RESUMEN
Amelogenesis imperfecta (AI) is an innate disorder that affects the formation and mineralization of the tooth enamel. When diagnosed with AI, one's teeth can be hypoplastic (thin enamel), hypomature (normal enamel thickness but discolored and softer than normal enamel), hypocalcified (normal enamel thickness but extremely weak), or mixed conditions of the above. Numerous studies have revealed the genes that are involved in causing AI. Recently, ACP4 (acid phosphatase 4) was newly found as a gene causing hypoplastic AI, and it was suggested that mutant forms of ACP4 might affect access to the catalytic core or the ability to form a homodimer. In this study, a Korean and a Turkish family with hypoplastic AI were recruited, and their exome sequences were analyzed. Biallelic mutations were revealed in ACP4: paternal (NM_033068: c.419C>T, p.(Pro140Leu)) and maternal (c.262C>A, p.(Arg88Ser)) mutations in family 1 and a paternal (c.713C>T, p.(Ser238Leu)) mutation and de novo (c.350A>G, p.(Gln117Arg)) mutation in the maternal allele in family 2. Mutations were analyzed by cloning, mutagenesis, immunofluorescence, immunoprecipitation, and acid phosphatase activity test. Comparison between the wild-type and mutant ACP4s showed a decreased amount of protein expression from the mutant forms, a decreased ability to form a homodimer, and a decreased acid phosphatase activity level. We believe that these findings will not only expand the mutational spectrum of ACP4 but also increase our understanding of the mechanism of ACP4 function during normal and pathologic amelogenesis.
Asunto(s)
Fosfatasa Ácida/genética , Amelogénesis Imperfecta , Diente , Amelogénesis Imperfecta/genética , Esmalte Dental , Humanos , Mutación/genética , LinajeRESUMEN
Amelogenesis imperfecta (AI) is a collection of genetic disorders affecting the quality and/or quantity of tooth enamel. More than 20 genes are, so far, known to be responsible for this condition. In this study, we recruited 3 Turkish families with hypomaturation AI. Whole-exome sequence analyses identified disease-causing mutations in each proband, and these mutations cosegregated with the AI phenotype in all recruited members of each family. The AI-causing mutations in family 1 were a novel AMELX mutation [NM_182680.1:c.143T>C, p.(Leu48Ser)] in the proband and a novel homozygous MMP20 mutation [NM_004771.3:c.616G>A, p.(Asp206Asn)] in the mother of the proband. Previously reported compound heterozygous MMP20 mutations [NM_004771.3:c.103A>C, p.(Arg35=) and c.389C>T, p.(Thr130Ile)] caused the AI in family 2 and family 3. Minigene splicing analyses revealed that the AMELX missense mutation increased exonic definition of exon 4 and the MMP20 synonymous mutation decreased exonic definition of exon 1. These mutations would trigger an alteration of exon usage during RNA splicing, causing the enamel malformations. These results broaden our understanding of molecular genetic pathology of tooth enamel formation.
