PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption

Abstract

Tooth eruption is a complex developmental process requiring coordinated navigation through alveolar bone and oral epithelium. Primary failure of tooth eruption (PFE) is associated with several syndromes primarily affecting skeletal development, but it is also known as a nonsyndromic autosomal-dominant condition. Teeth in the posterior quadrants of the upper and lower jaw are preferentially affected and usually result in an open bite extending from anterior to posterior. In this study, we show that familial, nonsyndromic PFE is caused by heterozygous mutations in the gene encoding the G protein-coupled receptor for parathyroid hormone and parathyroid hormone-like hormone (PTHR1). Three distinct mutations, namely c.1050-3C > G, c.543+1G > A, and c.463G > T, were identified in 15 affected individuals from four multiplex pedigrees. All mutations truncate the mature protein and therefore should lead to a functionless receptor, strongly suggesting that haplo-insufficiency of PTHR1 is the underlying cause of nonsyndromic PFE. Although complete inactivation of PTHR1 is known to underlie the autosomal-recessive Blomstrand osteochondrodysplasia (BOCD), a lethal form of short-limbed dwarfism, our data now imply that dominantly acting PTHR1 mutations that lead to haplo-insufficiency of the receptor result in a nonsyndromic phenotype affecting tooth development with high penetrance and variable expressivity.

Figure 1

PTHR1 Mutations in Individuals Affected by Nonsyndromic PFE and Their Effect on Transcript Splicing (A) Eruption failure of posterior teeth and deficits in alveolar bone growth result in a severe bilateral open bite. Shown are an intraoral view (upper chart) and orthopantomogram (lower chart) of patient ZD1-III:2. (B) Pedigree drawings showing individuals examined clinically and by mutation analysis. PTHR1 mutations segregating with the clinical phenotype are presented in brackets. (C) RT-PCR analysis of splice-site mutation c.1050-3C > G in gingival RNA of patient ZD1-III:3. Sequence traces of the normal allele and the shortened mutant allele demonstrate the excision of exon 12 in the mature transcript of the mutated allele. (D) In vitro minigene reporter analysis of splice-acceptor sequence mutation c.1050-3C > G. Irregular transcript splicing is observed for the mutant allele such that the entire PTHR1 exon 12 is skipped. (E) In vitro minigene reporter analysis of splice-donor sequence mutation c.543+1G > A. Irregular transcript splicing involving a vector-specific cryptic splice is observed for the mutant allele.