orthod Craniofac Res. 2021;24(2):233–40.

    Article  PubMed  Google Scholar 

  31. Massink MP, et al. Loss-of-Function Mutations in the WNT Co-receptor LRP6 Cause Autosomal-Dominant Oligodontia. Am J Hum Genet. 2015;97(4):621–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Goto H, Kimura M, Machida J, Ota A, Nakashima M, Tsuchida N, Adachi J, Aoki Y, Tatematsu T, Takahashi K, Sana M, Nakayama A, Suzuki S, Nagao T, Matsumoto N, Tokita Y. A novel LRP6 variant in a Japanese family with oligodontia. Hum Genome Var. 2021;8(1):30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li S, et al. Variants in the Wnt co-receptor LRP6 are associated with familial exudative vitreoretinopathy. J Genet Genomics. 2021.

  34. Huang YX, Gao CY, Zheng CY, Chen X, Yan YS, Sun YQ, Dong XY, Yang K, Zhang DL. Investigation of a novel LRP6 variant causing autosomal-dominant tooth agenesis. Front Genet. 2021;12:688241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature. 2000;407(6803):535–8.

    Article  CAS  PubMed  Google Scholar 

  36. Yu M, Wong SW, Han D, Cai T. Genetic analysis: Wnt and other pathways in nonsyndromic tooth agenesis. Oral Dis. 2019;25(3):646–51.

    Article  PubMed  Google Scholar 

  37. Du R, et al. Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis. Hum Genet. 2018;137(9):689–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chu KY, et al. Synergistic mutations of LRP6 and WNT10A in familial tooth agenesis. J Pers Med. 2021:11(11).

  39. Song S, Zhao R, He H, Zhang J, Feng H, Lin L. WNT10A variants are associated with non-syndromic tooth agenesis in the general population. Hum Genet. 2014;133(1):117–24.

    Article  CAS  PubMed  Google Scholar 

  40. Yuan Q, Zhao M, Tandon B, Maili L, Liu X, Zhang A, Baugh EH, Tran T, Silva RM, Hecht JT, Swindell EC, Wagner DS, Letra A. Role of WNT10A in failure of tooth development in humans and zebrafish. Mol Genet Genomic Med. 2017;5(6):730–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. van den Boogaard MJ, Créton M, Bronkhorst Y, van der Hout A, Hennekam E, Lindhout D, Cune M, Ploos van Amstel HK. Mutations in WNT10A are present in more than half of isolated hypodontia cases. J Med Genet. 2012;49(5):327–31.

    Article  PubMed  Google Scholar 

  42. Arzoo PS, Klar J, Bergendal B, Norderyd J, Dahl N. WNT10A mutations account for (1/4) of population-based isolated oligodontia and show phenotypic correlations. Am J Med Genet A. 2014;164A(2):353–9.

    Article  PubMed  Google Scholar 

  43. Fournier BP, Bruneau MH, Toupenay S, Kerner S, Berdal A, Cormier-Daire V, Hadj-Rabia S, Coudert AE, de la Dure-Molla M. Patterns of dental agenesis highlight the nature of the causative mutated genes. J Dent Res. 2018;97(12):1306–16.

    Article  CAS  PubMed  Google Scholar 

  44. Xu M, Horrell J, Snitow M, Cui J, Gochnauer H, Syrett CM, Kallish S, Seykora JT, Liu F, Gaillard D, Katz JP, Kaestner KH, Levin B, Mansfield C, Douglas JE, Cowart BJ, Tordoff M, Liu F, Zhu X, et al. WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation. Nat Commun. 2017;8:15397.

  45. Yang J, Wang SK, Choi M, Reid BM, Hu Y, Lee YL, Herzog CR, Kim-Berman H, Lee M, Benke PJ, Kent Lloyd KC, Simmer JP, Hu JCC. Taurodontism, variations in tooth number, and misshapened crowns in Wnt10a null mice and human kindreds. Mol Genet Genomic Med. 2015;3(1):40–58.

    Article  CAS  PubMed  Google Scholar 

  46. Yu P, Yang W, Han D, Wang X, Guo S, Li J, Li F, Zhang X, Wong SW, Bai B, Liu Y, du J, Sun ZS, Shi S, Feng H, Cai T. Mutations in WNT10B are identified in individuals with oligodontia. Am J Hum Genet. 2016;99(1):195–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Magruder S, Carter E, Williams MA, English J, Akyalcin S, Letra A. Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis. Orthod Craniofac Res. 2018;21(4):258–63.

    Article  PubMed  Google Scholar 

  48. Kantaputra PN, Hutsadaloi A, Kaewgahya M, Intachai W, German R, Koparal M, Leethanakul C, Tolun A, Ketudat Cairns JR. WNT10B mutations associated with isolated dental anomalies. Clin Genet. 2018;93(5):992–9.

    Article  CAS  PubMed  Google Scholar 

  49. Jonsson L, Magnusson TE, Thordarson A, Jonsson T, Geller F, Feenstra B, Melbye M, Nohr EA, Vucic S, Dhamo B, Rivadeneira F, Ongkosuwito EM, Wolvius EB, Leslie EJ, Marazita ML, Howe BJ, Moreno Uribe LM, Alonso I, Santos M, et al. Rare and common variants conferring risk of tooth agenesis. J Dent Res. 2018;97(5):515–22.

