ABSTRACT
OBJECTIVE: This study aimed to assess the different pathways between predictor factors such as zygosity, atypical swallowing, mouth breathing, breastfeeding and bottle feeding related to anterior open bite (AOB) in twins. METHODS: The study was conducted in monozygotic (MZ) and dizygotic (DZ) twin children aged 3-15 years. AOB, atypical swallowing, mouth breathing, feeding type, duration of bottle use, and mouth opening status during sleep were recorded during oral examination. Partial least squares structural equation model (PLS-SEM) and sobel tests were performed to assess the total and indirect effects among the variables on AOB. RESULTS: A total of 404 children (29.2% MZ;70.8% DZ) participated in this study. The effect of zygosity on mouth breathing in the PLS-SEM model was statistically significant. Conversely, it was determined that mouth breathing effected that atypical swallowing (p = 0.001). Atypical swallowing triggered AOB (p = 0.001). The atypical swallowing has a mediation effect between AOB and mouth breathing (p = 0.020). Mouth breathing causes atypical swallowing and therefore indirectly increases the likelihood of AOB. While breastfeeding decreases AOB incidence (p = 0.023), bottle feeding increases AOB incidence (p = 0.046). The sobel tests show that the fully mediator variable feature of mouth breathing is statistically significant in the negative relation between zygosity and atypical swallowing. CONCLUSION: The PLS-SEM model showed that mouth breathing triggers atypical swallowing and atypical swallowing triggers AOB. As a result of this chain of relationships, an indirect effect of zygosity on AOB was observed. According to sobel tests, zygosity has an indirect effect on atypical swallowing through mouth breathing, while mouth breathing has a positive indirect effect on AOB through atypical swallowing. CLINICAL RELEVANCE: This study identified the relationships between different factors and the presence of AOB. The findings of this study demonstrate in detail the relationships between AOB and zygosity, atypical swallowing, mouth breathing, breastfeeding and bottle feeding. Brestfeeding has a reducing effect on the frequency of AOB. Among the nutritional forms, breastfeeding ensures the proper development of the stomatognathic system by working the oro-facial muscles.
Subject(s)
Bottle Feeding , Breast Feeding , Deglutition , Open Bite , Twins, Dizygotic , Humans , Female , Child , Male , Child, Preschool , Adolescent , Deglutition/physiology , Twins, Monozygotic , Mouth Breathing/physiopathology , Latent Class AnalysisABSTRACT
AMELX mutations cause X-linked amelogenesis imperfecta (AI), known as AI types IE, IIB, and IIC in Witkop's classification, characterized by hypoplastic (reduced thickness) and/or hypomaturation (reduced hardness) enamel defects. In this study, we conducted whole exome analyses to unravel the disease-causing mutations for six AI families. Splicing assays, immunoblotting, and quantitative RT-PCR were conducted to investigate the molecular and cellular effects of the mutations. Four AMELX pathogenic variants (NM_182680.1:c.2T>C; c.29T>C; c.77del; c.145-1G>A) and a whole gene deletion (NG_012494.2:g.307534_403773del) were identified. The affected individuals exhibited enamel malformations, ranging from thin, poorly mineralized enamel with a "snow-capped" appearance to severe hypoplastic defects with minimal enamel. The c.145-1G>A mutation caused a -1 frameshift (NP_001133.1:p.Val35Cysfs*5). Overexpression of c.2T>C and c.29T>C AMELX demonstrated that mutant amelogenin proteins failed to be secreted, causing elevated endoplasmic reticulum stress and potential cell apoptosis. This study reveals a genotype-phenotype relationship for AMELX-associated AI: While amorphic mutations, including large deletions and 5' truncations, of AMELX cause hypoplastic-hypomaturation enamel with snow-capped teeth (AI types IIB and IIC) due to a complete loss of gene function, neomorphic variants, including signal peptide defects and 3' truncations, lead to severe hypoplastic/aplastic enamel (AI type IE) probably caused by "toxic" cellular effects of the mutant proteins.
