Failure Of Tooth Eruption Research Articles

New Insight into the genotype-phenotype correlation of PTH1R variants and primary failure of tooth eruption on an Italian Cohort.

Primary failure of tooth eruption (PFE) is an autosomal dominant disease with penetrance defect. While the clinical phenotype is relatively well-defined since the 70 s of the last centuries, much more need to be clarified about the genetic causes of this condition. In our previous paper we established clinical criteria to better identify PFE patients carrying PTH1R gene variants. We examined a new cohort of 32 patients, including one or more relatives for 7 patients (43 cases in total), referred to have PFE and recruited from our Hospital and from external outpatients. Sequencing analysis of the PTH1R coding sequence in this cohort of patients revealed 9 different variants, 4 exonic and 5 intronic. Through in silico prediction tools and databases, 3 of them (2 exonic and 1 in a splicing site) had been considered potentially involved in the PFE phenotype. Sequencing of cDNA was unsuccessfully attempted due to the low levels of PTH1R expression in the analysed tissues. The yield of the genetic test increases when the clinical selection of the patients with dental eruption failure is well-characterized. Dental eruption failure with pure clinical findings of PFE associated with familial history revealed variants in PTH1R gene, offering a diagnostic test for the family. Characterization of novel variants in the most relevant responsible gene of the PFE could bring to a more accurate diagnosis and therapeutic approach in the future and to a deeper comprehension of the disease.

Abnormal dental follicle cells: A crucial determinant in tooth eruption disorders (Review).

The dental follicle (DF) plays an indispensable role in tooth eruption by regulating bone remodeling through their influence on osteoblast and osteoclast activity. The process of tooth eruption involves a series of intricate regulatory mechanisms and signaling pathways. Disruption of the parathyroid hormone‑related protein (PTHrP) in the PTHrP‑PTHrP receptor signaling pathway inhibits osteoclast differentiation by DF cells (DFCs), thus resulting in obstructed tooth eruption. Furthermore, parathyroid hormone receptor‑1 mutations are linked to primary tooth eruption failure. Additionally, the Wnt/β‑catenin, TGF‑β, bone morphogenetic protein and Hedgehog signaling pathways have crucial roles in DFC involvement in tooth eruption. DFC signal loss or alteration inhibits osteoclast differentiation, affects osteoblast and cementoblast differentiation, and suppresses DFC proliferation, thus resulting in failed tooth eruptions. Abnormal tooth eruption is also associated with a range of systemic syndromes and genetic diseases, predominantly resulting from pathogenic gene mutations. Among these conditions, the following disorders arise due to genetic mutations that disrupt DFCs and impede proper tooth eruption: Cleidocranial dysplasia associated with Runt‑related gene 2 gene mutations; osteosclerosis caused by CLCN7 gene mutations; mucopolysaccharidosis type VI resulting from arylsulfatase B gene mutations; enamel renal syndrome due to FAM20A gene mutations; and dentin dysplasia caused by mutations in the VPS4B gene. In addition, regional odontodysplasia and multiple calcific hyperplastic DFs are involved in tooth eruption failure; however, they are not related to gene mutations. The specific mechanism for this effect requires further investigation. To the best of our knowledge, previous reviews have not comprehensively summarized the syndromes associated with DF abnormalities manifesting as abnormal tooth eruption. Therefore, the present review aims to consolidate the current knowledge on DFC signaling pathways implicated in abnormal tooth eruption, and their association with disorders of tooth eruption in genetic diseases and syndromes, thereby providing a valuable reference for future related research.

Etiological Mechanisms and Genetic/Biological Modulation Related to PTH1R in Primary Failure of Tooth Eruption.

