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

Abstract

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.

PTH receptor-1 signalling—mechanistic insights and therapeutic prospects

“…85 Heterozygous expression of such receptor variants is also observed in enchondromas in patients with Ollier’s disease 86 and is associated with familial primary failure of tooth eruption (Table 1). 87 Gain-of-function receptor variants for which ligand binding is not required for activation of signal transduction have also been identified. 88 Heterozygous expression of such constitutively active PTHR1 variants causes a rare, dominant disorder known as Jansen’s metaphyseal chondrodysplasia (Table 1).…”

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

“…In the heterozygous state, the P132L mutation, as well as several other predicted loss-of-function mutations in the PTHR1 gene have been linked to familial cases of defective tooth eruption (Decker et al, 2008;Frazier-Bowers et al, 2010;Yamaguchi et al, 2011;Risom et al, 2013). Four other heterozygous PTHR1 point mutations: G121E, A122T, R150C, and R255H, the first three of which also map to the receptor's ECD region and impair receptor function, have been identified in Ollier disease, a development condition defined by the occurrence of multiple enchondromas (Hopyan et al, 2002;Couvineau et al, 2008).…”

Genetic Disorders Caused by Mutations in the PTH/PTHrP Receptor and Downstream Effector Molecules

“…109 Three distinct mutations were initially identified that are truncating the mature protein and are therefore expected to lead to a functionless receptor. These studies, which were subsequently confirmed and extended, 110,[124][125][126] indicate that haploinsufficiency of PTH1R is most likely the underlying cause of non-syndromic PFE. The PTH1R mutations responsible for PFE include a heterozygous c.1353-1 G>A sequence alteration that caused a putative splice-site mutation and skipping of exon 15, as well as several missense mutations, including the P132L and the "R383Q" mutation that were first identified in Blomstrand cases.…”