Asunto(s)
Amelogénesis Imperfecta , Amelogénesis Imperfecta/genética , Esmalte Dental , Exones/genética , Humanos , Mutación , LinajeRESUMEN
AIM: Indirect pulp capping (IPC) is a treatment that preserves pulp vitality. Several materials have been used for this procedure. The aim of this study is to evaluate the radiographic and clinical outcomes of TheraCal LC (Bisco Inc., Schaumburg, IL, USA) and to compare it with mineral trioxide aggregate (MTA) (Pro Root MTA, Dentsply Tulsa, Johnson City, TN, USA) and calcium hydroxide [Ca(OH)2] (Dycal, Dentsply De Trey Konstanz, Germany) biomaterials in IPC treatment. MATERIALS AND METHODS: A total of 295 teeth, including second primary molars and first permanent molars with IPC indications from healthy and cooperative children aged between 4-15 years, were included in this study. Teeth were divided into three groups according to the materials used for pulp capping. Indirect pulp treatment was applied using Dycal for 91 teeth, ProRoot MTA for 89 teeth and TheraCal LC for 115 teeth. Primary molars were restored with the compomer material, and permanent molars were restored with the resin composite material. Restorations were evaluated with the Modified United States Public Health Service (modified USPHS) criteria. Clinical and radiographic findings were evaluated for 24 months at follow-up. STATISTICS: Statistical analysis was performed using the IBM SPSS Statistics 22 (IBM SPSS, Turkey) program, with descriptive statistical methods (means, standard deviations) and Chi-square, Fisher's exact test, and Yates's continuity correction (p<0.05 significance level) to evaluate the data. RESULTS: There were no statistically significant differences between the materials (p>0.05). The respective success rates of ProRoot MTA, Theracal LC, and Dycal were 94.4%, 87.8%, and 84.6%. There was no statistically significant difference between primary and permanent teeth according to the modified USPHS criteria (p>0.05). CONCLUSION: These results support the idea that the success of IPC is independent from the capping material. Recently produced calcium-silicate based materials can also be used for IPC. The most important factors are to apply the indirect pulp treatment carefully, avoiding bacterial contamination, and to seal the teeth with hermetic restoration. More clinical studies with longer follow-up periods are required for understanding the clinical efficiency of these materials.
Asunto(s)
Recubrimiento de la Pulpa Dental , Materiales de Recubrimiento Pulpar y Pulpectomía , Adolescente , Compuestos de Aluminio , Compuestos de Calcio , Niño , Preescolar , Pulpa Dental , Combinación de Medicamentos , Estudios de Seguimiento , Humanos , Óxidos , Silicatos , TurquíaRESUMEN
Dental enamel malformations, or amelogenesis imperfecta (AI), can be isolated or syndromic. To improve the prospects of making a successful diagnosis by genetic testing, it is important that the full range of genes and mutations that cause AI be determined. Defects in WDR72 (WD repeat-containing protein 72; OMIM *613214) cause AI, type IIA3 (OMIM #613211), which follows an autosomal recessive pattern of inheritance. The defective enamel is normal in thickness, severely hypomineralized, orange-brown stained, and susceptible to attrition. We identified 6 families with biallelic WDR72 mutations by whole exome sequence analyses that perfectly segregated with the enamel phenotype. The novel mutations included 3 stop-gains [NM_182758.2: c.377G>A/p.(Trp126*), c.1801C>T/p.(Arg601*), c.2350A>T/p.(Arg784*)], a missense mutation [c.1265G>T/p.(Gly422Val)], and a 62,138-base pair deletion (NG_017034.2: g.35441_97578del62138) that removed WDR72 coding exons 3 through 13. A previously reported WDR72 frameshift was also observed [c.1467_1468delAT/p.(Val491Aspfs*8)]. Three of the affected patients showed decreased serum pH, consistent with a diagnosis of renal tubular acidosis. Percentiles of stature and body weight varied among 8 affected individuals but did not show a consistent trend. These studies support that WDR72 mutations cause a syndromic form of AI and improve our ability to diagnose AI caused by WDR72 defects.
Asunto(s)
Acidosis , Amelogénesis Imperfecta , Proteínas/inmunología , Acidosis/genética , Amelogénesis Imperfecta/genética , Humanos , Mutación , LinajeRESUMEN
Tooth enamel, the hardest tissue in the human body, is formed after a complex series of interactions between dental epithelial tissue and the underlying ectomesenchyme. Nonsyndromic amelogenesis imperfecta (AI) is a rare genetic disorder affecting tooth enamel without other nonoral symptoms. In this study, we identified 2 novel ENAM mutations in 2 families with hypoplastic AI by whole exome sequencing. Family 1 had a heterozygous splicing donor site mutation in intron 4, NM_031889; c.123+2T>G. Affected individuals had hypoplastic enamel with or without the characteristic horizontal hypoplastic grooves in some teeth. Family 2 had a nonsense mutation in the last exon, c.1842C>G, p.(Tyr614*), that was predicted to truncate the protein by 500 amino acids. Participating individuals had at least 1 mutant allele, while the proband had a homozygous mutation. Most interestingly, the clinical phenotype of the individuals harboring the heterozygous mutation varied from a lack of penetrance to a mild hypoplastic enamel defect. We believe that these findings will broaden our understanding of the clinical phenotype of AI caused by ENAM mutations.