Primary failure of eruption (PFE) is a rare disorder that is characterized by the inability of a molar tooth/teeth to erupt to the occlusal plane or to normally react to orthodontic force. This condition is related to hereditary factors and has been extensively researched over many years. However, the etiological mechanisms of pathogenesis are still not fully understood. Evidence from studies on PFE cases has shown that PFE patients may carry parathyroid hormone 1 receptor (PTH1R) gene mutations, and genetic detection can be used to diagnose PFE at an early stage. PTH1R variants can lead to altered protein structure, impaired protein function, and abnormal biological activities of the cells, which may ultimately impact the behavior of teeth, as observed in PFE. Dental follicle cells play a critical role in tooth eruption and root development and are regulated by parathyroid hormone-related peptide (PTHrP)-PTH1R signaling in their differentiation and other activities. PTHrP-PTH1R signaling also regulates the activity of osteoblasts, osteoclasts and odontoclasts during tooth development and eruption. When interference occurs in the PTHrP-PTH1R signaling pathway, the normal function of dental follicles and bone remodeling are impaired. This review provides an overview of PTH1R variants and their correlation with PFE, and highlights that a disruption of PTHrP-PTH1R signaling impairs the normal process of tooth development and eruption, thus providing insight into the underlying mechanisms related to PTH1R and its role in driving PFE.

Primary Failure Eruption: Genetic Investigation, Diagnosis and Treatment: A Systematic Review.

The aim of this systematic review is to explore the pathology, diagnosis, treatment, and genetic basis of Primary Failure of Eruption (PFE) in the field of pediatric dentistry and orthodontics. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this review. The databases PubMed, Science Direct, Scopus, and Web of Science were searched from 1 July 2013 to 1 July 2023, using keywords "primary failure of tooth eruption" OR "primary failure of eruption" OR "tooth eruption failure" OR "PFE" AND "orthodontics". The study selection process involved screening articles based on the inclusion and exclusion criteria. A total of 1151 results were obtained from the database search, with 14 papers meeting the inclusion criteria. The review covers various aspects of PFE, including its clinical features, diagnosis, treatment options, and genetic associations with mutations in the PTH1R gene. Differentiation between PFE and Mechanical Failure of Eruption (MFE) is crucial for accurate treatment planning. Orthodontic and surgical interventions, along with multidisciplinary approaches, have been employed to manage PFE cases. Genetic testing for PTH1R mutations plays a significant role in confirming the diagnosis and guiding treatment decisions, although some cases may not be linked to this mutation. This systematic review provides valuable insights into the diagnosis, treatment, and genetic basis of PFE. Early diagnosis and personalized treatment planning are crucial for successful management. Genetic testing for PTH1R mutations aids in accurate diagnosis and may influence treatment decisions. However, further research is needed to explore the complex genetic basis of PFE fully and improve treatment outcomes for affected individuals.

Identification of a novel heterozygous PTH1R variant in a Chinese family with incomplete penetrance.

Mutations in PTH1R are associated with Jansen-type metaphyseal chondrodysplasia (JMC), Blomstrand osteochondrodysplasia (BOCD), Eiken syndrome, enchondroma, and primary failure of tooth eruption (PFE). Inheritance of the PTH1R gene can be either autosomal dominant or autosomal recessive, indicating the complexity of the gene. Our objective was to identify the phenotypic differences in members of a family with a novel PTH1R mutation. The proband was a 13-year, 6-month-old girl presenting with short stature, abnormal tooth eruption, skeletal dysplasia, and midface hypoplasia. The brother and father of the proband presented with short stature and abnormal tooth eruption. High-throughput sequencing was performed on the proband, and the variant was confirmed in the proband and other family members by Sanger sequencing. Amino acid sequence alignment was performed using ClustalX software. Three-dimensional structures were analyzed and displayed using the I-TASSER website and PyMOL software. High-throughput genome sequencing and Sanger sequencing validation showed that the proband, her father, and her brother all carried the PTH1R (NM_000316) c.1393G>A (p.E465K) mutation. The c.1393G>A (p.E465K) mutation was novel, as it has not been reported in the literature database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the p.E465K variant was considered to have uncertain significance. Biological information analysis demonstrated that this identified variant was highly conserved and highly likely pathogenic. We identified a novel heterozygous mutation in the PTH1R gene leading to clinical manifestations with incomplete penetrance that expands the spectrum of known PTH1R mutations.

