Sylvia A. Frazier-Bowers

Primary failure of eruption and PTH1R: The importance of a genetic diagnosis for orthodontic treatment planning

INTRODUCTION Primary failure of eruption (PFE) is characterized by nonsyndromic eruption failure of permanent teeth in the absence of mechanical obstruction. Recent studies support that this dental phenotype is inherited and that mutations in PTH1R genes explain several familial cases of PFE. The objective of our study was to investigate how genetic analysis can be used with clinical diagnostic information for improved orthodontic management of PFE. METHODS We evaluated a family (n = 12) that segregated an autosomal dominant form of PFE with 5 affected and 7 unaffected persons. Nine available family members (5 male, 4 female) were enrolled and subsequently characterized clinically and genetically. RESULTS In this family, PFE segregated with a novel mutation in the PTH1R gene. A heterozygous c.1353-1 G>A sequence alteration caused a putative splice-site mutation and skipping of exon 15 that segregated with the PFE phenotype in all affected family members. CONCLUSIONS A PTH1R mutation is strongly associated with failure of orthodontically assisted eruption or tooth movement and should therefore alert clinicians to treat PFE and ankylosed teeth with similar caution-ie, avoid orthodontic treatment with a continuous archwire.

Molecular characterization of a novel PAX9 missense mutation causing posterior tooth agenesis

Autosomal dominant mutations in the gene encoding the paired box containing transcription factor PAX9 are associated with nonsyndromic human tooth agenesis that primarily affect posterior dentition. The molecular mechanisms contributing to its pathogenesis are poorly understood. In this study, we describe a novel mutation in PAX9 in a family with molar oligodontia. This heterozygous mutation results in the substitution of a highly conserved isoleucine residue by phenylalanine within the carboxyl-terminal subdomain of the paired domain. Immunolocalization and cell fractionation studies to ascertain the subcellular localization of the Ile87Phe protein showed that both wild-type and mutant proteins are synthesized in mammalian cells and that the mutation does not alter the nuclear localization of the mutant protein. Gel-shift assays using two cognate paired-domain recognition sequences, e5 and CD19-2(A-ins), revealed that while wild-type Pax9 binds to both sequences, the mutant protein was unable to bind these sites. In addition, the latter did not alter the DNA-binding activities of wild-type Pax9. Furthermore, we evaluated the ability of the Ile87Phe mutant protein to form a complex with a partner protein, Msx1, and found that the mutation under study has no effect on this interaction. Based on our observed defects in DNA binding by the mutant protein, we propose a loss-of-function mechanism that contributes to haploinsufficiency of PAX9 in this family with posterior tooth agenesis.

Mechanism and control of tooth eruption: overview and clinical implications

OBJECTIVES To review pre- and post-emergent eruption, with particular emphasis on distinguishing isolated molar ankylosis from primary failure of eruption (PFE) and genetic considerations in eruption problems. MATERIAL AND METHODS Radiographic review of eruption failure patients; animal and human experiments; high precision observations of movements of erupting teeth. RESULTS In pre-emergent tooth eruption, the controlling element is the rate of resorption of overlying structures. A path is cleared, and then the erupting tooth moves along it. This has clinical importance in recognizing the cause of eruption problems, particularly PFE, in which all teeth distal to the most mesial involved tooth do not erupt or respond to orthodontics. In our study of by far the largest sample of PFE cases yet reported, familial cases of PFE accounted for approximately (1/4) of all cases examined. Candidate genes now are being evaluated. In post-emergent eruption, control seems to be light forces of long duration that oppose eruption, rather than heavy forces of short duration such as those during mastication. Studies of human premolars in their passage from gingival emergence to the occlusal plane show that in this phase eruption occurs only during a few hours in the early evening. The critical hours for eruption parallel the time that growth hormone levels are highest in a growing child. In this stage intermittent force does not affect the rate of eruption, but changes in periodontal blood flow do affect it.

Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis

Mutations of the Ectodysplasin-A (EDA) gene are generally associated with the syndrome hypohidrotic ectodermal dysplasia (MIM 305100), but they can also manifest as selective, non-syndromic tooth agenesis (MIM300606). We have performed an in vitro functional analysis of six selective tooth agenesis-causing EDA mutations (one novel and five known) that are located in the C-terminal tumor necrosis factor homology domain of the protein. Our study reveals that expression, receptor binding or signaling capability of the mutant EDA1 proteins is only impaired in contrast to syndrome-causing mutations, which we have previously shown to abolish EDA1 expression, receptor binding or signaling. Our results support a model in which the development of the human dentition, especially of anterior teeth, requires the highest level of EDA-receptor signaling, whereas other ectodermal appendages, including posterior teeth, have less stringent requirements and form normally in response to EDA mutations with reduced activity.

Phenotypic Characterization of Class III Patients

OBJECTIVE The objective of this study is to characterize the convergences of dentofacial form of skeletal Class III malocclusion in individuals to test the fundamental hypothesis that there are distinct subtypes of Class III malocclusion. MATERIALS AND METHODS A detailed phenotypic characterization was performed on a retrospective cohort of 309 subjects using cluster and principal component analyses on 67 cephalometric variables. RESULTS The results indicated that there are five clusters representing distinct subphenotypes. The principal component analysis suggested that the groupings of variables reflect anteroposterior and vertical dimensions rather than specific craniofacial structures. This may ultimately suggest that different genes are involved in controlling dimension vs structures. CONCLUSIONS Our phenotypic dissection of Class III malocclusion established distinct subtypes in a large sample of patients and will ultimately provide the basis for future familial studies to identify a causative gene.

