Identification of Six Novel PTH1R Mutations in Families with a History of Primary Failure of Tooth Eruption

Primary Failure of tooth Eruption (PFE) is a non-syndromic disorder which can be caused by mutations in the parathyroid hormone receptor 1 gene (PTH1R). Traditionally, the disorder has been identified clinically based on post-emergent failure of eruption of permanent molars. However, patients with PTH1R mutations will not benefit from surgical and/or orthodontic treatment and it is therefore clinically important to establish whether a given failure of tooth eruption is caused by a PTH1R defect or not. We analyzed the PTH1R gene in six patients clinically diagnosed with PFE, all of which had undergone surgical and/or orthodontic interventions, and identified novel PTH1R mutations in all. Four of the six mutations were predicted to abolish correct mRNA maturation either through introduction of premature stop codons (c.947C>A and c.1082G>A), or by altering correct mRNA splicing (c.544-26_544-23del and c.989G>T). The latter was validated by transfection of minigenes. The six novel mutations expand the mutation spectrum for PFE from eight to 14 pathogenic mutations. Loss-of-function mutations in PTH1R are also associated with recessively inherited Blomstrand chondrodysplasia. We compiled all published PTH1R mutations and identified a mutational overlap between Blomstrand chondrodysplasia and PFE. The results suggest that a genetic approach to preclinical diagnosis will have important implication for surgical and orthodontic treatment of patients with failure of tooth eruption

Orthopantomograms of three members from family F1.

<p>The pictures illustrate the variable phenotypic expression of the disorder in relation to symmetry and degree of affected teeth. F1; I:2 and F2; II:3 had affected teeth surgically removed, while F1; II:2 also had undergone unsuccessful orthodontic treatment. F1 II,2 is a 20 year old women showing primary failure of eruption (PFE) of maxillary and mandibulary premolars and molars. At age 16 the second molars in the left side of the maxilla and the mandible (27,37) were removed. The following orthodontic treatment was not succesfull. A new treatment plan including distraction osteogenesis of the posterior alveolar segment in the maxilla has been offered to the patient. The treatment has not yet been performed.</p