Skip to main content

Advertisement

SpringerLink
Log in

Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Objectives

Primary failure of tooth eruption (PFE) is a rare autosomal-dominant disease characterized by severe lateral open bite as a consequence of incomplete eruption of posterior teeth. Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been shown to cause PFE likely due to protein haploinsufficiency. To further expand on the mutational spectrum of PFE-associated mutations, we report here on the sequencing results of the PTH1R gene in 70 index PFE cases.

Materials and methods

Sanger sequencing of the PTH1R coding exons and their immediate flanking intronic sequences was performed with DNA samples from 70 index PFE cases.

Results

We identified a total of 30 unique variants, of which 12 were classified as pathogenic based on their deleterious consequences on PTH1R protein while 16 changes were characterized as unclassified variants with as yet unknown effects on disease pathology. The remaining two variants represent common polymorphisms.

Conclusions

Our data significantly increase the number of presently known unique PFE-causing PTH1R mutations and provide a series of variants with unclear pathogenicity which will require further in vitro assaying to determine their effects on protein structure and function.

Clinical relevance

Management of PTH1R-associated PFE is problematic, in particular when teeth are exposed to orthodontic force. Therefore, upon clinical suspicion of PFE, molecular DNA testing is indicated to support decision making for further treatment options.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Proffit WR, Vig KWL (1981) Primary failure of eruption: a possible cause of posterior open-bite. Am J Orthod 80:173–190

    Article  PubMed  Google Scholar 

  2. Frazier-Bowers SA, Koehler KE, Ackerman JL, Proffit WR (2007) Primary failure of eruption: further characterization of a rare eruption disorder. Am J Orthod Dentofac Orthop 131:578.e1–578.e11

    Article  Google Scholar 

  3. Decker E, Stellzig-Eisenhauer A, Fiebig BS, Rau C, Kress W, Saar K, Rüschendorf F, Hubner N, Grimm T, Weber BH (2008) PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption. Am J Hum Genet 83:781–786

    Article  PubMed Central  PubMed  Google Scholar 

  4. Stellzig-Eisenhauer A, Decker E, Meyer-Marcotty P, Rau C, Fiebig BS, Kress W, Saar K, Rüschendorf F, Hubner N, Grimm T, Witt E, Weber BH (2010) Primary failure of eruption (PFE)—clinical and molecular genetics analysis. J Orofac Orthop 71:6–16

    Article  PubMed  Google Scholar 

  5. Frazier-Bowers SA, Simmons D, Koehler K, Zhou J (2009) Genetic analysis of familial non-syndromic primary failure of eruption. Orthod Craniofac Res 12:74–81

    Article  PubMed Central  PubMed  Google Scholar 

  6. Yamaguchi T, Hosomichi K, Narita A, Shirota T, Tomoyasu Y, Maki K, Inoue I (2011) Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese. J Bone Miner Res 26:1655–1661

    Article  PubMed  Google Scholar 

  7. Mannstadt M, Jüppner H, Gardella TJ (1999) Receptors for PTH and PTHrP: their biological importance and functional properties. Am J Physiol 277:F665–F675

    PubMed  Google Scholar 

  8. Cormier S, Delezoide AL, Silve C (2003) Expression patterns of parathyroid hormone-related peptide (PTHrP) and parathyroid hormone receptor type1 (PTHR1) during human development are suggestive of roles specific for each gene that are not mediated through the PTHrP/PTHR1 paracrine signaling pathway. Gene Expr Patterns 3:59–63

    Article  PubMed  Google Scholar 

  9. Wysolmerski JJ, Cormier S, Philbrick WM, Dann P, Zhang JP, Roume J, Delezoide AL, Silve C (2001) Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction. J Clin Endocrinol Metab 86:1788–1794

    PubMed  Google Scholar 

  10. Houpis CH, Tosios KI, Papavasileiou D, Christopoulos PG, Koutlas IG, Sklavounou A, Alexandridis C (2010) Parathyroid hormone-related peptide (PTHrP), parathyroid hormone/parathyroid hormone-related peptide receptor 1 (PTHR1), and MSX1 protein are expressed in central and peripheral giant cell granulomas of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 109:415–424

    Article  PubMed  Google Scholar 

  11. Jobert A-S, Zhang P, Couvineau A, Bonaventure J, Roume J, Le Merrer M, Silve C (1998) Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J Clin Invest 102:34–40

    Article  PubMed Central  PubMed  Google Scholar 

  12. Duchatelet S, Ostergaard E, Cortes D, Lemainque A, Julier C (2005) Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Hum Mol Genet 14:1–5

    Article  PubMed  Google Scholar 

  13. Schipani E, Kruse K, Juppner H (1995) A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268:98–100

    Article  PubMed  Google Scholar 

  14. Hopyan S, Gokgoz N, Poon R, Gensure RC, Yu C, Cole WG, Bell RS, Jüppner H, Andrulis IL, Wunder JS, Alman BA (2002) A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat Genet 30:306–310

