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.
Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark.
Lotte
L
Risom
Line
L
Christoffersen
Jette
J
Daugaard-Jensen
Hanne Dahlgaard
HD
Hove
Henriette Skovgaard
HS
Andersen
Brage Storstein
BS
Andresen
Sven
S
Kreiborg
Morten
M
Duno
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D005097:Exostoses, Multiple Hereditary / Q000235:genetics; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics; D010375:Pedigree; D011862:Radiography, Panoramic; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics*; D014076:Tooth Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D055815:Young Adult
C473449:PTH1R protein, human; D044168:Receptor, Parathyroid Hormone, Type 1