Genetic analysis of familial non-syndromic primary failure of eruption

OBJECTIVES While some eruption disorders occur as part of a medical syndrome, primary failure of eruption (PFE) - defined as a localized failure of secondary tooth eruption - exists without systemic involvement. Recent studies support that heredity may play an important role in the pathogenesis of PFE. The objective of our human genetic study is to investigate the genetic contribution to PFE. MATERIALS AND METHODS Four candidate genes POSTN, RUNX2, AMELX, and AMBN) were investigated because of their relationship to tooth eruption or putative relationship to each other. Families and individuals were ascertained based on the clinical diagnosis of PFE. Pedigrees were constructed and analyzed by inspection to determine the mode of inheritance in four families. The candidate genes were directly sequenced for both unrelated affected individuals and unaffected individuals. A genome wide scan using 500 microsatellite markers followed by linkage analysis was carried out for one family. RESULTS Pedigree analysis of families suggests an autosomal dominant inheritance pattern with complete penetrance and variable expressivity. Sequence analysis revealed two non-functional polymorphisms in the POSTN gene and no other sequence variations in the remaining candidate genes. Genotyping and linkage analysis of one family yielded a LOD score of 1.51 for markers D13S272; D15S118 and D17S831 on chromosomes 13, 15 and 17 respectively. CONCLUSIONS While LOD scores were not significant evidence of linkage, extension of current pedigrees and novel SNP chip technology holds great promise for identification of a causative locus for PFE.

Simultaneous sequencing of oxidized methylcytosines produced by TET/JBP dioxygenases in Coprinopsis cinerea.

Significance A prominent epigenetic mechanism for gene regulation is methylation of cytosine bases in DNA. TET enzymes facilitate DNA demethylation by converting 5-methylcytosine (5mC) to oxidized methylcytosines (oxi-mCs). We show that oxi-mCs are generated by conserved TET/JBP enzymes encoded in the genome of the model organism Coprinopsis cinerea and present a method for simultaneous mapping of the three different species of oxi-mCs at near–base-pair resolution. We observe that centromeres and transposable elements exhibit distinctive patterns of 5mC and oxi-mC, and show that gene body 5mC and oxi-mC mark silent paralogous multicopy genes. Our study describes a method to map three species of oxi-mC simultaneously and reveals the colocation of 5mC and oxi-mC at functional elements throughout the C. cinerea genome. TET/JBP enzymes oxidize 5-methylpyrimidines in DNA. In mammals, the oxidized methylcytosines (oxi-mCs) function as epigenetic marks and likely intermediates in DNA demethylation. Here we present a method based on diglucosylation of 5-hydroxymethylcytosine (5hmC) to simultaneously map 5hmC, 5-formylcytosine, and 5-carboxylcytosine at near–base-pair resolution. We have used the method to map the distribution of oxi-mC across the genome of Coprinopsis cinerea, a basidiomycete that encodes 47 TET/JBP paralogs in a previously unidentified class of DNA transposons. Like 5-methylcytosine residues from which they are derived, oxi-mC modifications are enriched at centromeres, TET/JBP transposons, and multicopy paralogous genes that are not expressed, but rarely mark genes whose expression changes between two developmental stages. Our study provides evidence for the emergence of an epigenetic regulatory system through recruitment of selfish elements in a eukaryotic lineage, and describes a method to map all three different species of oxi-mCs simultaneously.

The future of dentistry: how will personalized medicine affect orthodontic treatment?

Scientists are rapidly developing and employ-ing diagnostic tests in medical diagnosis based on genomic, proteomics and metabolomics to better predict the patients’ responses to targeted therapy. This field termed ‘personalized medicine’ combines human genome, information technology, and bio-technology with nanotechnology to provide treat-ment based on individual variation versus popula-tion trends.

Genetic Disorders of Dental Development: Tales from the Bony Crypt

Purpose of ReviewThe ebb and flow of genetic influence relative to the understanding of craniofacial and dental disorders has evolved into a tacit acceptance of the current genetic paradigm. This review explores the science behind craniofacial and dental disorders through the lens of recent past and current findings and using tooth agenesis as a model of advances in craniofacial genetics.Recent FindingsContemporary studies of craniofacial biology takes advantage of the technological resources stemming from the genomic and post-genomic eras. Emerging data highlights the role of key genes and the epigenetic landscape controlling these genes, in causing dentofacial abnormalities. We also report here a novel Glu78FS MSX1 mutation in one family segregating an autosomal dominant form of severe tooth agenesis as an illustration of an evolving theme, i.e., different mutations in the same gene can result in a spectrum of dentofacial phenotypic severity.SummaryThe future of clinical therapeutics will benefit from advances in genetics and molecular biology that refine the genotype-phenotype correlation. Indeed, the past century suggests a continued convergence of genetic science in the practice of clinical dentistry.

Failure of Tooth Eruption: Diagnosis and Management

Tooth eruption disorders are diverse in their etiologies and can be difficult to diagnose. Management of tooth eruption disorders is predicated largely on establishing a correct diagnosis and will depend on the clinical phenotype (e.g., what teeth are affected, severity of the condition, patient age, and health status). The etiologies of abnormalities in tooth eruption include inadequate space, presence of obstructions such as cysts, ankyloses, and hereditary conditions, to name just a few. Treatment approaches will depend on the age of the patient, number of teeth involved, diagnosis, treatment cost, and other factors. The goal of this chapter is to provide a foundation for the diagnosis of tooth eruption disorders and review some of the available treatment options.