Identification of a novel PTH1R variant in a family with primary failure of eruption

BackgroundPrimary failure of tooth eruption (PFE) is a rare autosome genetic disorder that causes open bite. This work aimed to report a small family of PFE(OMIM: # 125,350) with a novel PTH1R variant. One of the patients has a rare clinical phenotype of the anterior tooth involved only.Case presentationThe proband was a 13-year-old young man with an incomplete eruption of the right upper anterior teeth, resulting in a significant open-bite. His left first molar partially erupted. Family history revealed that the proband’s 12-year-old brother and father also had teeth eruption disorders. Genetic testing found a novel PTH1R variant (NM_000316.3 c.1325-1336del), which has never been reported before. The diagnosis of PFE was based on clinical and radiographic characteristics and the result of genetic testing. Bioinformatic analysis predicted this variant would result in the truncation of the G protein-coupled receptor encoded by the PTH1R, affecting its structure and function.ConclusionA novel PTH1R variant identified through whole-exome sequencing further expands the mutation spectrum of PFE. Patients in this family have different phenotypes, which reflects the characteristics of variable phenotypic expression of PFE.

Primary failure of tooth eruption: Etiology and management.

Primary failure of eruption (PFE) is a rare disorder defined as incomplete tooth eruption despite the presence of a clear eruption pathway. PFE is known to be caused by rare variants in the parathyroid hormone 1 receptor gene (PTH1R). Although several PTH1R variants have been reported, the etiology of PFE remains unclear. However, important studies that help elucidate the pathology of PFE have recently been published. The purpose of this review is to summarize current treatment options, clinical symptoms or phenotypes for diagnosis, genetic information including solid evidence in mouse disease models and disease-specific induced pluripotent stem cells, thus approaching the etiology of PFE from the perspective of the latest research.

Ameloblastic Fibro-Odontoma

Introduction: Ameloblastic fibro-odontoma (AFO) is a benign odontogentic tumor without an aggressive behavior, unlike the similar ameloblastic fibroma. Case Presentation: A 9-year-old boy, with tooth eruption failure, underwent enucleation and curettage of a well-defined variable radiolucent and radio-opaque right mandible lesion. There was odontogenic epithelium with peripheral palisading in a loose myxoid stroma as well as a disorganized component of dentin, enamel, and cementum, features of an AFO. Conclusion: AFO is an odontogenic mixed tumor of epithelium and mesenchyme.

A rare entity-lateral inflammatory follicular cyst

Sometimes, there is failure in tooth eruption not because of any physical barrier or abnormal position. The reason for the failure of tooth eruption in this current case is due to uncommon phenomenon. There was a swelling in the lower canine region bilaterally with impacted the 32,33,42 and 43. This case also shares a detailed CBCT report and microscopic features of the rare entity, the lateral inflammatory follicular cyst.

Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism.

ABSTRACTConsistent with a vital role of parathyroid hormone (PTH) receptor type 1 (PTH1R) in skeletal development, homozygous loss‐of‐function PTH1R mutations in humans results in neonatal lethality (Blomstrand chondrodysplasia), whereas such heterozygous mutations cause a primary failure of tooth eruption (PFE). Despite a key role of PTH1R in calcium and phosphate homeostasis, blood mineral ion levels are not altered in such cases of PFE. Recently, two nonlethal homozygous PTH1R mutations were identified in two unrelated families in which affected members exhibit either dental and skeletal abnormalities (PTH1R‐V204E) or hypocalcemia and hyperphosphatemia (PTH1R‐R186H). Arg186 and Val204 map to the first transmembrane helix of the PTH1R, and thus to a critical region of this class B G protein‐coupled receptor. We used cell‐based assays and PTH and PTH‐related protein (PTHrP) ligand analogs to assess the impact of the R186H and V204E mutations on PTH1R function in vitro. In transiently transfected HEK293 cells, PTH1R‐R186H mediated cyclic adenosine monophosphate (cAMP) responses to PTH(1‐34) and PTHrP(1‐36) that were of comparable potency to those observed on wild‐type PTH1R (PTH1R‐WT) (half maximal effective concentrations [EC50s] = 0.4nM to 1.2nM), whereas the response‐maxima were significantly reduced for the PTH1R‐V204E mutant (maximum effect [Emax] = 81%–77% of PTH1R‐WT, p ≤ 0.004). Antibody binding to an extracellular hemagglutinin (HA) tag was comparable for PTH1R‐R186H and PTH1R‐WT, but was significantly reduced for PTH1R‐V204E (maximum binding level [Bmax] = 44% ± 11% of PTH1R‐WT, p = 0.002). The potency of cAMP signaling induced by a PTH(1‐11) analog was reduced by ninefold and threefold, respectively, for PTH1R‐R186H and PTH1R‐V204E, relative to PTH1R‐WT, and a PTH(1‐15) radioligand analog that bound adequately to PTH1R‐WT exhibited little or no specific binding to either mutant receptor. The data support a general decrease in PTH1R surface expression and/or function as a mechanism for PFE and a selective impairment in PTH ligand affinity as a potential PTH1R‐mutation‐based mechanism for pseudohypoparathyroidism. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A UNIQUE CASE OF REGIONAL ODONTODYSPLASIA

