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Advances in Genetic Diseases of Teeth
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Advances in Genetic Diseases of Teeth

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 16759

Special Issue Editors

Dr. Yongbo Lu

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Guest Editor
Department of Biomedical Sciences, Texas A&M University College of Dentistry, 3302 Gaston Ave, Dallas, TX 75246, USA
Interests: bone biology; tooth development; odontoblast differentiation; ameloblast differentiation; dentinogenesis imperfecta (DGI); endoplasmic reticulum (ER) stress
Prof. Dr. Chunlin Qin

E-Mail Website
Guest Editor
Department of Biomedical Sciences, Texas A&M University College of Dentistry, 3302 Gaston Ave, Dallas, TX 75246, USA
Interests: bone biology; tooth development; odontoblast differentiation; dentinogenesis; dentinogenesis imperfecta (DGI); phosphate homeostasis
Prof. Dr. Thomas G. H. Diekwisch

E-Mail Website
Guest Editor
Department of Periodontics, Texas A&M University College of Dentistry, 3302 Gaston Ave, Dallas, TX 75246, USA
Interests: enamel development and evolution; periodontal development and tissue engineering; epigenetics and chromatin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Healthy teeth are essential for human health and well-being. From an anatomical perspective, healthy teeth are comprised of three mineralized tissues, enamel, dentin, and cementum, which perform important functions related to protection against oral microorganisms and the anchorage and stability of teeth in the jaws. These three unique mineralized tissues are fabricated by highly specialized cells: ameloblasts, odontoblasts, and cementoblasts. Ameloblasts are derived from the oral ectoderm, while odontoblasts and cementoblasts originate from the cranial neural crest, either via the dental papilla (odontoblasts) or the dental follicle (cementoblasts). The intricate interplay of proteins involved in the secretion of tooth-specific extracellular matrices and the associated transport and diffusion of mineral ions is precisely timed and regulated by genetic networks, primarily within the major odontogenic cell populations.  Any change in the timing, coordination, or the dosage of tooth mineral-specific gene products profoundly affects the integrity of enamel, dentin, and cementum, and the overall health of the tooth.  Initial studies of hereditary tooth defects have focused on the extracellular effects of mutant proteins involved in amelogenesis, dentinogenesis, and cementogenesis.  However, in recent years there has been increasing evidence suggesting that mutant matrix proteins such as amelogenin, enamelin, or dentin sialophosphoprotein are prone to misfolding, resulting in intracellular pathologies such as endoplasmic reticulum (ER) stress and unfolded protein response (UPR), which in turn affect the composition and mechanical properties of dental mineralized tissues. The purpose of the present Special Issue is to present an update on the genetics of dental mineralized tissue defects and their related mechanisms, taking novel cellular causalities into account.  We anticipate that a broader understanding of odontogenic mineralized tissue pathologies will provide new insights into potential therapeutic approaches to intervene in the deleterious consequences of dental birth defects. 

This Special Issue aims to publish case reports, original research articles, and critical reviews that report recent advances in inherited tooth defects, including the identification of novel gene mutations, the elucidation of cellular and molecular mechanisms, the generation of animal models to investigate the pathogenesis of a mutant gene/protein, and the development of therapeutic interventions.

Dr. Yongbo Lu
Prof. Dr. Chunlin Qin
Prof. Dr. Thomas G.H. Diekwisch
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • teeth
  • genetic disease
  • gene mutation
  • amelogenesis
  • dentinogenesis
  • cementogenesis
  • amelogenesis imperfecta (AI)
  • dentinogenesis imperfecta (DGI)
  • dentin dysplasia (DD)
  • enamel defects
  • dentin defects
  • cementum defects

Published Papers (6 papers)