Subject(s)
Amelogenesis Imperfecta , Amelogenin , Genetic Association Studies , Mutation , Amelogenesis Imperfecta/genetics , Amelogenesis Imperfecta/pathology , Humans , Amelogenin/genetics , Male , Female , Pedigree , Phenotype , Child , Endoplasmic Reticulum Stress/genetics , Genotype , Exome SequencingABSTRACT
BACKGROUND: The black staining effect of silver-containing solutions for use to arrest caries can have a negative aesthetic impact on children and parents. This study aims to assess the staining effects of Silver Diamine Fluoride/Potassium Iodide (SDF/KI), SDF and Nanosilver Fluoride (NSF). MATERIALS AND METHODS: Forty-four extracted carious primary molars were collected and randomly divided into four groups (n = 11). The carious tissue in all teeth was removed using a chemo-mechanical caries removal agent with an excavator. After caries removal in all groups, SDF, SDF/KI, and NSF were applied to the different groups, while no solution was applied to the control group. Subsequently, the teeth in all groups were restored with compomer. Color values L*, a* and b* were measured using a spectrophotometer at three time points: immediately after compomer restoration (T0), one week later (T1), and four week later (T2). Changes in brightness (ΔL) and color (ΔE) over time were calculated and comparisons among groups were made. RESULTS: The SDF solution induced statistically significant black staining (p = 0.013) and a decrease in L* value (p < 0.001) on the compomer material compared to the other groups over time. CONCLUSIONS: It was observed that SDF/KI has the potential to reduce the black staining effect of SDF, though not entirely. Novel experimental solutions like NSF may offer an alternative to counteract the staining effect of SDF.
Subject(s)
Fluorides, Topical , Potassium Iodide , Quaternary Ammonium Compounds , Silver Compounds , Quaternary Ammonium Compounds/pharmacology , Quaternary Ammonium Compounds/therapeutic use , Potassium Iodide/therapeutic use , Humans , Fluorides, Topical/therapeutic use , In Vitro Techniques , Cariostatic Agents/therapeutic use , Dental Caries/prevention & control , Tooth Discoloration/chemically induced , Tooth, Deciduous , Spectrophotometry , MolarABSTRACT
OBJECTIVE: Amelogenesis imperfecta (AI) is defined as inherited enamel malformations. LAMA3 (laminin alpha-3) encodes a critical protein component of the basement membrane (laminin-332). Individuals carrying heterozygous LAMA3 mutations have previously been shown to have localized enamel defects. This study aimed to define clinical phenotypes and to discern the genetic etiology for four AI kindreds. MATERIALS AND METHODS: Whole-exome analyses were conducted to search for sequence variants associated with the disorder, and micro-computed tomography (µCT) to characterize the enamel defects. RESULTS: The predominant enamel phenotype was generalized thin enamel with defective pits and grooves. Horizonal bands of hypoplastic enamel with chalky-white discoloration and enamel hypomineralization were also observed and demonstrated by µCT analyses of affected teeth. Four disease-causing LAMA3 mutations (NM_198129.4:c.3712dup; c.5891dup; c.7367del; c.9400G > C) were identified. Compound heterozygous MMP20 mutations (NM_004771.4:c.539A > G; c.692C > T) were also found in one proband with more severe enamel defects, suggesting a mutational synergism on disease phenotypes. Further analyses of the AI-causing mutations suggested that both α3A (short) and α3B (long) isoforms of LAMA3 are essential for enamel formation. CONCLUSIONS: Heterozygous LAMA3 mutations can cause generalized enamel defects (AI1A) with variable expressivity. Laminin-332 is critical not only for appositional growth but also enamel maturation.
