Clinical Oral Investigations

, Volume 18, Issue 2, pp 377–384 | Cite as

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

  • Helmut Roth
  • Lars G. Fritsche
  • Christoph Meier
  • Peter Pilz
  • Martin Eigenthaler
  • Philipp Meyer-Marcotty
  • Angelika Stellzig-Eisenhauer
  • Peter Proff
  • Cláudia M. Kanno
  • Bernhard HF WeberEmail author
Original Article



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.


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.


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.


Primary failure of tooth eruption Parathyroid hormone 1 receptor gene Mutation detection Protein truncating mutation Nonsynonymous variant Familial cases Simplex cases 



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.

Supplementary material

784_2013_1014_MOESM1_ESM.docx (24 kb)
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 ( 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)
784_2013_1014_MOESM2_ESM.docx (15 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)
784_2013_1014_MOESM3_ESM.docx (25 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)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Helmut Roth
    • 1
  • Lars G. Fritsche
    • 1
  • Christoph Meier
    • 1
  • Peter Pilz
    • 2
  • Martin Eigenthaler
    • 2
  • Philipp Meyer-Marcotty
    • 2
  • Angelika Stellzig-Eisenhauer
    • 2
  • Peter Proff
    • 3
  • Cláudia M. Kanno
    • 4
  • Bernhard HF Weber
    • 1
    Email author
  1. 1.Institute of Human GeneticsUniversity of RegensburgRegensburgGermany
  2. 2.Department of OrthodonticsUniversity of WuerzburgWuerzburgGermany
  3. 3.Dental School, Department of OrthodonticsUniversity Medical Centre of RegensburgRegensburgGermany
  4. 4.Araçatuba Dental SchoolUniversity Estadual Paulista (UNESP)AraçatubaBrazil

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