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