Subject(s)
Amelogenesis Imperfecta , Humans , Amelogenesis Imperfecta/diagnostic imaging , Amelogenesis Imperfecta/genetics , Laminin/genetics , X-Ray Microtomography , Dental Enamel/diagnostic imaging , Extracellular Matrix Proteins/genetics , Mutation , Phenotype , Biological Variation, Population , PedigreeABSTRACT
AIM: Biallelic loss-of-function FAM20A mutations cause amelogenesis imperfecta (AI) type IG, better known as enamel renal syndrome (ERS), characterized by severe enamel hypoplasia, delayed/failed tooth eruption, intrapulpal calcifications, gingival hyperplasia and nephrocalcinosis. FAM20A binds to FAM20C, the Golgi casein kinase (GCK) and potentiates its function to phosphorylate secreted proteins critical for biomineralization. While many FAM20A pathogenic mutations have been reported, the pathogeneses of orodental anomalies in ERS remain to be elucidated. This study aimed to identify disease-causing mutations for patients with ERS phenotypes and to discern the molecular mechanism underlying ERS intrapulpal calcifications. METHODOLOGY: Phenotypic characterization and whole exome analyses were conducted for 8 families and 2 sporadic cases with hypoplastic AI. A minigene assay was performed to investigate the molecular consequences of a FAM20A splice-site variant. RNA sequencing followed by transcription profiling and gene ontology (GO) analyses were carried out for dental pulp tissues of ERS and the control. RESULTS: Biallelic FAM20A mutations were demonstrated for each affected individual, including 7 novel pathogenic variants: c.590-5T>A, c.625T>A (p.Cys209Ser), c.771del (p.Gln258Argfs*28), c.832_835delinsTGTCCGACGGTGTCCGACGGTGTC CA (p.Val278Cysfs*29), c.1232G>A (p.Arg411Gln), c.1297A>G (p.Arg433Gly) and c.1351del (p.Gln451Serfs*4). The c.590-5T>A splice-site mutation caused Exon 3 skipping, which resulted in an in-frame deletion of a unique region of the FAM20A protein, p.(Asp197_Ile214delinsVal). Analyses of differentially expressed genes in ERS pulp tissues demonstrated that genes involved in biomineralization, particularly dentinogenesis, were significantly upregulated, such as DSPP, MMP9, MMP20 and WNT10A. Enrichment analyses indicated overrepresentation of gene sets associated with BMP and SMAD signalling pathways. In contrast, GO terms related to inflammation and axon development were underrepresented. Among BMP signalling genes, BMP agonists GDF7, GDF15, BMP3, BMP8A, BMP8B, BMP4 and BMP6 were upregulated, while BMP antagonists GREM1, BMPER and VWC2 showed decreased expression in ERS dental pulp tissues. CONCLUSIONS: Upregulation of BMP signalling underlies intrapulpal calcifications in ERS. FAM20A plays an essential role in pulp tissue homeostasis and prevention of ectopic mineralization in soft tissues. This critical function probably depends upon MGP (matrix Gla protein), a potent mineralization inhibitor that must be properly phosphorylated by FAM20A-FAM20C kinase complex.
Subject(s)
Amelogenesis Imperfecta , Calcinosis , Dental Enamel Proteins , Nephrocalcinosis , Humans , Nephrocalcinosis/genetics , Nephrocalcinosis/pathology , Amelogenesis Imperfecta/genetics , Amelogenesis Imperfecta/metabolism , Amelogenesis Imperfecta/pathology , Dental Pulp/metabolism , Dental Enamel Proteins/genetics , Mutation , Gene Expression Profiling , Carrier Proteins/geneticsABSTRACT
BACKGROUND: The aim of this study is to investigate the relative contributions of genetic and environmental factors to variations in dental dimensions in a sample of Turkish twins, and to estimate heritability using dental casts. STUDY DESIGN: The study samples were selected from the twin children between 3-15 years old who referred for their first dental examination. Fifty nine monozygotic and one hundred and forty three dizygotic twin pairs were examined in the study. The alginate impression material used to create the plaster model of maxilla and mandible. Anterior arch width, posterior arch width, arch length and arch circumference were measured on models prepared from measurements taken for both maxilla and mandible with digital caliper. The similarities and differences of the measurements were compared between pairs of twins and zygocytes. Morever, the effects of bad oral habits, bruxism, a result of psychosocial factors on measurements were examined. Statistical analysis was performed using Paired T Test, Wilcoxon Test and Mann Whitney U test. RESULTS: A total of 404 dental models of 118 (29.2%) monozygotic and 286 (70.8%) dizygotic twins were evaluated. There was no statistical difference between sibling pairs in both monozygotic and dizygotic twins. The measurement similarity between twin siblings differed according to zygosity in all measurements (p<0.05). It has been observed that the finger sucking and mouth breathing affect the dental arch measurements (p<0.05). CONCLUSION: These results indicate that the differences in dental arch dimensions between monozygotic twin pairs are less than the difference between dizygotic twin pairs.
