SpringerLink
Log in

In-Silico Analysis of the High-Risk Missense Variants in PTH1R Gene and Association with Primary Failure of Tooth Eruption (PFE)

  • Conference paper
  • First Online:
International Conference on Advanced Intelligent Systems for Sustainable Development (AI2SD’2023) (AI2SD 2023)

Part of the book series: Lecture Notes in Networks and Systems ((LNNS,volume 905))

  • 57 Accesses

Abstract

Primary eruption failure (PFE) is a rare condition characterized by the cessation of tooth eruption posteriorly. Due to a mutation in the PTH1R gene, this dental phenotype is distinguished by a severe posterior open bite. The current study was used to investigate and evaluate the most deleterious nsSNPs in the dbSNP-extracted PTH1R gene using a variety of computational tools, including SIFT, PolyPhen-2, PROVEAN, Condel, Meat LR, Meat SVM, SWISS-MODEL, DUET, Yassara, ConSurf, and STRING. A total of 29 nsSNPs were found to be deleterious according to the ConSurf analysis. The majority of high-risk SNP amino acid positions (79.16%) were found in conserved regions. The Duet server determined that 16 of these variants decreased protein stability. Furthermore, hydrophobic and hydrogen interaction analyses and evaluation of structural effects of the deleterious nsSNPs on PTH1R by the YASARA program and Project HOPE server revealed significant changes between the wild-type and the 16 tested mutants. According to our results, 16 deleterious variants were identified as having an impact on the structure and probably function of the PTH1R protein involved in the PFE phenotype. These findings could contribute to the development of more efficient genetic tests for detecting mutations in the PTH1R gene.

H. Fellah and L. Wakrim—These authors contributed equally to this work.

Abreviations: PTH1R, The Parathyroid Hormone Receptor; PTHLH, Parathyroid Hormone-Like Hormone; PTH, Parathyroid Hormone; PTHrP, Parathyroid Hormone-Related Protein; ECD, Extracellular Domain; TMD, Transmembrane Domain; nsSNPs, Nonsynonymous SNPs; SIFT, Sorting Intolerant from Tolerant; PolyPhen, Polymorphism Phenoty**; Meat LR, Meta-analytic logic regression; VEP, Variant Effect Predictor; STRING, Search Tool for Recurring Instances of Neighboring Genes; HOPE, Have (y) Our Protein Explained; PDB, Protein Data Bank; OMIM, Online Mendelian Inheritance in Man; B, Buried; S, Structural; E, Exposed; F, Functional; WT, Wild-Type

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
EUR 29.95
Price includes VAT (Germany)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
EUR 160.49
Price includes VAT (Germany)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
EUR 213.99
Price includes VAT (Germany)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Ehrmann, J., Schöppe, J., Klenk, C., Rappas, M., Kummer, L., Doré, A.S.: High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist. Nat. Struct. Mol. Biol. 25(12), 1086–1092 (2018). https://doi.org/10.1038/s41594-018-0151-4

    Article  Google Scholar 

  2. Grippaudo, C., Cafiero, C., D’Apolito, I., Ricci, B., Frazier-Bowers, S.A.: Primary failure of eruption: clinical and genetic findings in the mixed dentition. Angle Orthod. 88(3), 275–282 (2018). https://doi.org/10.2319/062717-430.1

    Article  Google Scholar 

  3. Pilz, P., Meyer-Marcotty, P., Eigenthaler, M., Roth, H., Weber, B.H., Stellzig-Eisenhauer, A.: Differential diagnosis of primary failure of eruption (PFE) with and without evidence of pathogenic mutations in the PTHR1 gene. J. Orofacial Orthopedics Fortschritte der Kieferorthopadie Organ/Official J. Deutsche Gesellschaft fur Kieferorthopadie 75(3), 226–239 (2014). https://doi.org/10.1007/s00056-014-0215-y

  4. Kanno, C.M., de Oliveira, J.A., Garcia, J.F., Roth, H., Weber, B.H.F.: Twenty-year follow-up of a familial case of PTH1R-associated primary failure of tooth eruption. Am. J. Orthod. Dentofacial Orthop. 151(3), 598–606 (2017). https://doi.org/10.1016/j.ajodo.2016.09.012

  5. Subramanian, H., Döring, F., Kollert, S., Rukoyatkina, N., Sturm, J., Gambaryan, S.: PTH1R mutants found in patients with primary failure of tooth eruption disrupt G-protein signaling. PLoS ONE 11(11) (2016). https://doi.org/10.1371/journal.pone.0167033

  6. Jobert, A.S., et al.: Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in blomstrand chondrodysplasia. J. Clin. Invest. 102(1), 34–40 (1998). https://doi.org/10.1172/JCI2918