Asunto(s)
Amelogénesis Imperfecta/genética , Proteínas de la Matriz Extracelular/genética , Mutación/genética , Niño , Consanguinidad , Femenino , Humanos , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Turquía , Secuenciación del Exoma , Adulto JovenRESUMEN
OBJECTIVE: To identify the molecular genetic aetiology of a family with autosomal dominant amelogenesis imperfecta (AI). SUBJECTS AND METHODS: DNA samples were collected from a six-generation family, and the candidate gene approach was used to screen for the enamelin (ENAM) gene. Whole-exome sequencing and linkage analysis with SNP array data identified linked regions, and candidate gene screening was performed. RESULTS: Mutational analysis revealed a mutation (c.561_562delCT and p.Tyr188Glnfs*13) in the DLX3 gene. After finding a recurrent DLX3 mutation, the clinical phenotype of the family members was re-examined. The proband's mother had pulp elongation in the third molars. The proband had not hair phenotype, but her cousin had curly hair at birth. CONCLUSIONS: In this study, we identified a recurrent 2-bp deletional DLX3 mutation in a new family. The clinical phenotype was the mildest one associated with the DLX3 mutations. These results will advance the understanding of the functional role of DLX3 in developmental processes.
Asunto(s)
Amelogénesis Imperfecta/genética , Secuencia de Bases , Proteínas de Homeodominio/genética , Eliminación de Secuencia , Factores de Transcripción/genética , Adulto , Amelogénesis Imperfecta/diagnóstico por imagen , Niño , Análisis Mutacional de ADN , Exoma , Femenino , Humanos , Masculino , Linaje , Fenotipo , Radiografía DentalRESUMEN
In order to achieve highly mineralized tooth enamel, enamel proteinases serve the important function of removing the remaining organic matrix in the mineralization and maturation of the enamel matrix. Mutations in the kallikrein 4 (KLK4), enamelysin (MMP20), and WDR72 genes have been identified as causing hypomaturation enamel defects in an autosomal-recessive hereditary pattern. In this report, 2 consanguineous families with a hypomaturation-type enamel defect were recruited, and mutational analysis was performed to determine the molecular genetic etiology of the disease. Whole exome sequencing and autozygosity mapping identified novel homozygous mutations in the KLK4 (c.620_621delCT, p.Ser207Trpfs*38) and MMP20 (c.1054G>A, p.Glu352Lys) genes. Further analysis on the effect of the mutations on the translation, secretion, and function of KLK4 and MMP20 revealed that mutant KLK4 was degraded intracellularly and became inactive while mutant MMP20 was expressed at a normal level but secreted only minimally with proteolytic function.
Asunto(s)
Amelogénesis Imperfecta/genética , Calicreínas/genética , Metaloproteinasa 20 de la Matriz/genética , Mutación , Amelogénesis Imperfecta/diagnóstico por imagen , Western Blotting , Niño , Consanguinidad , Femenino , Genotipo , Homocigoto , Humanos , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Radiografía Panorámica , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: Hereditary defects in tooth enamel formation, amelogenesis imperfecta (AI), can be non-syndromic or syndromic phenotype. Integrins are signaling proteins that mediate cell-cell and cell-extracellular matrix communication, and their involvement in tooth development is well known. The purposes of this study were to identify genetic cause of an AI family and molecular pathogenesis underlying defective enamel formation. MATERIALS AND METHODS: We recruited a Turkish family with isolated AI and performed mutational analyses to clarify the underlying molecular genetic etiology. RESULTS: Autozygosity mapping and exome sequencing identified a novel homozygous ITGB6 transversion mutation in exon 4 (c.517G>C, p.Gly173Arg). The glycine at this position in the middle of the ßI-domain is conserved among a wide range of vertebrate orthologs and human paralogs. Clinically, the enamel was generally thin and pitted with pigmentation. Thicker enamel was noted at the cervical area of the molars. CONCLUSIONS: In this study, we identified a novel homozygous ITGB6 mutation causing isolated AI, and this advances the understanding of normal and pathologic enamel development.