Subject(s)
Dental Arch , Twins, Dizygotic , Adolescent , Child , Child, Preschool , Humans , Mandible , Maxilla , Twins, Dizygotic/genetics , Twins, Monozygotic/geneticsABSTRACT
BACKGROUND: The aim of this study is to investigate the relative contributions of genetic and environmental factors to variations in dental dimensions in a sample of Turkish twins, and to estimate heritability using dental casts. STUDY DESIGN: The study samples were selected from the twin children between 3-15 years old who referred for their first dental examination. Fifty nine monozygotic and one hundred and forty three dizygotic twin pairs were examined in the study. The alginate impression material used to create the plaster model of maxilla and mandible. Anterior arch width, posterior arch width, arch length and arch circumference were measured on models prepared from measurements taken for both maxilla and mandible with digital caliper. The similarities and differences of the measurements were compared between pairs of twins and zygocytes. Morever, the effects of bad oral habits, bruxism, a result of psychosocial factors on measurements were examined. Statistical analysis was performed using Paired T Test, Wilcoxon Test and Mann Whitney U test. RESULTS: A total of 404 dental models of 118 (29.2%) monozygotic and 286 (70.8%) dizygotic twins were evaluated. There was no statistical difference between sibling pairs in both monozygotic and dizygotic twins. The measurement similarity between twin siblings differed according to zygosity in all measurements (p<0.05). It has been observed that the finger sucking and mouth breathing affect the dental arch measurements (p<0.05). CONCLUSION: These results indicate that the differences in dental arch dimensions between monozygotic twin pairs are less than the difference between dizygotic twin pairs.
Subject(s)
Dental Arch , Twins, Dizygotic , Adolescent , Child , Child, Preschool , Humans , Mandible , Maxilla , Twins, MonozygoticABSTRACT
Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders affecting tooth enamel. The affected enamel can be hypoplastic and/or hypomineralized. In this study, we identified ACPT (testicular acid phosphatase) biallelic mutations causing non-syndromic, generalized hypoplastic autosomal-recessive amelogenesis imperfecta (AI) in individuals from six apparently unrelated Turkish families. Families 1, 4, and 5 were affected by the homozygous ACPT mutation c.713C>T (p.Ser238Leu), family 2 by the homozygous ACPT mutation c.331C>T (p.Arg111Cys), family 3 by the homozygous ACPT mutation c.226C>T (p.Arg76Cys), and family 6 by the compound heterozygous ACPT mutations c.382G>C (p.Ala128Pro) and 397G>A (p.Glu133Lys). Analysis of the ACPT crystal structure suggests that these mutations damaged the activity of ACPT by altering the sizes and charges of key amino acid side chains, limiting accessibility of the catalytic core, and interfering with homodimerization. Immunohistochemical analysis confirmed localization of ACPT in secretory-stage ameloblasts. The study results provide evidence for the crucial function of ACPT during amelogenesis.
Subject(s)
Acid Phosphatase/genetics , Amelogenesis Imperfecta/genetics , Dental Enamel Proteins/genetics , Genes, Recessive , Mutation , Acid Phosphatase/metabolism , Amelogenesis Imperfecta/diagnosis , Child , Dental Enamel/abnormalities , Dental Enamel Proteins/metabolism , Exons , Female , Homozygote , Humans , Male , Pedigree , Protein Conformation , Sequence Alignment , TurkeyABSTRACT
Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. This process requires the intricate regulation of ion transport and controlled changes to the pH of the developing enamel matrix. The means by which the enamel organ regulates pH during amelogenesis is largely unknown. We identified rare homozygous variants in GPR68 in three families with amelogenesis imperfecta, a genetically and phenotypically heterogeneous group of inherited conditions associated with abnormal enamel formation. Each of these homozygous variants (a large in-frame deletion, a frameshift deletion, and a missense variant) were predicted to result in loss of function. GPR68 encodes a proton-sensing G-protein-coupled receptor with sensitivity in the pH range that occurs in the developing enamel matrix during amelogenesis. Immunohistochemistry of rat mandibles confirmed localization of GPR68 in the enamel organ at all stages of amelogenesis. Our data identify a role for GPR68 as a proton sensor that is required for proper enamel formation.