    Article  Google Scholar 

  7. Decker, E., Stellzig-Eisenhauer, A., Fiebig, B.S., Rau, C., Kress, W., Saar, K.: PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption. Am. J. Hum. Genet. 83(6), 781–786 (2008). https://doi.org/10.1016/j.ajhg.2008.11.006

    Article  Google Scholar 

  8. Tokavanich, N., Gupta, A., Nagata, M., Takahashi, A., Matsushita, Y., Yatabe, M.: A three-dimensional analysis of primary failure of eruption in humans and mice. Oral Dis. 26(2), 391 (2020). https://doi.org/10.1111/odi.13249

  9. Proffit, W.R., Vig, K.W.L.: Primary failure of eruption: a possible cause of posterior open bite. Am. J. Orthod. 80(2), 173–190 (1981). https://doi.org/10.1016/0002-9416(81)90217-7

    Article  Google Scholar 

  10. Ahmad, S., Bister, D., Cobourne, M.T.: The clinical features and aetiological basis of primary eruption failure. Eur. J. Orthod. 28(6), 535–540 (2006). https://doi.org/10.1093/ejo/cj/033

    Article  Google Scholar 

  11. Frazier-Bowers, S.A., Hendricks, H.M., Wright, J.T., Lee, J., Long, K., Dibble, C.F.: Novel mutations in PTH1R associated with primary failure of eruption and osteoarthritis. J. Dent. Res. 93(2), 134 (2014). https://doi.org/10.1177/0022034513513588

    Article  Google Scholar 

  12. Frazier-Bowers, S., Simmons, D., Koehler, K., Zhou, J.: Genetic analysis of familial non-syndromic primary failure of eruption. Orthod. Craniofac. Res. 12(2), 74–81 (2009). https://doi.org/10.1111/j.1601-6343.2009.01440.x

    Article  Google Scholar 

  13. Frazier-Bowers, S.A., Simmons, D., Wright, J.T., Proffit, W.R., Ackerman, J.L.: Primary failure of eruption and PTH1R: the importance of a genetic diagnosis for orthodontic treatment planning. Am. J. Orthod. Dentofac. Orthop. 137(2), 160.e1–160.e7 (2010). https://doi.org/10.1016/j.ajo.b.2009.10.019

    Article  Google Scholar 

  14. Risom, L., Christoffersen, L., Daugaard-Jensen, J., Hove, H.D., Andersen, H.S., Andresen, B.S.: Identification of six novel PTH1R mutations in families with a history of primary failure of tooth eruption. PLoS ONE 8(9) (2013). https://doi.org/10.1371/journal.pone.0074601

  15. Roth, H., Fritsche, L.G., Meier, C., Pilz, P., Eigenthaler, M., Meyer-Marcotty, P.: Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption. Clin. Oral Investig. 18(2), 377–384 (2014). https://doi.org/10.1007/S00784-013-1014-3

    Article  Google Scholar 

  16. Grippaudo, C., et al.: A novel nonsense PTH1R variant shows incomplete penetrance of primary failure of eruption: a case report. BMC Oral Health 19 (2019). https://doi.org/10.1186/s12903-019-0944-9

  17. Grippaudo, C., D’Apolito, I., Cafiero, C., Re, A., Chiurazzi, P., Frazier-Bowers, S.A.: Validating clinical characteristics of primary failure of eruption (PFE) associated with PTH1R variants. Prog Orthod. 22 (2021). https://doi.org/10.1186/s40510-021-00387-z

  18. Rhoads, S.G., Hendricks, H.M., Frazier-Bowers, S.A.: Establishing the diagnostic criteria for eruption disorders based on genetic and clinical data. Am. J. Orthod. Dentofac. Orthop. 144(2), 194–202 (2013). https://doi.org/10.1016/j.ajodo.2013.03.015

    Article  Google Scholar 

  19. Zhao, L.-I.M.A., Sutkeviciute, I., Shen, D.D., Zhou, X.E., Waal, P.W.: Structure and dynamics of the active human parathyroid hormone receptor-1. Science 364(6436), 148–153 (2019). https://doi.org/10.1126/science.aav7942

    Article  Google Scholar 

  20. Izumida, E., Suzawa, T., Miyamoto, Y., Yamada, A., Otsu, M., Saito, T.: Functional analysis of PTH1R variants found in primary failure of eruption. J. Dent. Res. 99(4), 429–436 (2020). https://doi.org/10.1177/0022034520901731

    Article  Google Scholar 

  21. Eigenthaler, M., Lohmann, S.M., Walter, U., Pilz, R.B.: Signal transduction by cAMP-dependent protein kinases and their emerging roles in the regulation of cell adhesion and gene expression. Rev. Physiol. Biochem. Pharmacol. 135, 173–209 (1999). https://doi.org/10.1007/BFb0033673

