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.

Un contexte familial de défaut primaire d’éruption (DPE): identification d’une nouvelle mutation du gène PTHR-1. Cas clinique et revue de littérature

“…Depuis, plusieurs équipes (Decker en 2008 [6], FrazierBowers en 2010 [5], Risom en 2013 [10] et Roth en 2014 [22]) ont identifié différents types de mutations impliquées dans les DPE.…”

“…Cette mutation a été retrouvée chez plusieurs membres d'une fratrie [3,[5][6][7]. Il a été rapporté que, dans 10 à 40 % des cas, un contexte familial est retrouvé [4,[7][8][9].…”

“…Il a été rapporté que, dans 10 à 40 % des cas, un contexte familial est retrouvé [4,[7][8][9]. Ces études ont évoqué la possibilité d'un diagnostic moléculaire consistant en la recherche de mutations sur le gène PTHR-1 situé sur le locus chromosomique 3p22-p21.1, en complément des éléments cliniques [6]. Il s'agit d'une mutation hétérozygote du gène codant pour le récepteur (RCPG de type 2) de l'hormone parathyroïdienne transmise selon un mode autosomique dominant [10,11].…”

The Identification of Differentially Expressed Genes of Human Prolactinoma by Microarray

“…DEGs are also enriched in Neuroactive ligandreceptor interaction, which are mainly involved in osteoporosis, sexual precocity and ovarian h y -perstimulation syndrome. It means that this kegg pathway has strong correlation with prolactinoma (Decker et al, 2008;Frimberger and Gearhart, 2005;Bertelloni and Mul, 2008;Kasum, 2010).…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…Several oral manifestations have been described in patients with PHP and related disorders, including aplasia, thin enamel with enlarged pulp chamber, hypoplasia, hypodontia, pulp calcification, multiple carious teeth, multiple unerupted teeth or delayed tooth eruption, crowded anterior teeth, anterior open bite, gingival hyperplasia, gingivitis with spontaneous bleeding and pain 88,260 . Familial nonsyndromic primary failure of tooth eruption has also been described in patients with mutations in PTHR1 and PTHrP 88,261 . Recommendations 3.37.…”