Subject(s)
Amelogenesis Imperfecta/genetics , Mutation , Receptors, G-Protein-Coupled/genetics , Amelogenesis/genetics , Animals , Base Sequence , Dental Enamel/growth & development , Dental Enamel/pathology , Female , Homozygote , Humans , Hydrogen-Ion Concentration , Male , Pedigree , Rats , Receptors, G-Protein-Coupled/analysisABSTRACT
Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.
Subject(s)
Cleft Palate/genetics , DNA-Binding Proteins/genetics , Polymorphism, Single Nucleotide , Transcription Factors/genetics , Animals , Case-Control Studies , Cleft Palate/diagnosis , Disease Models, Animal , Ethnicity/genetics , Genetic Loci , Genome-Wide Association Study , Genotyping Techniques , Humans , Mutation, Missense , Risk Factors , Zebrafish/embryology , Zebrafish/geneticsABSTRACT
Hypohidrotic or anhidrotic ectodermal dysplasia (HED/EDA) is characterized by impaired development of the hair, teeth, or sweat glands. HED/EDA is inherited in an X-linked, autosomal dominant, or autosomal recessive pattern and caused by the pathogenic variants in 4 genes: EDA, EDAR, EDARADD, and WNT10A. The aim of the present study was to perform molecular screening of these 4 genes in a cohort of Turkish individuals diagnosed with HED/EDA. We screened for pathogenic variants of WNT10A, EDA, EDAR, and EDARADD through Sanger sequencing. We further assessed the clinical profiles of the affected individuals in order to establish phenotype-genotype correlation. In 17 (63%) out of 27 families, 17 pathogenic variants, 8 being novel, were detected in the 4 well-known ectodermal dysplasia genes. EDAR and EDA variants were identified in 6 families each, WNT10A variants in 4, and an EDARADD variant in 1, accounting for 35.3, 35.3, 23.5, and 5.9% of mutation-positive families, respectively. The low mutation detection rate of the cohort and the number of the EDAR pathogenic variants being as high as the EDA ones were the most noteworthy findings which could be attributed to the high consanguinity rate.
Subject(s)
Ectodermal Dysplasia/genetics , Ectodysplasins/genetics , Edar Receptor/genetics , Edar-Associated Death Domain Protein/genetics , Mutation , Sequence Analysis, DNA/methods , Wnt Proteins/genetics , Consanguinity , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Male , Pedigree , Phenotype , TurkeyABSTRACT
Amelogenesis imperfecta (AI) is a collection of isolated (non-syndromic) inherited diseases affecting dental enamel formation or a clinical phenotype in syndromic conditions. We characterized three consanguineous AI families with generalized irregular hypoplastic enamel with rapid attrition that perfectly segregated with homozygous defects in a novel gene: RELT that is a member of the tumor necrosis factor receptor superfamily (TNFRSF). RNAscope in situ hybridization of wild-type mouse molars and incisors showed specific Relt mRNA expression by secretory stage ameloblasts and by odontoblasts. Relt-/- mice generated by CRISPR/Cas9 exhibited incisor and molar enamel malformations. Relt-/- enamel had a rough surface and underwent rapid attrition. Normally unmineralized spaces in the deep enamel near the dentino-enamel junction (DEJ) were as highly mineralized as the adjacent enamel, which likely altered the mechanical properties of the DEJ. Phylogenetic analyses showed the existence of selective pressure on RELT gene outside of tooth development, indicating that the human condition may be syndromic, which possibly explains the history of small stature and severe childhood infections in two of the probands. Knowing a TNFRSF member is critical during the secretory stage of enamel formation advances our understanding of amelogenesis and improves our ability to diagnose human conditions featuring enamel malformations.