    Article  Google Scholar 

  22. Philbrick, W.M., Dreyer, B.E., Nakchbandi, I.A., Karaplis, A.C.: Parathyroid hormone-related protein is required for tooth eruption. Proc. Natl. Acad. Sci. U.S.A. 95(20), 11846–11851 (1998). https://doi.org/10.1073/pnas.95.20.11846

    Article  Google Scholar 

  23. Singh, A., Thakur, M., Singh, S.K., Sharma, L.K., Chandra, K.: Exploring the effect of nsSNPs in human YPEL3 gene in cellular senescence. Sci. Rep. 10(1), 15301 (2020). https://doi.org/10.1038/s41598-020-72333-8

    Article  Google Scholar 

  24. Yamaguchi, T., Hosomichi, K., Narita, A., Shirota, T., Tomoyasu, Y., Maki, K.: Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese. J. Bone Miner. Res. 26(7), 1655–1661 (2011). https://doi.org/10.1002/jbmr.385

    Article  Google Scholar 

  25. Ng., H.S., Pauline, C.: SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 31(13), 3812 (2003). https://doi.org/10.1093/nar/gkg509

  26. Adzhubei, I., Jordan, D.M, Sunyaev, S.R.: Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet 76, 7–20 (2013). https://doi.org/10.1002/0471142905.hg.72s76

  27. Choi, Y., Chan, A.P.: PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. BMC Bioinf. 31(16), 2745 (2015). https://doi.org/10.1093/bioinformaticas/btv195

    Article  Google Scholar 

  28. Yuan, X., Bai, J., Zhang, J., Yang, L., Duan, J., Li, Y.: CONDEL: detecting copy number variation and genoty** deletion zygosity from single tumor samples using sequence data. IEEE/ACM Trans. Comput. Biol. Bioinform. 17(4), 1141–1153 (2020). https://doi.org/10.1109/TCBB.2018.2883333

  29. Kim, S., Jhong, J-H., Lee, J., Koo, J.-Y.: Meta-analytic support vector machine for integrating multiple omics data. Bio Data Min. 10 (2017). https://doi.org/10.1186/s13040-017-0126-8

  30. Ashkenazy, H., Erez, E., Martz, E., Pupko, T., Ben-Tal, N.: ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucleic Acids Res. 38(Web Server issue), W529 (2010). https://doi.org/10.1093/nar/gkq399

  31. Pires, D.E.V., Ascher, D.B., Blundell, T.L.: DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res. 42(Web Server issue), W314 (2014). https://doi.org/10.1093/nar/gku411

  32. Yilmaz, A., Çetin, İ.: In silico prediction of the effects of nonsynonymous single nucleotide polymorphisms in the human Catechol-O-Methyltransferase (COMT) gene. Cell Biochem. Biophys. 78(2), 227–239 (2020). https://doi.org/10.1007/s12013-020-00905-6

    Article  Google Scholar 

  33. Krieger, E., Vriend, G.: YASARA view—molecular graphics for all devices—from smartphones to workstations. BMC Bioinf. 30(20), 2981 (2014). https://doi.org/10.1093/bioinformatics/btu426

    Article  Google Scholar 

  34. Mistri, M., Datar, C., Sheth, F., Gupta, S., Sheth, J.: Identification of novel mutations in HEXA gene in children affected with Tay-Sachs disease from India. Mol. Cytogenet. 7(1), P53 (2014). https://doi.org/10.1371/journal.pone.0039122

    Article  Google Scholar 

  35. Venselaar, H., Beek, T.A., Kuipers, R.K., Hekkelman, M.L., Vriend, G.: Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinf. 11, 548 (2010). https://doi.org/10.1186/1471-2105-11-548

  36. Szklarczyk, D., Franceschini, A., Wyder, S., Forslund, K., Heller, D., Huerta-Cepas, J.: STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43(Database issue), D447 (2015). https://doi.org/10.1093/nar/gku1003

  37. Emadi, E., Akhoundi, F., Kalantar, S.M., Emadi-Baygi, M.: Predicting the most deleterious missense nsSNPs of the protein isoforms of the human HLA-G gene and in silico evaluation of their structural and functional consequences. BMC Genet. 21 (2020). https://doi.org/10.1186/s12863-020-00890-y

  38. Kumar, P., Mahalingam, K.: In silico approach to identify non-synonymous SNPs with highest predicted deleterious effect on protein function in human obesity related gene, neuronal growth regulator 1 (NEGR1). 3 Biotech. 8(11), 466 (2018). https://doi.org/10.1007/s13205-018-1463-0

  39. Yuan, M.D., Chan, E., Wei, M.Q., Liu, J-P., Zhou, S-F.: Prediction of deleterious non-synonymous single-nucleotide polymorphisms of human uridine diphosphate glucuronosyltransferase genes. AAPS J. 11(3) (2009). https://doi.org/10.1208/s12248-009-9126-z