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Research

14 pages, 1886 KiB  
Article
Genome-Wide Analysis of Dental Caries Variability Reveals Genotype-by-Environment Interactions
by Tianyu Zou, Betsy Foxman, Daniel W. McNeil, Seth M. Weinberg, Mary L. Marazita and John R. Shaffer
Genes 2023, 14(3), 736; https://doi.org/10.3390/genes14030736 - 17 Mar 2023
Viewed by 1733
Abstract
Genotype-by-environment interactions (GEI) may influence dental caries, although their effects are difficult to detect. Variance quantitative trait loci (vQTL) may serve as an indicator of underlying GEI effects. The aim of this study was to investigate GEI effects on dental caries by prioritizing [...] Read more.
Genotype-by-environment interactions (GEI) may influence dental caries, although their effects are difficult to detect. Variance quantitative trait loci (vQTL) may serve as an indicator of underlying GEI effects. The aim of this study was to investigate GEI effects on dental caries by prioritizing variants from genome-wide vQTL analysis. First, we identified vQTLs from ~4.3 M genome-wide variants in three cohorts of white children aged 3–5 (n = 396, n = 328, n = 773) using Levene’s test. A total of 39 independent vQTLs with p < 1 × 10−6 were identified, some of which were located in or near genes with plausible biological roles in dental caries (IGFBP7, SLC5A8, and SHH involved in tooth development and enamel mineralization). Next, we used linear regression to test GEI effects on dental caries with the 39 prioritized variants and self-reported environmental factors (demographic, socioeconomic, behavioral, and dietary factors) in the three cohorts separately. We identified eight significant GEIs indicating that children with vQTL risk genotypes had higher caries experience if they had less educated parents, lower household/parental income, brushed their teeth less frequently, consumed sugar-sweetened beverages more frequently, were not breastfed, and were female. We reported the first genome-wide vQTL analysis of dental caries in children nominating several novel genes and GEI for further investigations. Full article
(This article belongs to the Special Issue Advances in Genetic Diseases of Teeth)
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17 pages, 6917 KiB  
Article
Epigenetic Repression of RUNX2 and OSX Promoters Controls the Nonmineralized State of the Periodontal Ligament
by Gokul Gopinathan, Xianghong Luan and Thomas G. H. Diekwisch
Genes 2023, 14(1), 201; https://doi.org/10.3390/genes14010201 - 12 Jan 2023
Cited by 3 | Viewed by 1542
Abstract
The nonmineralized state of the mammalian periodontal ligament is one of the hallmarks of vertebrate evolution as it provides resilient and nontraumatic tooth anchorage for effective predation. Here we sought to determine how the chromatin state of key mineralization gene promoters contributes to [...] Read more.
The nonmineralized state of the mammalian periodontal ligament is one of the hallmarks of vertebrate evolution as it provides resilient and nontraumatic tooth anchorage for effective predation. Here we sought to determine how the chromatin state of key mineralization gene promoters contributes to the nonmineralized periodontal ligament in the midst of fully mineralized alveolar bone and cementum anchor tissues. In developing mouse periodontal tissues, RUNX2 was localized to alveolar bone–lining cells, while OSX was localized throughout the periodontal ligament’s soft tissue. Matching RT-PCR amplification data and western blot comparisons demonstrated that the expression of RUNX2 and OSX bone mineralization transcription factors was at least 2.5-fold elevated in alveolar bone osteoblasts versus periodontal ligament fibroblasts. ChIP enrichment data along the RUNX2 and OSX promoters revealed increased H3K4me3 marks in alveolar bone osteoblasts, while H3K9me3 and H3K27me3 marks were elevated in periodontal ligament fibroblasts. In support of an epigenetic mechanism responsible for the inhibition of mineralization gene expression in periodontal progenitors, histone methylation inhibitors DZNep and Chaetocin reactivated RUNX2 and OSX expression in periodontal progenitors and increased alkaline phosphatase and Alizarin Red, while the in vivo application of DZNep in rat maxillae resulted in aberrant mineralization in the periodontal ligament and a narrowing of the nonmineralized periodontal space. Together, these studies demonstrate that the nonmineralized state of the mammalian periodontal ligament is controlled by an epigenetic regulation of the RUNX2 and OSX key mineralization gene promoters. Full article
(This article belongs to the Special Issue Advances in Genetic Diseases of Teeth)
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17 pages, 1052 KiB  
Article
Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study
by Ekaterina Orlova, Tom Dudding, Jonathan M. Chernus, Rasha N. Alotaibi, Simon Haworth, Richard J. Crout, Myoung Keun Lee, Nandita Mukhopadhyay, Eleanor Feingold, Steven M. Levy, Daniel W. McNeil, Betsy Foxman, Robert J. Weyant, Nicholas J. Timpson, Mary L. Marazita and John R. Shaffer
Genes 2023, 14(1), 59; https://doi.org/10.3390/genes14010059 - 24 Dec 2022
Cited by 6 | Viewed by 2669
Abstract
Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral [...] Read more.
Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10−6; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes. Full article
(This article belongs to the Special Issue Advances in Genetic Diseases of Teeth)
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17 pages, 2086 KiB  
Article
An Intron c.103-3T>C Variant of the AMELX Gene Causes Combined Hypomineralized and Hypoplastic Type of Amelogenesis Imperfecta: Case Series and Review of the Literature
by Tina Leban, Katarina Trebušak Podkrajšek, Jernej Kovač, Aleš Fidler and Alenka Pavlič
Genes 2022, 13(7), 1272; https://doi.org/10.3390/genes13071272 - 18 Jul 2022