Subject(s)
Amelogenesis Imperfecta/diagnosis , Amelogenesis Imperfecta/genetics , Genes, Recessive , Genetic Association Studies , Genetic Predisposition to Disease , Mutation , Receptors, Tumor Necrosis Factor/genetics , Consanguinity , Genotype , Germ-Line Mutation , Humans , In Situ Hybridization , Pedigree , Phenotype , RNA Splicing , Exome SequencingABSTRACT
OBJECTIVE: Amelogenesis imperfecta (AI) is a rare hereditary disorder affecting the quality and quantity of the tooth enamel. The purpose of this study was to identify the genetic etiology of hypoplastic AI families based on the candidate gene approach. MATERIALS AND METHODS: We recruited three Turkish families with hypoplastic AI and performed a candidate gene screening based on the characteristic clinical feature to find the pathogenic genetic etiology. RESULTS: The candidate gene sequencing of the LAMB3 gene for family 1 revealed a heterozygous nonsense mutation in the last exon [c.3431C > A, p.(Ser1144*)]. FAM20A gene sequencing for families 2 and 3 identified a homozygous deletion [c.34_35delCT, p.(Leu12Alafs*67)] and a homozygous deletion-insertion (c.1109 + 3_1109 + 7delinsTGGTC) mutation, respectively. CONCLUSION: The candidate gene approach can be successfully used to identify the genetic etiology of the AI in some cases with characteristic clinical features. CLINICAL RELEVANCE: Identification of the genetic etiology of the AI will help both the family members and dentist understand the nature of the disorder. Characteristic clinical feature can suggest possible genetic causes.
Subject(s)
Amelogenesis Imperfecta/genetics , Cell Adhesion Molecules/genetics , Dental Enamel Proteins/genetics , Codon, Nonsense , DNA Mutational Analysis , Homozygote , Humans , INDEL Mutation , Pedigree , Sequence Deletion , Turkey , KalininABSTRACT
Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.
Subject(s)
Cleft Lip/genetics , Cleft Palate/genetics , Asian People/genetics , Black People/genetics , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 2/genetics , Ethnicity , Female , Genetic Loci , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide/genetics , Risk Factors , White People/geneticsABSTRACT
OBJECTIVE: Aplasia of lacrimal and salivary glands (ALSG) is a rare autosomal dominant inherited disease, characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary systems with variable expressivity. The purpose of this study was to identify genetic etiology of an ALSG family. MATERIALS AND METHODS: We recruited a Turkish family with ALSG and performed a mutational analysis, based on the candidate gene approach, to clarify the molecular genetic etiology. RESULTS: The candidate gene sequencing of the FGF10 gene identified a novel heterozygous nonsense mutation (c.237G > A, p.Trp79*) in the exon 1. CONCLUSION: The identified novel mutation would result in a haploinsufficiency of the FGF10, because of nonsense-mediated mRNA decay caused by a premature stop codon. This report further confirms that ALSG is caused by the haploinsufficiency of functional FGF10. CLINICAL RELEVANCE: Identification of the genetic etiology of the ALSG will help both the family members and dentist understand the nature of the disorder. Therefore, it will positively motivate oral health care to avoid further destruction of the tooth due to the lack of salivary production.
Subject(s)
Codon, Nonsense , Fibroblast Growth Factor 10/genetics , Lacrimal Apparatus/abnormalities , Salivary Glands/abnormalities , Adult , Child, Preschool , Exons , Female , Humans , Infant , Lacrimal Apparatus/diagnostic imaging , Male , Molecular Sequence Data , Pedigree , Polymerase Chain Reaction , Salivary Glands/diagnostic imaging , TurkeyABSTRACT
BACKGROUND: Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans. METHODS: We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice. RESULTS: Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience. CONCLUSIONS: The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy.