<h3>BACKGROUND</h3> Regional odontodysplasia is a rare condition involving defective enamel and dentin in a group of adjacent teeth. It may also include calcifications within the dental pulp and/or dental follicle.^1,2 First described by Hitchin in 1934,³ regional odontodysplasia affects dental mesodermal and ectodermal tissues along particular segments of the maxilla and/or mandible in the primary and/or permanent dentitions. There is a sex predilection, affecting women more than men.⁴ The current case is of a 6-year-old girl who presented with asymmetry of the face at a children's hospital in the eastern United States. <h3>CASE REPORT</h3> A 6-year-old female patient presented with a history of extractions of abscessed teeth #H and #I. Tooth #I was extracted because of abscess and facial cellulitis. The patient was admitted for intravenous antibiotics. Medical history was noncontributory. Dental history was positive for a drooping upper left lip and expansion of the upper left alveolar ridge. Panoramic and multiple periapical radiographs were acquired. Radiographically, the permanent maxillary left first and second molars and primary second molar had defective enamel and dentin along with taurodontism. The pulp chamber and canal were elongated. These features had the appearance of "ghost teeth." The bone around the maxillary left posterior aspect was also affected. <h3>DISCUSSION/CONCLUSIONS</h3> The presented tooth specimen exhibited irregular, abnormally distributed dentinal tubules. Globular calcified masses within the pulp were seen. Based on clinical, histopathologic, and radiographic findings, the case was diagnosed as regional odontodysplasia. Treatment included comprehensive dental care including endodontic, prosthodontic, orthodontic, and surgical intervention. Regional odontodysplasia is a rare developmental anomaly. It presents with a slight female predilection in a bimodal age distribution, most commonly affecting a single quadrant, with the maxilla more commonly involved. Clinical manifestations may include hyperplastic gingiva, failure of tooth eruption, periapical inflammation, bony changes, alterations of the dentition, and cutaneous nevi in the affected area.⁵

The Role of Wnt Signaling in Postnatal Tooth Root Development.

Appropriate tooth root formation and tooth eruption are critical for achieving and maintaining good oral health and quality of life. Tooth eruption is the process through which teeth emerge from their intraosseous position to their functional position in the oral cavity. This temporospatial process occurs simultaneously with tooth root formation through a cascade of interactions between the epithelial and adjoining mesenchymal cells. Here, we will review the role of the Wnt system in postnatal tooth root development. This signaling pathway orchestrates the process of tooth root formation and tooth eruption in conjunction with several other major signaling pathways. The Wnt signaling pathway is comprised of the canonical, or Wnt/β-catenin, and the non-Canonical signaling pathway. The expression of multiple Wnt ligands and their downstream transcription factors including β-catenin is found in the cells in the epithelia and mesenchyme starting from the initiation stage of tooth development. The inhibition of canonical Wnt signaling in an early stage arrests odontogenesis. Wnt transcription factors continue to be present in dental follicle cells, the progenitor cells responsible for differentiation into cells constituting the tooth root and the periodontal tissue apparatus. This expression occurs concurrently with osteogenesis and cementogenesis. The conditional ablation of β-catenin in osteoblast and odontoblast causes the malformation of the root dentin and cementum. On the contrary, the overexpression of β-catenin led to shorter molar roots with thin and hypo-mineralized dentin, along with the failure of tooth eruption. Therefore, the proper expression of Wnt signaling during dental development is crucial for regulating the proliferation, differentiation, as well as epithelial-mesenchymal interaction essential for tooth root formation and tooth eruption.