Cited by 2 | Viewed by 2338
Abstract
Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders of dental enamel. X-linked AI results from disease-causing variants in the AMELX gene. In this paper, we characterise the genetic aetiology and enamel histology of female AI patients from two unrelated families with [...] Read more.
Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders of dental enamel. X-linked AI results from disease-causing variants in the AMELX gene. In this paper, we characterise the genetic aetiology and enamel histology of female AI patients from two unrelated families with similar clinical and radiographic findings. All three probands were carefully selected from 40 patients with AI. In probands from both families, scanning electron microscopy confirmed hypoplastic and hypomineralised enamel. A neonatal line separated prenatally and postnatally formed enamel of distinctly different mineralisation qualities. In both families, whole exome analysis revealed the intron variant NM_182680.1: c.103-3T>C, located three nucleotides before exon 4 of the AMELX gene. In family I, an additional variant, c.2363G>A, was found in exon 5 of the FAM83H gene. This report illustrates a variant in the AMELX gene that was not previously reported to be causative for AI as well as an additional variant in the FAM83H gene with probably limited clinical significance. Full article
(This article belongs to the Special Issue Advances in Genetic Diseases of Teeth)
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10 pages, 1255 KiB  
Article
A Novel 90-kbp Deletion of RUNX2 Associated with Cleidocranial Dysplasia
by Yanli Zhang and Xiaohong Duan
Genes 2022, 13(7), 1128; https://doi.org/10.3390/genes13071128 - 23 Jun 2022
Cited by 5 | Viewed by 1967
Abstract
Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia caused by runt-related transcription factor 2 (RUNX2) mutations. In addition to the regular missense, small or large fragment deletions are the common mutation types of RUNX2. This study aimed to [...] Read more.
Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia caused by runt-related transcription factor 2 (RUNX2) mutations. In addition to the regular missense, small or large fragment deletions are the common mutation types of RUNX2. This study aimed to find the rules of deletions in RUNX2. The clinical information of one Chinese CCD family was collected. Genomic DNA was extracted for whole-exome sequencing (WES). Bioinformatics analyzed the pathogenicity of the variants. Polymerase chain reaction (PCR) and Sanger sequencing were carried out using specific primers. RT-PCR and Q-PCR were also used to detect the mRNA level of RUNX2. The CCD studies related with deletions in RUNX2 from 1999 to 2021 from HGMD and PubMed were collected and analyzed for the relationship between the phenotypes and the length of deleted fragments. The proband presented typical CCD features, including delayed closure of cranial sutures, clavicle dysplasia, abnormal teeth. WES, PCR with specific primers and Sanger sequencing revealed a novel heterozygous 90-kbp deletion in RUNX2 (NG_008020.2 g.103671~193943), which caused a substitution (p.Asn183Ile) and premature termination (p.Asp184*). In addition, the mRNA expression of RUNX2 was decreased by 75.5% in the proband. Herein, 31 types of deletions varying from 2 bp to 800 kbp or covering the whole gene of RUNX2 were compared and the significant phenotypic difference was not found among these deletions. The CCD phenotypes were related with the final effects of RUNX2 mutation instead of the length of deletion. WES has the defects in identifying large indels, and direct PCR with specific primers and Sanger sequencing could make up for the shortcoming. Full article
(This article belongs to the Special Issue Advances in Genetic Diseases of Teeth)
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31 pages, 10135 KiB  
Article
The Modified Shields Classification and 12 Families with Defined DSPP Mutations
by James P. Simmer, Hong Zhang, Sophie J. H. Moon, Lori A-J. Donnelly, Yuan-Ling Lee, Figen Seymen, Mine Koruyucu, Hui-Chen Chan, Kevin Y. Lee, Suwei Wu, Chia-Lan Hsiang, Anthony T. P. Tsai, Rebecca L. Slayton, Melissa Morrow, Shih-Kai Wang, Edward D. Shields and Jan C.-C. Hu
Genes 2022, 13(5), 858; https://doi.org/10.3390/genes13050858 - 12 May 2022
Cited by 9 | Viewed by 5320
Abstract
Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). DSPP mutations fall into two groups: a 5′-group that affects protein targeting and a [...] Read more.
Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). DSPP mutations fall into two groups: a 5′-group that affects protein targeting and a 3′-group that shifts translation into the −1 reading frame. Using whole-exome sequence (WES) analyses and Single Molecule Real-Time (SMRT) sequencing, we identified disease-causing DSPP mutations in 12 families. Three of the mutations are novel: c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80). We propose genetic analysis start with WES analysis of proband DNA to identify mutations in COL1A1 and COL1A2 causing dominant forms of osteogenesis imperfecta, 5′-DSPP mutations, and 3′-DSPP frameshifts near the margins of the DSPP repeat region, and SMRT sequencing when the disease-causing mutation is not identified. After reviewing the literature and incorporating new information showing distinct differences in the cell pathology observed between knockin mice with 5′-Dspp or 3′-Dspp mutations, we propose a modified Shields Classification based upon the causative mutation rather than phenotypic severity such that patients identified with 5′-DSPP defects be diagnosed as DGI-III, while those with 3′-DSPP defects be diagnosed as DGI-II. Full article
(This article belongs to the Special Issue Advances in Genetic Diseases of Teeth)
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