Asunto(s)
Amelogénesis Imperfecta/etiología , Amelogénesis Imperfecta/genética , Cadenas beta de Integrinas/genética , Mutación , Amelogénesis/genética , Amelogénesis Imperfecta/sangre , Amelogénesis Imperfecta/diagnóstico por imagen , Niño , Análisis Mutacional de ADN , Exones , Femenino , Humanos , Diente Molar/patología , Linaje , Reacción en Cadena de la Polimerasa , Alineación de Secuencia , TurquíaRESUMEN
BACKGROUND: The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth condition characterised by macrosomia, mental deficiency, large head, prominent skull sutures, midface deficiency, hypertelorism, broad nose, wide mouth, macroglossia, malocclusion, highly arched palate, and musculoskeletal and limb abnormalities. The aim of this case report is to present clinical and oral findings of an 8-year-old boy who had been diagnosed with SGBS. CASE REPORT: This patient had supernumerary nipples on the right side, cubitus valgus webbed fingers, scoliosis, umbilical hernia, a coarse face, macrocephaly, hypertelorism, a short broad nose, a wide mouth, a straight facial profile and hearing loss. The patient also had macroglossia, diastemas, over-retained primary tooth, absent mandibular permanent central incisors, and highly arched palate. Lateral cephalometric analysis revealed a large anterior cranial base, a large maxilla and mandible, a large inferior face height, and skeletal Class III jaw relationship. FOLLOW-UP: After extraction of the over-retained primary central tooth, a partial prosthesis was fabricated in order to maintain function. The patient has been recalled regularly at 6-month intervals for 2 years. Over the following years the prosthesis was replaced due to facial growth. CONCLUSION: Long term follow-up is essential for the patient with SGBS. Preventive dental care, including oral hygiene instructions, diet counselling and the use of fluoride has been implemented.
Asunto(s)
Anodoncia/diagnóstico , Arritmias Cardíacas/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Gigantismo/diagnóstico , Cardiopatías Congénitas/diagnóstico , Discapacidad Intelectual/diagnóstico , Macroglosia/diagnóstico , Maloclusión de Angle Clase III/diagnóstico , Cefalometría/métodos , Niño , Dentadura Parcial Removible , Diastema/patología , Estudios de Seguimiento , Humanos , Hipertelorismo/diagnóstico , Incisivo/anomalías , Macrostomía/diagnóstico , Masculino , Nariz/anomalías , Hueso Paladar/anomalías , Diente Primario/patologíaRESUMEN
Amelogenesis imperfecta (AI) is a genetic disease affecting tooth enamel formation. AI can be an isolated entity or a phenotype of syndromes. To date, more than 10 genes have been associated with various forms of AI. We have identified 2 unrelated Turkish families with hypoplastic AI and performed mutational analysis. Whole-exome sequencing identified 2 novel heterozygous nonsense mutations in the ENAM gene (c.454G>T p.Glu152* in family 1, c.358C>T p.Gln120* in family 2) in the probands. Affected individuals were heterozygous for the mutation in each family. Segregation analysis within each family revealed individuals with incomplete penetrance or extremely mild enamel phenotype, in spite of having the same mutation with the other affected individuals. We believe that these findings will broaden our understanding of the clinical phenotype of AI caused by ENAM mutations.
