Novel Mutations in <i>PTH1R</i> Associated with Primary Failure of Eruption and Osteoarthritis

Frazier‐Bowers, Sylvia A.; Hendricks, Heather; Wright, J. Timothy; Lee, J.; Long, Kristin M.; Dibble, Christopher F.; Bencharit, Sompop

doi:10.1177/0022034513513588

Cited by 58 publications

(53 citation statements)

References 34 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this system, the transfection of human wild type PTH1R and stimulation of the cells with PTH showed good response with regard to intracellular cAMP signaling. This provides a new model system for testing the functional effects of the known PTH1R mutants derived from patients with PFE [3, 6, 7, 8]. …”

Section: Discussionmentioning

confidence: 99%

PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling

et al. 2016

View full text Add to dashboard Cite

AimPrimary failure of tooth eruption (PFE) is causally linked to heterozygous mutations of the parathyroid hormone receptor (PTH1R) gene. The mutants described so far lead to exchange of amino acids or truncation of the protein that may result in structural changes of the expressed PTH1R. However, functional effects of these mutations have not been investigated yet.Materials and MethodsIn HEK293 cells, PTH1R wild type was co-transfected with selected PTH1R mutants identified in patients with PFE. The effects on activation of PTH-regulated intracellular signaling pathways were analyzed by ELISA and Western immunoblotting. Differential effects of wild type and mutated PTH1R on TRESK ion channel regulation were analyzed by electrophysiological recordings in Xenopus laevis oocytes.ResultsIn HEK293 cells, activation of PTH1R wild type increases cAMP and in response activates cAMP-stimulated protein kinase as detected by phosphorylation of the vasodilator stimulated phosphoprotein (VASP). In contrast, the PTH1R mutants are functionally inactive and mutant PTH1R/Gly452Glu has a dominant negative effect on the signaling of PTH1R wild type. Confocal imaging revealed that wild type PTH1R is expressed on the cell surface, whereas PTH1R/Gly452Glu mutant is mostly retained inside the cell. Furthermore, in contrast to wild type PTH1R which substantially augmented K+ currents of TRESK channels, coupling of mutated PTH1R to TRESK channels was completely abolished.ConclusionsPTH1R mutations affect intracellular PTH-regulated signaling in vitro. In patients with primary failure of tooth eruption defective signaling of PTH1R mutations is suggested to occur in dento-alveolar cells and thus may lead to impaired tooth movement.

show abstract

Section: Discussionmentioning

confidence: 99%

PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Récemment, l'équipe de Frazier-Bowers a mis en évidence deux nouvelles mutations à partir de dix familles ainsi que des cas associés à de l'ostéoarthrite [11].…”

Section: Discussionunclassified

“…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]. Des études plus récentes ont confirmé la présence de mutations géné-tiques PTHR-1 [11][12] (MIM 125350).…”

Section: Introductionunclassified

See 1 more Smart Citation

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

Quinque

Clauss

Siebert

et al. 2016

Med Buccale Chir Buccale

View full text Add to dashboard Cite

Résumé -Introduction :Le défaut primaire d'éruption désigne l'échec de l'éruption d'une dent permanente postérieure non ankylosée en l'absence d'une obstruction d'origine mécanique. Une anomalie des processus biologiques de l'éruption dentaire, d'origine génétique, constitue le mécanisme étiologique. Elle est la conséquence de la mutation du gène codant pour le récepteur de l'hormone parathyroïdienne PTHR-1. Observation : Le cas rapporté décrit un défaut primaire d'éruption dans le cadre d'une fratrie de deux enfants. Les manifestations cliniques sont une infraclusion latérale sévère à droite dans un contexte de classe I tendance classe III par brachygnathie. Le diagnostic génétique a mis en évidence une mutation du gène PTHR-1. Discussion : Toute tentative de traction chirurgico-orthodontique d'une dent atteinte de DPE s'expose à un échec de traction voire une aggravation de l'inclusion ou une évolution vers l'ankylose. Conclusion : Un diagnostic positif précoce est donc essentiel en cas d'échec primaire d'éruption. Il est basé sur différents critères diagnostiques cliniques, radiologiques et moléculaires.Abstract -A novel PTHR-1 gene mutation in a context of familial primary failure of eruption: case report and literature review. Introduction: Primary failure of eruption is characterized by the failure of eruption of a posterior permanent tooth in the absence of mechanical obstruction. An abnormality of the biological processes of tooth eruption linked to a genetic mutation is the etiologic mechanism. It is the result of mutation of the gene encoding for the parathyroid hormone receptor PTHR-1. Observation: We report a case of primary failure of eruption of two children in a family. The clinical report describes a severe infraclusion on the right side in a context of Class I tendency Class III by maxillary hypoplasia. Molecular diagnosis based on the use of a DNA chip revealed a PTHR-1 gene mutation. Discussion: Since any orthodontic treatment results in traction failure, a worsening inclusion or ankylosis, an early positive diagnosis is essential in cases of primary failure of eruption. Conclusion: There are several criteria for clinical diagnosis, radiological and genetic, to identify these cases.

show abstract

“…To date, over 25 unique mutations within the PTH1R gene appear to be associated with PFE; with some mutations introducing an immediate stop code or frameshifts in the code leading to the premature truncation of the protein and haploinsufficiency, while other mutations lead to aberrant RNA splicing of the PTH1R messenger RNA. 74,78–82 Advancements in this area could not only help to define patients who are likely to develop or have PFE, but also potentially result in the molecular manipulation of selective tooth eruption rates to enhance treatment protocols on an individual basis. 83 …”

Section: Primary Failure Of Eruption (Pfe)mentioning

confidence: 99%

Heredity, genetics and orthodontics: How much has this research really helped?

Hartsfield

Jacob

Morford³

2017

Seminars in Orthodontics

View full text Add to dashboard Cite

Uncovering the genetic factors that correlate with a clinical deviation of previously unknown etiology helps to diminish the unknown variation influencing the phenotype. Clinical studies, particularly those that consider the effects of an appliance or treatment regimen on growth, need to be a part of these types of genetic investigations in the future. While the day-to-day utilization of “testing” for genetic factors is not ready for practice yet, genetic testing for monogenic traits such as Primary Failure of Eruption (PFE) and Class III malocclusion is showing more promise as knowledge and technology advances. Although the heterogeneous complexity of such things as facial and dental development, the physiology of tooth movement, and the occurrence of External Apical Root Resorption (EARR) make their precise prediction untenable, investigations into the genetic factors that influence different phenotypes, and how these factors may relate to or impact environmental factors (including orthodontic treatment) are becoming better understood. The most important “genetic test” the practitioner can do today is to gather the patient’s individual and family history. This would greatly benefit the patient, and augment the usefulness of these families in future clinical research in which clinical findings, environmental, and genetic factors can be studied.

show abstract

Novel Mutations in PTH1R Associated with Primary Failure of Eruption and Osteoarthritis

Cited by 58 publications

References 34 publications

PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling

PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling

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

Heredity, genetics and orthodontics: How much has this research really helped?

Contact Info

Product

Resources

About