Effective CRISPR interference of an endogenous gene via a single transgene in mice

Drawbacks of conditional gene deletion in mice include the need for extensive breeding and, often, a lack of cell type-specificity. CRISPR interference (CRISPRi) is an alternative approach for loss-of-function studies that inhibits expression by guiding a transcriptional repressor to the transcription start-site of target genes. However, there has been limited exploration of CRISPRi in mice. We tested the effectiveness of a single CRISPRi transgene broadly expressing a single guide RNA and a catalytically dead Cas9 fused to the KRAB repressor domain to suppress a well-characterized target gene, Tnfsf11. The phenotype of CRISPRi transgenic mice was compared to mice with germline deletion of Tnfsf11, which are osteopetrotic and do not form lymph nodes. High transgene expression mimicked gene deletion, with failure of lymph node development and classic signs of osteopetrosis such as high bone mass and failure of tooth eruption. Mice with low transgene expression were normal and mice with medium expression displayed an intermediate phenotype. Transgene expression in tissues from these mice correlated inversely with Tnfsf11 mRNA levels. These results demonstrate that a single CRISPRi transgene can effectively suppress a target gene in mice and suggest that this approach may be useful for cell type-specific loss-of-function studies.

KMT2C, a histone methyltransferase, is mutated in a family segregating non-syndromic primary failure of tooth eruption

Primary failure of tooth eruption (PFE) is a rare odontogenic defect and is characterized by failure of eruption of one or more permanent teeth. The aim of the study is to identify the genetic defect in a family with seven affected individuals segregating autosomal dominant non-syndromic PFE. Whole genome single-nucleotide polymorphism (SNP) genotyping was performed. SNP genotypes were analysed by DominantMapper and multiple shared haplotypes were detected on different chromosomes. Four individuals, including three affected, were exome sequenced. Variants were annotated and data were analysed while considering candidate chromosomal regions. Initial analysis of variants obtained by whole exome sequencing identified damaging variants in C15orf40, EPB41L4A, TMEM232, KMT2C, and FBXW10 genes. Sanger sequencing of all family members confirmed segregation of splice acceptor site variant (c.1013-2 A > G) in the KMT2C gene with the phenotype. KMT2C is considered as a potential candidate gene based on segregation analysis, the absence of variant in the variation databases, the presence of variant in the shared identical by descent (IBD) region and in silico pathogenicity prediction. KMT2C is a histone methyltransferase and recently the role of another member of this family (KMT2D) has been implicated in tooth development. Moreover, protein structures of KMT2C and KMT2D are highly similar. In conclusion, we have identified that the KMT2C gene mutation causes familial non-syndromic PFE. These findings suggest the involvement of KMT2C in the physiological eruption of permanent teeth.

Primary failure of eruption – a review and case report

Partial or complete failure of tooth eruption may be due to several causes, including primary failure of eruption (PFE), and an accurate diagnosis is essential for appropriate management. This article reviews PFE and the possible treatment options. Case reports of two patients diagnosed with PFE are presented and their management discussed. CPD/Clinical Relevance: Primary failure of eruption can be difficult to diagnose and differentiate from other causes of failure of eruption. This paper highlights the clinical presentation of PFE through a review of the literature and by illustration with two clinical cases.

Regional odontodysplasia: An analysis of 161 cases from 1953 to 2017

Regional odontodysplasia (RO) is a localized developmental anomaly involving both dentitions. The characteristic clinical findings are soft discolored several contiguous teeth with atypical morphology associated with swelling or abscess formation. Radiographic images of the involved teeth show a ghost-like appearance because enamel and dentin are hypoplastic and hypocalcified. Although RO is known for more than seven decades, the literature on RO is mostly limited to case reports. Background and objectiveMany authors have considered RO to be an uncommon condition. Review of the literature reveals that most publications are case reports. The purpose of this investigation was to provide an updated review of the English-language literature with regards to clinical presentation and epidemiology of RO. Because of its rarity, retrospective analysis of the published reports across the world is considered one of the most appropriate available methods to analyze epidemiological and clinical data of RO. ResultsBetween 1953 and 2017, 161 cases were reported in the English literature. At the time of diagnosis, the age of all reported patients ranged between 1 and 25 years. There was a slight female predilection with a ratio of (1.37:1). When examined collectively, the maxilla was commonly affected compared to the mandible. RO occurred in both dentitions in 75 reported cases. While it affects the deciduous teeth alone in 19.3% and the permanent teeth in 34.2% of the cases. Failure of tooth eruption was the most common presenting finding (41.6%) followed by swelling of the affected area (32.3%). ConclusionAlthough RO was first described almost 80 years ago and the total subsequent case reports were over 160 cases, there is no consensus on its pathogenesis and how it should be treated. The descriptive nature of the examined case reports reveals the limited information on this condition. Further experimental and genetic studies are needed.

Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption

Formation of functional skeletal tissues requires highly organized steps of mesenchymal progenitor cell differentiation. The dental follicle (DF) surrounding the developing tooth harbors mesenchymal progenitor cells for various differentiated cells constituting the tooth root-bone interface and coordinates tooth eruption in a manner dependent on signaling by parathyroid hormone-related peptide (PTHrP) and the PTH/PTHrP receptor (PPR). However, the identity of mesenchymal progenitor cells in the DF and how they are regulated by PTHrP-PPR signaling remain unknown. Here, we show that the PTHrP-PPR autocrine signal maintains physiological cell fates of DF mesenchymal progenitor cells to establish the functional periodontal attachment apparatus and orchestrates tooth eruption. A single-cell RNA-seq analysis revealed cellular heterogeneity of PTHrP+ cells, wherein PTHrP+ DF subpopulations abundantly express PPR. Cell lineage analysis using tamoxifen-inducible PTHrP-creER mice revealed that PTHrP+ DF cells differentiate into cementoblasts on the acellular cementum, periodontal ligament cells, and alveolar cryptal bone osteoblasts during tooth root formation. PPR deficiency induced a cell fate shift of PTHrP+ DF mesenchymal progenitor cells to nonphysiological cementoblast-like cells precociously forming the cellular cementum on the root surface associated with up-regulation of Mef2c and matrix proteins, resulting in loss of the proper periodontal attachment apparatus and primary failure of tooth eruption, closely resembling human genetic conditions caused by PPR mutations. These findings reveal a unique mechanism whereby proper cell fates of mesenchymal progenitor cells are tightly maintained by an autocrine system mediated by PTHrP-PPR signaling to achieve functional formation of skeletal tissues.

Primary failure of eruption, A review

Primary failure of tooth eruption (PFE) is defined as a non-syndromic condition in which non-ankylosed teeth fail to erupt fully or partially due to malfunction of the eruption mechanism. Although the eruption path is clear without any mechanical obstruction like cyst or supernumerary tooth, affected teeth fail to erupt. Patients diagnosed with PFE have revealed mutation in the gene encoding the G protein of parathyroid hormone 1 receptor (PTH1R). The condition is characterized by progressive posterior open bite due to involvement of all the teeth distal to the first affected tooth. These teeth fail to respond to orthodontic forces and attempts to correct open bite orthodontically cause the affected teeth to ankylose, thus worsening the open bite. Diagnosis of PFE is critical as management differs from the infra-occluded teeth due to mechanical obstruction or systemic etiology. This review attempts to discuss etiology, clinical features, diagnosis and management of the teeth affected with primary failure of tooth eruption.

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

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.

A novel homozygous PTH1R variant identified through whole-exome sequencing further expands the clinical spectrum of primary failure of tooth eruption in a consanguineous Saudi family

ObjectivesThe present study aimed to identify the genetic cause of non-syndromic primary failure of tooth eruption in a five-generation consanguineous Saudi family using whole-exome sequencing (WES) analysis. DesignThe family pedigree and phenotype were obtained from patient medical records. WES of all four affected family members was performed using the 51Mb SureSelect V4 library kit and then sequenced using the Illumina HiSeq2000 sequencing system. Sequence alignment, variant calling, and the annotation of single nucleotide polymorphisms and indels were performed using standard bioinformatics pipelines. The genotype of candidate variants was confirmed in all available family members by Sanger sequencing. ResultsPedigree analysis suggested that the inheritance was autosomal recessive. WES of all affected individuals identified a novel homozygous variant in exon 8 of the parathyroid hormone 1 receptor gene (PTH1R) (NM_000316: c.611T>A: p.Val204Glu). ConclusionTo the best of our knowledge, this is the first report of primary failure of eruption caused by a homozygous mutation in PTH1R. Our findings prove the application of WES as an efficient molecular diagnostics tool for this rare phenotype and further broaden the clinical spectrum of PTH1R pathogenicity.