transforming-growth-factor-beta and Anodontia

Tooth agenesis (TA) is one of the most common developmental anomalies that affects the number of teeth. An extensive analysis of publicly accessible databases revealed 15 causative genes responsible for nonsyndromic TA, along with their signaling pathways in Wnt/β-catenin, TGF-β/BMP, and Eda/Edar/NF-κB. However, genotype-phenotype correlation analysis showed that most of the causal genes are also responsible for syndromic TA or other conditions. In a total of 198 different mutations of the 15 genes responsible for nonsyndromic TA, 182 mutations (91.9%) are derived from seven genes (AXIN2, EDA, LRP6, MSX1, PAX9, WNT10A, and WNT10B) compared with the remaining 16 mutations (8.1%) identified in the remaining eight genes (BMP4, DKK1, EDAR, EDARADD, GREM2, KREMEN1, LTBP3, and SMOC2). Furthermore, specificity analysis in terms of the ratio of nonsyndromic TA mutations versus syndromic mutations in each of the aforementioned seven genes showed a 98.2% specificity rate in PAX9, 58.9% in WNT10A, 56.6% in MSX1, 41.2% in WNT10B, 31.4% in LRP6, 23.8% in AXIN2%, and 8.4% in EDA. These findings underscore an important role of the Wnt and Wnt-associated pathways in the genetic etiology of this heterozygous disease and shed new lights on the discovery of novel molecular mechanisms associated with tooth agenesis.

Topics: Animals; Anodontia; Axin Protein; Bone Morphogenetic Protein 4; Calcium-Binding Proteins; Cytokines; Ectodysplasins; Edar Receptor; Edar-Associated Death Domain Protein; Humans; Intercellular Signaling Peptides and Proteins; Latent TGF-beta Binding Proteins; Low Density Lipoprotein Receptor-Related Protein-6; Membrane Proteins; MSX1 Transcription Factor; Mutation; NF-kappa B; PAX9 Transcription Factor; Proto-Oncogene Proteins; Transforming Growth Factor beta; Wnt Proteins; Wnt Signaling Pathway

The embryonic head development, including the formation of dental structures, is a complex and delicate process guided by specific genetic programs. Genetic changes and environmental factors can disturb the execution of these programs and result in abnormalities in orofacial and dental structures. Orofacial clefts and hypodontia/ oligodontia are examples of such abnormalities frequently seen in dental clinics. An insight into the mechanisms and genes involved in the formation of orofacial and dental structures has been gradually gained by genetic analysis of families and by the use of experimental vertebrate models such as the mouse and chick models. The development of novel clinical therapies for orofacial and dental pathological conditions depends very much on a detailed knowledge of the molecular and cellular processes that are involved in head formation.

Topics: Animals; Anodontia; Cleft Lip; Cleft Palate; Fibroblast Growth Factors; Hedgehog Proteins; Humans; Mice; MSX1 Transcription Factor; Neural Crest; Paired Box Transcription Factors; Palate, Hard; PAX9 Transcription Factor; Signal Transduction; Skull; Transforming Growth Factor beta; Wnt Proteins

The aims of this study were to investigate the eruption pattern of maxillary permanent canines in the alveolar cleft area after secondary alveolar bone grafting and to assess the risk indicators for canine impaction.. The sample consisted of 75 patients with unilateral cleft lip and palate who underwent secondary alveolar bone grafting with rhBMP-2 with a mean age of 9.8 years of age at 1 center. A split-mouth study design was used, with the noncleft hemiarch comprising the control group. Panoramic radiographs taken before, immediately after, and 1 year after secondary alveolar bone grafting were used to assess the following parameters in both cleft side (CS) and noncleft side: canine mesiodistal angulation, canine height relative to the occlusal plane, canine mesial displacement, and superimposition with the neighboring maxillary incisors. The frequency of associated dental anomalies was compared between patients with and without CS canine impaction. Data were evaluated using analysis of variance, t tests, Fisher tests, and multiple logistic regression analysis (P <0.05).. On the CS, maxillary canines were usually more mesially angulated and more distant from the occlusal plane compared with the noncleft side. The prevalences of canine impaction on the CS and noncleft side were 24% and 1.3%, respectively. Maxillary impacted canines on the CS demonstrated increased mesiodistal angulation and height at all time points. No association between CS canine impaction and mesial displacement (sectors) was found. An increased prevalence of lateral incisor agenesis on the CS was observed in the subgroup with canine impaction.. Increased mesial angulation and lateral incisor agenesis on the CS are early risk indicators for maxillary canine impaction in patients with unilateral cleft lip and palate.

Topics: Alveolar Bone Grafting; Anodontia; Bone Morphogenetic Protein 2; Child; Cleft Lip; Cleft Palate; Cuspid; Female; Humans; Incisor; Male; Postoperative Complications; Radiography, Panoramic; Recombinant Proteins; Retrospective Studies; Risk Factors; Tooth Eruption; Tooth, Impacted; Transforming Growth Factor beta

Latent TGFB-binding protein 3 (LTBP3) is known to increase bio-availability of TGFB. A homozygous mutation in this gene has previously been associated with oligodontia and short stature in a single family. We report on two sisters with homozygous truncating mutations in LTBP3. In addition to oligodontia and short stature, both sisters have mitral valve prolapse, suggesting a link between truncating LTBP3 mutations and mitral valve disease mediated through the TGFB pathway.