Asunto(s)
Amelogénesis Imperfecta/genética , Codón sin Sentido/genética , Proteínas de la Matriz Extracelular/genética , Penetrancia , Adolescente , Niño , Segregación Cromosómica/genética , Codón de Terminación/genética , Consanguinidad , Citosina , Esmalte Dental/patología , Hipoplasia del Esmalte Dental/genética , Exoma/genética , Exones/genética , Femenino , Ácido Glutámico/genética , Glutamina/genética , Guanina , Heterocigoto , Humanos , Masculino , Fenotipo , TiminaRESUMEN
Dental enamel formation depends upon the transcellular transport of Ca(2+) by ameloblasts, but little is known about the molecular mechanism, or even if the same process is operative during the secretory and maturation stages of amelogenesis. Identifying mutations in genes involved in Ca(2+) homeostasis that cause inherited enamel defects can provide insights into the molecular participants and potential mechanisms of Ca(2+) handling by ameloblasts. Stromal Interaction Molecule 1 (STIM1) is an ER transmembrane protein that activates membrane-specific Ca(2+) influx in response to the depletion of ER Ca(2+) stores. Solute carrier family 24, member 4 (SLC24A4), is a Na(+)/K(+)/Ca(2+) transporter that exchanges intracellular Ca(2+) and K(+) for extracellular Na(+). We identified a proband with syndromic hypomaturation enamel defects caused by a homozygous C to T transition (g.232598C>T c.1276C>T p.Arg426Cys) in STIM1, and a proband with isolated hypomaturation enamel defects caused by a homozygous C to T transition (g.124552C>T; c.437C>T; p.Ala146Val) in SLC24A4. Immunohistochemistry of developing mouse molars and incisors showed positive STIM1 and SLC24A4 signal specifically in maturation-stage ameloblasts. We conclude that enamel maturation is dependent upon STIM1 and SLC24A4 function, and that there are important differences in the Ca(2+) transcellular transport systems used by secretory- and maturation-stage ameloblasts.
Asunto(s)
Amelogénesis/fisiología , Antiportadores/fisiología , Proteínas de la Membrana/fisiología , Proteínas de Neoplasias/fisiología , Alanina/genética , Ameloblastos/fisiología , Amelogénesis/genética , Animales , Antiportadores/genética , Arginina/genética , Señalización del Calcio/fisiología , Niño , Preescolar , Consanguinidad , Cisteína/genética , Citosina , Hipoplasia del Esmalte Dental/genética , Femenino , Variación Genética/genética , Homocigoto , Humanos , Proteínas de la Membrana/genética , Ratones , Mutación Missense/genética , Proteínas de Neoplasias/genética , Linaje , Molécula de Interacción Estromal 1 , Timina , Valina/genéticaRESUMEN
Amelogenesis imperfecta is a heterogeneous group of genetic conditions affecting enamel formation. Recently, mutations in solute carrier family 24 member 4 (SLC24A4) have been identified to cause autosomal recessive hypomaturation amelogenesis imperfecta. We recruited a consanguineous family with hypomaturation amelogenesis imperfecta with generalized brown discoloration. Sequencing of the candidate genes identified a 10-kb deletion, including exons 15, 16, and most of the last exon of the SLC24A4 gene. Interestingly, this deletion was caused by homologous recombination between two 354-bp-long homologous sequences located in intron 14 and the 3' UTR. This is the first report of exonal deletion in SLC24A4 providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of amelogenesis.
