title: 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.
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Decker
authors.forename: Angelika
authors.initials: A
authors.lastname: Stellzig-Eisenhauer
authors.forename: Britta S
authors.initials: BS
authors.lastname: Fiebig
authors.forename: Christiane
authors.initials: C
authors.lastname: Rau
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.forename: Kathrin
authors.initials: K
authors.lastname: Saar
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Tiemo
authors.initials: T
authors.lastname: Grimm
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
mesh_terms: D002893:Chromosomes, Human, Pair 3; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D005819:Genetic Markers; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics*; D014078:Tooth Eruption / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D044168:Receptor, Parathyroid Hormone, Type 1