    Article  PubMed  Google Scholar 

  15. Rozeman LB, Sangiorgi L, Briaire-de Bruijn IH, Mainil-Varlet P, Bertoni F, Cleton-Jansen AM, Hogendoorn PCW, Bovee JVMG (2004) Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C. Hum Mutat 24:466–473

    Article  PubMed  Google Scholar 

  16. Ahmad S, Bister D, Cobourne MT (2006) The clinical features and aetiological basis of primary eruption failure. Eur J Orthod 28:535–540

    Article  PubMed  Google Scholar 

  17. Karperien M, van der Harten HJ, van Schooten R, Farih-Sips H, den Hollander NS, Kneppers SL, Nijweide P, Papapoulos SE, Löwik CW (1999) A frame-shift mutation in the type I parathyroid hormone (PTH)/PTH-related peptide receptor causing Blomstrand lethal osteochondrodysplasia. J Clin Endocrinol Metab 84:3713–3720

    Article  PubMed  Google Scholar 

  18. Frazier-Bowers SA, Simmons D, Wright JT, Proffit WR, Ackerman JL (2010) Primary failure of eruption and PTH1R: the importance of a genetic diagnosis for orthodontic treatment planning. Am J Orthod Dentofac Orthop 137:160.e1–160.e7

    Google Scholar 

  19. Hoogendam J, Farih-Sips H, Wÿnaendts LC, Löwik CW, Wit JM, Karperien M (2007) Novel mutations in the parathyroid hormone (PTH)/PTH-related peptide receptor type 1 causing Blomstrand osteochondrodysplasia types I and II. J Clin Endocrinol Metab 92:1088–1095

    Google Scholar 

Download references

Acknowledgments

We are grateful to the patients for consenting to participate in this study and to the following colleagues for referring the patients for DNA diagnostics and sharing clinical information (listed in alphabetical order): KD Beyer (Traunwalchen), C Denfeld (Frechen), S Fritz (Peine), B Gattung (Brühl), K Hagemann (Essen), P Hausmann (Fürstenfeldbruck), M Haugk (Schenklengsfeld), H Hoederath (Bonn), C Holtkamp (Meerbusch), M Kilb (Weißenhorn), A Kilgenstein (Aschaffenburg), H Klöcker (Cloppenburg), H Lummert (Uetze), M Madhoun (Neuwied), H Michl (Ebenhausen), E Müller-Menkens (Schwarme), A Neetz (Garbsen), B Orth (Bad Neustadt), K Pfister (Cloppenburg), P Rosenberg (Goldbach), M Schatz (Zell), J Scheel (Bamberg), A Schulze-Berge (Bad Kissingen), M Seibert (Ronnenberg), J Strasser (Brühl), M Thiel (Emmering), C Voss (Heidelberg), S Wallbrecht (Berlin), W Weigelt (Wipshausen), P Wieacker (Münster), and K Wittlinger (Traunstein). We are also indebted to the DNA Diagnostics Group for their help with the analysis and Jennifer Loewen-Horsch for improving the manuscript writing.

Author information

Authors and Affiliations

  1. Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany

    Helmut Roth, Lars G. Fritsche, Christoph Meier & Bernhard HF Weber

  2. Department of Orthodontics, University of Wuerzburg, Wuerzburg, Germany

    Peter Pilz, Martin Eigenthaler, Philipp Meyer-Marcotty & Angelika Stellzig-Eisenhauer

  3. Dental School, Department of Orthodontics, University Medical Centre of Regensburg, Regensburg, Germany

    Peter Proff

  4. Araçatuba Dental School, University Estadual Paulista (UNESP), Araçatuba, SP, Brazil

    Cláudia M. Kanno

Authors
  1. Helmut Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lars G. Fritsche
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christoph Meier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Pilz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martin Eigenthaler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Philipp Meyer-Marcotty
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Angelika Stellzig-Eisenhauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Proff
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cláudia M. Kanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bernhard HF Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernhard HF Weber.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. S1

Multiple sequence alignments. The amino acid sequence of human PTH1R (Homo sapiens, NP_000307.1) is aligned with that of rhesus (Macaca mulatta), mouse (Mus musculus), dog (Canis lupus familiaris), elephant (Loxodonta africana), opussum (Monodelphis domestica), and zebrafish (Danio rerio) using the MUltiple Sequence Comparison by Log-Expectation tool (MUSCLE) from the EMBL-EBI website (http://www.ebi.ac.uk/Tools/msa/muscle/). All 13 missense variants described in the paper are indicated below the alignment, the human amino acid is labeled in red. Conserved amino acids are shaded. The number of the last amino acid of each row of the human protein is also indicated above the alignment (DOCX 24 kb)

Table S1

Oligonucleotide primer sequences for PCR amplifications and sequencing of coding exons and exon/intron boundaries of the PTH1R gene (DOCX 14 kb)

Table S2

Splicing prediction analysis of synonymous and nonsynonymous missense coding and immediately flanking intronic sequence variants at the PTH1R locus (DOCX 25 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roth, H., Fritsche, L.G., Meier, C. et al. Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption. Clin Oral Invest 18, 377–384 (2014). https://doi.org/10.1007/s00784-013-1014-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-013-1014-3

Keywords

Search

Navigation