Asunto(s)
Amelogénesis Imperfecta/genética , Antiportadores/genética , Exones/genética , Eliminación de Gen , Regiones no Traducidas 3'/genética , Emparejamiento Base/genética , Niño , Hibridación Genómica Comparativa , Consanguinidad , Femenino , Homocigoto , Humanos , Intrones/genética , LinajeRESUMEN
AIM: Evidence suggests caries experience is higher in children with asthma. This study compared caries experience in asthmatic and non-asthmatic children and defined whether variation in the distribution of caries experience differed between the two groups and was dependent on the presence of genetic variation in enamel formation genes. METHODS: Children with asthma were recruited at the Istanbul University, Faculty of Medicine, Department of Paediatrics, Division of Paediatric Allergy and Pulmonary Diseases, and non-affected children were recruited at the Istanbul University, Faculty of Dentistry, Department of Paedodontics. Cases (N = 100) were defined as children between the ages of 6 and 12 years with asthma and controls (N = 100) as children without asthma. Cases and controls were matched by sex and age. All study subjects received a complete dental exam, provided demographic and other caries and asthma risk factors data, and a saliva sample for DNA extraction. Caries experience was defined based on DMFT/dmft and DMFS/dmfs scores. Genotypes of 11 SNPs were selected in intronic regions of enamel development genes. PCR with TaqMan chemistry was used for genotyping all selected markers. Association between caries experience (caries-free versus caries affected) depending on asthma status and SNPs was tested with PLINK by logistic regression, adjusting by risk, and other preventive measures. p values below 0.0045 (0.05/11) were considered statistically significant. RESULTS: Logistic regression analysis showed an association between AMBN rs4694075 and caries experience (p = 2.525e-007). CONCLUSIONS: This study provides, for the first time, evidence that ameloblastin is associated with caries in asthmatic children.
Asunto(s)
Asma/complicaciones , Índice CPO , Proteínas del Esmalte Dental/genética , Variación Genética/genética , Amelogénesis/genética , Amelogenina/genética , Estudios de Casos y Controles , Niño , Caries Dental/complicaciones , Caries Dental/genética , Índice de Placa Dental , Proteínas de la Matriz Extracelular/genética , Femenino , Genotipo , Humanos , Intrones/genética , Masculino , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Empalme de ARN , Timina , Cepillado DentalRESUMEN
The runt-related transcription factor 2 gene (RUNX2), which is also known as CBFA1, is a master regulatory gene in bone formation. Mutations in RUNX2 have been identified in cleidocranial dysplasia (CCD) patients. CCD is a rare autosomal dominant skeletal dysplasia that is characterized by delayed closure of cranial sutures, aplastic or hypoplastic clavicle formation, short stature, and dental anomalies, including malocclusion, supernumerary teeth, and delayed eruption of permanent teeth. In this study, we recruited three de novo CCD families and performed mutational analysis of the RUNX2 gene as a candidate gene approach. The mutational study revealed three disease-causing mutations: a missense mutation (c.674G>A, p.Arg225Gln), a frameshift mutation (c.1119delC, p.Arg374Glyfs*), and a nonsense mutation (c.1171C>T, p.Arg391*). Clinical examination revealed a unique dental phenotype (no typical supernumerary teeth, but duplication of anterior teeth) in one patient. We believe that this finding will broaden the understanding of the mechanism of supernumerary teeth formation and CCD-related phenotypes.
Asunto(s)
Displasia Cleidocraneal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Adolescente , Secuencia de Bases , Niño , Displasia Cleidocraneal/diagnóstico por imagen , Codón sin Sentido , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura , Estudios de Asociación Genética , Humanos , Maxilares/diagnóstico por imagen , Masculino , Mutación Missense , Radiografía , Anomalías Dentarias/diagnóstico por imagen , Anomalías Dentarias/genéticaRESUMEN
Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related.