Subject(s)
Dental Caries/genetics , Hearing Loss, Sensorineural/pathology , Receptors, Estrogen/genetics , Tooth Demineralization/genetics , Adolescent , Adult , Animals , Cell Line, Tumor , Child , Child, Preschool , Chromosomes, Human, Pair 14 , Dental Enamel/growth & development , Female , Genetic Association Studies , Hearing Loss, Sensorineural/genetics , Humans , Linkage Disequilibrium , Male , Mice , Pedigree , Polymorphism, Single Nucleotide , Receptors, Estrogen/physiology , Young AdultABSTRACT
OBJECTIVES: This study aims to evaluate antibacterial effects of silver diamine fluoride (SDF), SDF/potassium iodide (KI), and nanosilver fluoride (NSF). METHODS: Antimicrobial activity of sterile saline, 5% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX), SDF, SDF/KI, NSF, and KI solutions against Streptococcus mutans and Lactobacillus casei was assessed through disc diffusion tests. A dual-species biofilm of S. mutans-L. casei was formed on 48 enamel samples, divided into six groups (n = 8). Group 1 was treated with sterile saline, Group 2 with 5% NaOCl, Group 3 with 2% CHX, Group 4 with SDF, Group 5 with SDF/KI, and Group 6 with NSF. The samples were analysed using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Statistical analysis utilized Shapiro-Wilk and Kruskal-Wallis tests and multiple comparisons were conducted using Dunn test. RESULTS: SDF, SDF/KI, and NaOCl displayed significantly higher antibacterial activity against dual-species biofilm compared to NSF and CHX (p < 0.050). CONCLUSIONS: In conclusion, SDF and SDF/KI demonstrated greater antibacterial activity than NSF. SDF's antibacterial activity was unaffected by KI. Further research is needed to determine the appropriate content and concentration for achieving effective antibacterial activity with NSF. CLINICAL SIGNIFICANCE: The use of silver-containing materials is increasing in popularity within pediatric dentistry. In this study, an endeavor has been made to assist pediatric dentists in determining which solution might be more advantageous for preventing caries.
Subject(s)
Anti-Bacterial Agents , Biofilms , Fluorides, Topical , Lacticaseibacillus casei , Potassium Iodide , Quaternary Ammonium Compounds , Silver Compounds , Streptococcus mutans , Silver Compounds/pharmacology , Biofilms/drug effects , Potassium Iodide/pharmacology , Quaternary Ammonium Compounds/pharmacology , Anti-Bacterial Agents/pharmacology , Streptococcus mutans/drug effects , Fluorides, Topical/pharmacology , Humans , Lacticaseibacillus casei/drug effects , Sodium Hypochlorite/pharmacology , Chlorhexidine/pharmacology , Dental Enamel/drug effects , Microscopy, Electron, Scanning , Microscopy, Confocal , Materials Testing , Fluorides/pharmacology , Metal NanoparticlesABSTRACT
Caries is the most common chronic, multifactorial disease in the world today; and little is still known about the genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified five loci related to caries susceptibility: 5q13.3, 13q31.1, 14q11.2, 14q 24.3, and Xq27. In the present study, we fine mapped the 14q11.2 locus to identify genetic contributors to caries susceptibility. Four hundred seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. An additional 387 DNA samples from unrelated individuals were used to determine allele frequencies. For replication purposes, a total of 1,446 independent subjects from four different populations were analyzed based on their caries experience (low versus high). Forty-eight markers in 14q11.2 were genotyped using TaqMan chemistry. Transmission disequilibrium test was used to detect over transmission of alleles in the Filipino families, and Chi-square, Fisher's exact and logistic regression were used to test for association between low caries experience and variant alleles in the replication data sets. We finally assessed the mRNA expression of TRAV4 in the saliva of 143 study subjects. In the Filipino families, statistically significant associations were found between low caries experience and markers in TRAV4. We were able to replicate these results in the populations studied that were characteristically from underserved areas. Direct sequencing of 22 subjects carrying the associated alleles detects one missense mutation (Y30R) that is predicted to be probably damaging. Finally, we observed higher expression in children and teenagers with low caries experience, correlating with specific alleles in TRAV4. Our results suggest that TRAV4 may have a role in protecting against caries.