title: Novel mutations in PTH1R associated with primary failure of eruption and osteoarthritis.
abstract: Autosomal dominant mutations in PTH1R segregate with primary failure of eruption (PFE), marked by clinical eruption failure of adult teeth without mechanical obstruction. While the diagnosis of PFE conveys a poor dental prognosis, there are no reports of PFE patients who carry PTH1R mutations and exhibit any other skeletal problems. We performed polymerase chain reaction-based mutational analysis of the PTH1R gene to determine the genetic contribution of PTH1R in 10 families with PFE. Sequence analysis of the coding regions and intron-exon boundaries of the PTH1R gene in 10 families (n = 54) and 7 isolated individuals revealed 2 novel autosomal dominant mutations in PTH1R (c.996_997insC and C.572delA) that occur in the coding region and result in a truncated protein. One family showed incomplete penetrance. Of 10 families diagnosed with PFE, 8 did not reveal functional (nonsynonymous) mutations in PTH1R; furthermore, 4 families and 1 sporadic case carried synonymous single-nucleotide polymorphisms. Five PFE patients in 2 families carried PTH1R mutations and presented with osteoarthritis. We propose that the autosomal dominant mutations of PTH1R that cause PFE may also be associated with osteoarthritis; a dose-dependent model may explain isolated PFE and osteoarthritis in the absence of other known symptoms in the skeletal system.
authors.affiliation: Department of Orthodontics, School of Dentistry, University of North Carolina at Chapel Hill.
authors.forename: S A
authors.initials: SA
authors.lastname: Frazier-Bowers
authors.forename: H M
authors.initials: HM
authors.lastname: Hendricks
authors.forename: J T
authors.initials: JT
authors.lastname: Wright
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Long
authors.forename: C F
authors.initials: CF
authors.lastname: Dibble
authors.forename: S
authors.initials: S
authors.lastname: Bencharit
mesh_terms: D000225:Adenine; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D003062:Codon / Q000235:genetics; D018388:Codon, Terminator / Q000235:genetics; D003596:Cytosine; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010003:Osteoarthritis / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013941:Thymine; D014076:Tooth Diseases / Q000235:genetics*; D014078:Tooth Eruption / Q000235:genetics; D055815:Young Adult
chemical_list: D003062:Codon; D018388:Codon, Terminator; C473449:PTH1R protein, human; D044168:Receptor, Parathyroid Hormone, Type 1; D003596:Cytosine; D000225:Adenine; D013941:Thymine
keywords: arthritis; genetics; incomplete penetrance; orthodontics; polymorphism; tooth eruption