Asunto(s)
Amelogénesis Imperfecta/genética , Moléculas de Adhesión Celular/genética , Niño , Codón sin Sentido , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura , Genes Dominantes , Humanos , KalininaRESUMEN
INTRODUCTION: The majority of tooth agenesis cases are mild (hypodontia) and typically not associated with the gene mutations linked to oligodontia. From this, we hypothesise that most cases of tooth agenesis fit a polygenic mode of inheritance, where several genes with small effects cause a variety of varying phenotypes. MATERIALS AND METHODS: In this study, we looked at 18 not typically studied genes in this condition, to ascertain their contribution to hypodontia. Our study subjects consisted of 167 patients with hypodontia and their parents from two cohorts (one from Brazil and one from Turkey). An additional 465 DNA samples (93 cases with hypodontia and 372 controls without family history for tooth agenesis or oral clefts) from Brazil were also available for this study. Ninety-three single nucleotide polymorphisms that maximally represent the linkage disequilibrium structure of the genes for the 18 genes were selected and genotyped using Taqman chemistry. Chi square was used to test if genotype distributions were in Hardy-Weinberg equilibrium, and 24 markers that were in Hardy-Weinberg equilibrium and had allele frequencies higher than 5 % in a panel of 50 CEPH samples were further tested. Association between hypodontia and genetic variants was tested with the transmission disequilibrium test within the programme Family-Based Association Test (FBAT) and by using Chi square and Fisher's exact tests. Alpha at a level of 0.05 was used to report results. RESULTS: Results suggest possible associations between several genes and hypodontia in the three populations. In the Turkish cohort (n = 51 parent-affected child trios) the most significant results were as follows: FGF3 rs1893047, p = 0.08; GLI3 rs929387, p = 0.03; GLI3 haplotype rs929387-rs846266, p = 0.002; and PAX9 rs2073242, p = 0.03. In the Brazilian cohort (n = 116 parent-affected child trios), the results were as follows: DLX1 rs788173, p = 0.07; FGF3 rs12574452, p = 0.03; GLI2 rs1992901, p = 0.03; and PITX2 rs2595110, p = 0.01. The second Brazilian cohort also suggested that FGF3 (rs12574452, p = 0.01) is associated with hypodontia and added EDAR (rs17269487, p = 0.04), LHX6 (rs989798, p = 0.02), and MSX1 (rs12532, p = 0.003). CONCLUSION: Our results suggest that several genes are potentially associated with hypodontia and their individual contributions may be modest. Hence, these cases may not be explained by inactivating mutations such as many oligodontia cases segregating in a Mendelian fashion but rather are influenced by one or more susceptibility alleles in multiple small effect genes.
Asunto(s)
Anodoncia , Frecuencia de los Genes , Anodoncia/genética , Estudios de Casos y Controles , Genotipo , Humanos , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Caries is a multifactorial disease and little is still known about the host genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified the interval 5q12.1-5q13.3 as linked to low caries susceptibility in Filipino families. Here we fine-mapped this region in order to identify genetic contributors to caries susceptibility. Four hundred and seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. DMFT scores and genotype data of 75 single-nucleotide polymorphisms were evaluated in the Filipino families with the Family-Based Association Test. For replication purposes, a total 1,467 independent subjects from five different populations were analyzed in a case-control format. In the Filipino cohort, statistically significant and borderline associations were found between low caries experience and four genes spanning 13 million base pairs (PART1, ZSWIM6, CCNB1, and BTF3). We were able to replicate these results in some of the populations studied. We detected PART1 and BTF3 expression in whole saliva, and the expression of BTF3 was associated with caries experience. Our results suggest BTF3 may have a functional role in protecting against caries.