  40. Zhang, P., Jobert, A.S., Couvineau, A., Silve, C.: A homozygous inactivating mutation in the parathyroid hormone/parathyroid hormone-related peptide receptor causing Blomstrand chondrodysplasia. J. Clin. Endocrinol. Metab. 83(9), 3365–3368 (1998). https://doi.org/10.1210/jcem.83.9.5243

    Article  Google Scholar 

  41. Chen, Y., Lu, H., Zhang, N., Zhu, Z., Wang, S., Li, M.: PremPS: predicting the impact of missense mutations on protein stability. PLOS Comput. Biol. 16(12), e1008543 (2020). https://doi.org/10.1371/journal.pcbi.1008543

    Article  Google Scholar 

  42. Yue, P., Moult, J.: Identification and analysis of deleterious human SNPs. J. Mol. Biol. 356(5), 1263–1274 (2006). https://doi.org/10.1016/j.jmb.2005.12.025

    Article  Google Scholar 

  43. Klenk, C., Hommers, L., Lohse, M.J.: Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone 1 receptor. Front Endocrinol. 13 (2022). https://www.frontiersin.org/articles/10.3389/fendo.2022.839351. Accessed 22 Sept 2022. https://doi.org/10.3389/fendo.2022.839351

  44. Plati, J., Tsomaia, N., Piserchio, A., Mierke, D.F.: Structural features of parathyroid hormone receptor coupled to gαs-protein. Biophys. J. 92(2), 535–540 (2007). https://doi.org/10.1529/biophysj.106.094813

    Article  Google Scholar 

Download references

Acknowledgements

We are thankful to the Pasteur Institute of Morocco for providing encouragement and facilities and resources.

Author information

Authors and Affiliations

  1. Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, 20360, Casablanca, Morocco

    Imane Ettaki, Asmae Saih, Hana Baba & Lahcen Wakrim

  2. Laboratory of Cellular and Molecular Pathology, Research Team on Immunopathology of Infectious and Systemic Diseases, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, 20000, Casablanca, Morocco

    Imane Ettaki & Hassan Fellah

  3. Laboratory of Biology and Health, URAC 34, Faculty of Sciences, Ben M’Sik Hassan II University of Casablanca, Casablanca, Morocco

    Asmae Saih & Hana Baba

  4. Research Unit of Epidemiology, Biostatistics and Bioinformatics, Institut Pasteur du Maroc, Casablanca, Morocco

    Hicham Charoute

  5. Environmental Health Laboratory, Institut Pasteur du Maroc, 20360, Casablanca, Morocco

    Salsabil Hamdi

  6. International Faculty of Dental Medicine Campus, UIR Technopolis Rocade Rabat, Rabat, Morocco

    Mustapha El Alloussi

  7. Laboratoire de biologie moléculaire, Institut Pasteur Casablanca, Casablanca, Morocco

    Hamid Barakat

Authors
  1. Imane Ettaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asmae Saih
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hicham Charoute
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hana Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Salsabil Hamdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mustapha El Alloussi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hamid Barakat
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hassan Fellah
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lahcen Wakrim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and approved the final manuscript.

Corresponding author

Correspondence to Imane Ettaki .

Editor information

Editors and Affiliations

  1. Computer Sciences Department, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaâdi University, Tangier, Morocco

    Mostafa Ezziyyani

  2. Systems Research Institute, Polish Academy of Science, Warsaw, Poland

    Janusz Kacprzyk

  3. Department of Automatics and Applied Software at the Faculty of Engineering, University "Aurel Vlaicu" Arad and Romanian Academy of Scientists, Arad, Romania

    Valentina Emilia Balas

Ethics declarations

Authors declare no conflict of interest exists.

Supplementary Data

Supplementary Data

Appendix 1: Analysis of structural effects of deleterious SNPs on PTH1R by Project HOPE.

figure a
figure b
figure c
figure d

Appendix 2: STRING Prediction of the PTH1R gene with legend

figure e
figure f

Rights and permissions

Reprints and permissions

Copyright information

© 2024 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this paper

Check for updates. Verify currency and authenticity via CrossMark

Cite this paper

Ettaki, I. et al. (2024). In-Silico Analysis of the High-Risk Missense Variants in PTH1R Gene and Association with Primary Failure of Tooth Eruption (PFE). In: Ezziyyani, M., Kacprzyk, J., Balas, V.E. (eds) International Conference on Advanced Intelligent Systems for Sustainable Development (AI2SD’2023). AI2SD 2023. Lecture Notes in Networks and Systems, vol 905. Springer, Cham. https://doi.org/10.1007/978-3-031-52385-4_26

Download citation

Publish with us

Policies and ethics

Search

Navigation