  50. Dinckan N, du R, Akdemir ZC, Bayram Y, Jhangiani SN, Doddapaneni H, Hu J, Muzny DM, Guven Y, Aktoren O, Kayserili H, Boerwinkle E, Gibbs RA, Posey JE, Lupski JR, Uyguner ZO, Letra A. A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis. Am J Med Genet A. 2018;176(4):1015–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. McGrath JA, Pulkkinen L, Christiano AM, Leigh IM, Eady RAJ, Uitto J. Altered laminin 5 expression due to mutations in the gene encoding the beta 3 chain (LAMB3) in generalized atrophic benign epidermolysis bullosa. J Invest Dermatol. 1995;104(4):467–74.

    Article  CAS  PubMed  Google Scholar 

  52. Kivirikko S, McGrath JA, Baudoin C, Aberdam D, Ciatti S, Dunnill MGS, McMillan JR, Eady RAJ, Ortonne JP, Meneguzzi G, Ultto J, Christiano AM. A homozygous nonsense mutation in the alpha 3 chain gene of laminin 5 (LAMA3) in lethal (Herlitz) junctional epidermolysis bullosa. Hum Mol Genet. 1995;4(5):959–62.

    Article  CAS  PubMed  Google Scholar 

  53. Nakano A, Chao SC, Pulkkinen L, Murrell D, Bruckner-Tuderman L, Pfendner E, Uitto J. Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes. Hum Genet. 2002;110(1):41–51.

    Article  CAS  PubMed  Google Scholar 

  54. Smith CEL, Poulter JA, Antanaviciute A, Kirkham J, Brookes SJ, Inglehearn CF, Mighell AJ. Amelogenesis imperfecta; genes, proteins, and pathways. Front Physiol. 2017;8:435.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Delmaghani S, Aghaie A, Michalski N, Bonnet C, Weil D, Petit C. Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness. Hum Mol Genet. 2012;21(17):3835–44.

    Article  CAS  PubMed  Google Scholar 

  56. Peled A, Sarig O, Samuelov L, Bertolini M, Ziv L, Weissglas-Volkov D, Eskin-Schwartz M, Adase CA, Malchin N, Bochner R, Fainberg G, Goldberg I, Sugawara K, Baniel A, Tsuruta D, Luxenburg C, Adir N, Duverger O, Morasso M, et al. Mutations in TSPEAR, encoding a regulator of notch signaling, affect tooth and hair follicle morphogenesis. PLoS Genet. 2016;12(10):e1006369.

  57. Song JS, Bae M, Kim JW. Novel TSPEAR mutations in non-syndromic oligodontia. Oral Dis. 2020;26(4):847–9.

    Article  PubMed  Google Scholar 

  58. Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011;12(3):167–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kantaputra PN, Kaewgahya M, Hatsadaloi A, Vogel P, Kawasaki K, Ohazama A, Ketudat Cairns JR. GREMLIN 2 Mutations and Dental Anomalies. J Dent Res. 2015;94(12):1646–52.

    Article  CAS  PubMed  Google Scholar 

  60. Karaca E, Posey JE, Coban Akdemir Z, Pehlivan D, Harel T, Jhangiani SN, Bayram Y, Song X, Bahrambeigi V, Yuregir OO, Bozdogan S, Yesil G, Isikay S, Muzny D, Gibbs RA, Lupski JR. Phenotypic expansion illuminates multilocus pathogenic variation. Genet Med. 2018;20(12):1528–37.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, Walkiewicz M, Bi W, Xiao R, Ding Y, Xia F, Beaudet AL, Muzny DM, Gibbs RA, Boerwinkle E, Eng CM, Sutton VR, Shaw CA, Plon SE, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med. 2017;376(1):21–31.

  62. Zhou M, Zhang H, Camhi H, Seymen F, Koruyucu M, Kasimoglu Y, Kim JW, Kim-Berman H, Yuson NMR, Benke PJ, Wu Y, Wang F, Zhu Y, Simmer JP, Hu JCC. Analyses of oligodontia phenotypes and genetic etiologies. Int J Oral Sci. 2021;13(1):32.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ott J, Kamatani Y, Lathrop M. Family-based designs for genome-wide association studies. Nat Rev Genet. 2011;12(7):465–74.

    Article  CAS  PubMed  Google Scholar 

  64. Zeng Y, Baugh E, Akyalcin S, Letra A. Functional effects of WNT10A rare variants associated with tooth agenesis. J Dent Res. 2021;100(3):302–9.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by grants from the National Institute for Dental and Craniofacial Research R56DE028302 (AL).

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  1. Department of Oral and Craniofacial Sciences, and Center for Craniofacial and Dental Genetics, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA, 15219, USA

    Ariadne Letra

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Letra, A. Rethinking the Genetic Etiology of Nonsyndromic Tooth Agenesis. Curr Osteoporos Rep 20, 389–397 (2022). https://doi.org/10.1007/s11914-022-00761-8

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