Asunto(s)
Mapeo Cromosómico/métodos , Cromosomas Humanos Par 5/genética , Susceptibilidad a Caries Dentarias/genética , Caries Dental/genética , Estudios de Casos y Controles , Índice CPO , Caries Dental/prevención & control , Humanos , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple , Proteínas y Péptidos Salivales/genética , Factores de Transcripción/genéticaRESUMEN
Non-syndromic amelogenesis imperfecta (AI) is a collection of isolated inherited enamel malformations that follow X-linked, autosomal-dominant, or autosomal-recessive patterns of inheritance. The AI phenotype is also found in syndromes. We hypothesized that whole-exome sequencing of AI probands showing simplex or recessive patterns of inheritance would identify causative mutations among the known candidate genes for AI. DNA samples obtained from 12 unrelated probands with AI were analyzed. Disease-causing mutations were identified in three of the probands: a novel single-nucleotide deletion in both KLK4 alleles (g.6930delG; c.245delG; p.Gly82Alafs*87) that shifted the reading frame, a novel missense transition mutation in both MMP20 alleles (g.15390A>G; c.611A>G; p.His204Arg) that substituted arginine for an invariant histidine known to coordinate a structural zinc ion, and a previously described nonsense transition mutation in a single allele of FAM83H (c.1379G>A; g.5663G>A; p.W460*). Erupted molars and cross-sections from unerupted parts of the mandibular incisors of Mmp20 null mice were characterized by scanning electron microscopy. Their enamel malformations closely correlated with the enamel defects displayed by the proband with the MMP20 mutation. We conclude that whole-exome sequencing is an effective means of identifying disease-causing mutations in kindreds with AI, and this technique should prove clinically useful for this purpose.
Asunto(s)
Amelogénesis Imperfecta/genética , Análisis Mutacional de ADN/métodos , Exoma/genética , Calicreínas/genética , Metaloproteinasa 20 de la Matriz/genética , Proteínas/genética , Adolescente , Alelos , Animales , Niño , Codón sin Sentido , Esmalte Dental/ultraestructura , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , Ratones , Ratones Mutantes , Mutación Missense , LinajeRESUMEN
Individuals with clefts present considerably more dental anomalies than individuals without clefts. We also have shown that these individuals report cancer in their families more often than do unaffected individuals. We investigated how these conditions correlated with genetic variants associated with clefts to ascertain if specific molecular signatures exist that could help identify individuals at risk for having offspring with these defects. We examined 573 individuals, 158 with clefts, 254 unaffected family members, and 161 non-related controls. Several clinical features, such as laterality, the presence of dental anomalies, medical history, and pregnancy history, were used to assess each individual's cleft status. Then, we performed molecular studies with genes that have been independently associated with oral clefts. We analyzed two datasets: nuclear families and case-control individuals where the case was the child from the family and controls were unrelated non-clefted individuals. In the family data, we confirmed association between clefts and rs987525 on chromosome 8 (p = 0.007) and found an association with rs987525 and tooth agenesis (p = 0.0003). In the case-control data, clefts, supernumerary teeth and familial cancer history were associated with ABCA4-rs481931 on chromosome 1 (p = 2E-19, 0.0007, 2E-06, respectively), and clefts and microdontia were associated with rs1325474 on chromosome 6 (p = 1E-06, 0.0002, respectively).
Asunto(s)
Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 8/genética , Labio Leporino/genética , Fisura del Paladar/genética , Estudio de Asociación del Genoma Completo , Anomalías Dentarias/genética , Adolescente , Adulto , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Niño , Preescolar , Labio Leporino/etiología , Fisura del Paladar/etiología , Salud de la Familia , Femenino , Marcadores Genéticos , Humanos , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Anamnesis , Persona de Mediana Edad , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Embarazo , Efectos Tardíos de la Exposición Prenatal , Factores de Riesgo , Fumar/efectos adversos , Anomalías Dentarias/complicaciones , Adulto JovenRESUMEN
Ekman-Westborg and Julin is a trait that shows multiple macrodontia and multituberculism affecting only the teeth with no other anomalies (E-WJ). The aim of this report is to present a case which appears to manifest all the clinical signs of the E-WJ trait including odontoma formation. A 18-year-old girl with gingival inflammation particularly in the maxillary insicor area was referred to the authors' department. Panoramic, periapical and cephalometric radiographs were examined and complex odontoma associated with unerupted maxillary permanent lateral incisors was revealed. Intraoral examination revealed anterior crossbite, Angle Class III type malocclusion with mandibulary prominence and macrodontia of teeth 37, 12, 11 and 21. The patient was accepted as a new sporadic case of E-WJ. More case reports are needed to elucidate the causes and pathogenesis of this condition.