Topics: Adolescent; Anodontia; Base Sequence; Dwarfism; Exome; Female; Gene Expression; Genes, Recessive; High-Throughput Nucleotide Sequencing; Homozygote; Humans; Latent TGF-beta Binding Proteins; Mitral Valve Prolapse; Molecular Sequence Data; Mutation; Pedigree; Phenotype; Siblings; Transforming Growth Factor beta; Young Adult

Hypodontia, the congenital absence of one or a few teeth, is one of the most common alterations of the human dentition. The most common permanent missing teeth are the third molars, second premolars, and maxillary lateral incisors. Although hypodontia does not represent a serious public health problem, it may cause masticatory and speech dysfunctions and esthetic problems. Transforming growth factor-beta1 (TGF-beta1) is believed to play an important role in tooth development. Its gene is expressed at bud, cap, and bell stages of odontogenesis. Genetic polymorphisms in the TGF-beta1 gene promoter were shown to interfere with the transcriptional activity of this gene. To further investigate the role of the TGF-beta1 gene in human hypodontia, we analyzed the frequencies of the -509 polymorphism (C-T) alleles and -800 polymorphism (G-A) alleles and genotypes in the TGF-beta1 gene promoter in 51 Caucasian subjects with hypodontia and 48 control individuals. Our data suggest that these TGF-beta1 promoter polymorphisms are not associated with hypodontia.

Topics: Adenine; Alleles; Anodontia; Base Pairing; Chi-Square Distribution; Cytosine; Gene Frequency; Genotype; Guanine; Humans; Odontogenesis; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Thymine; Transcription, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1

The purpose of this study was to determine whether the candidate genes previously studied in subjects with cleft lip, cleft palate, or both are associated with hypodontia outside the region of the cleft.. One hundred twenty subjects from the Iowa Craniofacial Anomalies Research Center were selected based on the availability of both dental records and genotype information.. The type of orofacial clefting and type and location of dental anomalies (missing teeth, supernumerary teeth, or peg laterals) were assessed by dental chart review and radiographic examination. Genotype analysis of candidate genes was performed using polymerase chain reaction/single-strand conformation polymorphism analysis.. The prevalence of hypodontia in this sample was 47.5%, with 30.0% of subjects having missing teeth outside the cleft. There was a positive association between subjects with cleft lip or cleft lip and palate who had hypodontia outside the cleft region (compared with noncleft controls) and both muscle segment homeo box homolog 1 (MSX1) (p =.029) and transforming growth factor beta 3 (TGFB3) (p =.024). It was not possible in this analysis to determine whether this association was specifically associated with orofacial clefting combined with hypodontia or whether it was due primarily to the clefting phenotype.. In this sample, there was a significantly greater incidence of hypodontia outside the cleft region in subjects with cleft lip and palate, compared with cleft lip only or cleft palate only. Cleft lip and/or palate with hypodontia outside the cleft region was positively associated with both TGFB3 and MSX1, compared with noncleft controls.

Topics: Anodontia; Chi-Square Distribution; Child; Cleft Lip; Cleft Palate; DNA-Binding Proteins; Gene Frequency; Genetic Markers; Homeodomain Proteins; Humans; MSX1 Transcription Factor; PAX9 Transcription Factor; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Statistics, Nonparametric; Transcription Factors; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transforming Growth Factor beta3

Van der Woude syndrome (VWS) is an autosomal dominant disorder associated with one or more of the following features: clefting of the primary or secondary palate, hypodontia or lower lip pits. It has been estimated to account for 2% of all cases of cleft lip and palate. VWS is one of the rare disorders in which clefting of the primary and secondary palate may be seen to segregate as components associated with the same gene. Because of its autosomal dominant inheritance, VWS is readily accessable to linkage analysis as a preliminary step in the identification of the molecular abnormality underlying the clefting effect in the primary and secondary palate. A reported linkage between REN and VWS has promoted us to use pHRnX3.6 (REN) and several markers surrounding REN for a linkage analysis in a large Swiss family. In a second step, linkage analysis was performed to study restriction fragment length polymorphisms for the candidate gene TGFB2 and other loci recently mapped to the candidate region 1q32-1q41. Evidence for linkage (theta = 0.00, lod score = 3.01) between REN and VWS could be confirmed in this pedigree. TGFB2 demonstrated recombination with the disease locus and is unlikely to be causative in VWS. The results of a multipoint linkage analysis showed that VWS was flanked by D1S65 and TGFB2 at a maximum location score of 20.3.

Topics: Adolescent; Anodontia; Cleft Palate; Female; Genetic Linkage; Genetic Markers; Humans; Lod Score; Male; Pedigree; Renin; Switzerland; Syndrome; Transforming Growth Factor beta