Tooth agenesis is one of the most common craniofacial disorders in humans. More than 350 genes have been associated with teeth development. In this study, we enrolled 60 child patients (age 13 to 17) with various types of tooth agenesis. Whole gene sequences of PAX9, MSX1, AXIN2, EDA, EDAR and WNT10a genes were sequenced by next generation sequencing on the Illumina MiSeq platform. We found previously undescribed heterozygous nonsense mutation g.8177G>T (c.610G>T) in MSX1 gene in one child. Mutation was verified by Sanger sequencing. Sequencing analysis was performed in other family members of the affected child. All family members carrying g.8177G>T mutation suffered from oligodontia (missing more than 6 teeth excluding third molars). Mutation g.8177G>T leads to a stop codon (p.E204X) and premature termination of Msx1 protein translation. Based on previous in vitro experiments on mutation disrupting function of Msx1 homeodomain, we assume that the heterozygous g.8177G>T nonsense mutation affects the amount and function of Msx1 protein and leads to tooth agenesis.

• MeSH
• Anodontia genetics   pathology   MeSH
• Humans MeSH
• Nails, Malformed MeSH
• Adolescent MeSH
• Models, Molecular MeSH
• Codon, Nonsense * MeSH
• Family MeSH
• Pedigree MeSH
• MSX1 Transcription Factor genetics   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Humans MeSH
• Adolescent MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The first step in the development of human colorectal cancer is aberrant activation of the Wnt signaling pathway. Wnt signaling hyperactivation is predominantly caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene that encodes the pathway negative regulator. In order to identify genes affected by the Apc loss, we performed expression profiling of intestinal epithelium isolated from mice harboring a conditional Apc allele. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. Histological analysis of the Apc-deficient epithelium revealed that in the small intestine, the Msx1 protein was localized exclusively in ectopic crypts, i.e., in pockets of proliferating cells abnormally positioned on the villi. Ablation of the Msx1 gene leads to the disappearance of ectopic crypts and loss of differentiated cells. Moreover, tumors arising from Msx1-deficient cells display altered morphology reminiscent of villous adenomas. In human tumor specimens, MSX1 displayed significantly increased expression in colonic neoplasia with a descending tendency during the lesion progression towards colorectal carcinoma. In summary, the results indicate that Msx1 represents a novel marker of intestinal tumorigenesis. In addition, we described the previously unknown relationship between the Msx1-dependent formation of ectopic crypts and cell differentiation.

• MeSH
• beta Catenin metabolism   MeSH
• Cell Differentiation MeSH
• Colorectal Neoplasms genetics   pathology   MeSH
• Humans MeSH
• Mice, Knockout MeSH
• Colonic Neoplasms genetics   pathology   MeSH
• Adenomatous Polyposis Coli Protein genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Wnt Signaling Pathway MeSH
• Gene Expression Profiling MeSH
• Intestinal Mucosa metabolism   pathology   MeSH
• Intestine, Small pathology   MeSH
• MSX1 Transcription Factor genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• Publication type
• Meeting Abstract MeSH

• Publication type
• Meeting Abstract MeSH

Předmět sdělení: Ageneze zubu je nejčastější vývojovou poruchou dentice, kterou podle databáze Online Mendelian Inheritance in Man (OMIM) nacházíme přibližně u 20 % populace. Přestože se jedná o tak běžnou anomálii, její etiologie zatím není zcela objasněna. Vznik ageneze je ve většině případů podmíněn genetickou poruchou, pouze malé procento agenezí je zapříčiněno vlivem zevního prostředí. Mohou se uplatnit somatická onemocnění, jako rubeola, syfilis, spála, rachitis nebo nutriční poškození plodu během těhotenství a dětství. Chybění zubů může způsobit také ozařování kraniální oblasti v období raného vývoje organismu, poškození mateřského organismu ozářením, chemickými látkami a léky (thalidomid, cytostatika). Z místních příčin jsou nejčastější různé druhy traumat, dále nádory a osteomyelitis. Hypodoncie se může objevit jako izolovaná vývojová vada (nesyndromická hypodoncie) nebo jako symptom komplexních syndromů (syndromická hypodoncie). Dosud popsanými příčinami nesyndromické hypodoncie uvedenými v databázi OMIM jsou mutace v genech MSX1 (muscle segment homeobox gene 1), PAX9 (paired box gene 9), AXIN2 (axis inhibition protein 2), EDA (ectodysplasin A), WNT10A (Wingless-type MMTV integration site family, member 10A) a LTBP3 (latent transforming growth factor beta binding protein 3). Publikovány byly také případy, kdy byla ageneze podmíněna mutacemi v genech EDARADD (EDAR-associated death domain), NEMO (nuclear factor-kappaB essential modulator), KRT17 (keratin 17) a TGFA (transforming growth factor-alfa). Jednotlivé geny se liší jak z hlediska počtu identifikovaných mutací, tak z hlediska počtu dokumentovaných pacientů. Tyto mutace vysvětlují vznik poruchy jen u části postižených jedinců, u většiny nebyly identifikovány žádné defekty v těchto genech. Cestou pro selekci dalších genů, které zodpovídají za nesyndromické formy hypodoncie, může být identifikace genů, které zapříčiňují vznik syndromů, mezi jejichž symptomy patří hypodoncie.

Background: Tooth agenesis represents the most common anomaly of dental development, which according to Online Mendelian Inheritance in Man (OMIM) database, affects approximately 20% of the population. Although the anomaly is so common, the ethiology is still undisclosed. In most cases the agenesis is caused by genetic disorder, only a few develop due to external factors. Some of the external factors are rubeolla, syphilis, vitamin D deficiency or nutritional damage during pregnancy and early childhood. Other harmful factors are radiation therapy in orofacial area in early stages of the development of the patient, harms the mother caused by radiation, chemical substances or drugs (e.g. thalidomide, cytostatics). Local factors include various types of injuries, tumors and osteomyelitis. Hypodontia can occur as an isolated condition (non-syndromic hypodontia) or can be associated with a systemic condition or syndrome (syndromic hypodontia). Despite the fact that, tooth agenesis is so common, little is known about the genetic defects responsible for this complex condition. To date, the genes associated with the non-syndromic form of tooth agenesis, listed in OMIM, are MSX1 (muscle segment homeobox gene 1), PAX9 (paired box gene 9), AXIN2 (axis inhibition protein 2), EDA (ectodysplasin A), WNT10A (Wingless-type MMTV integration site family, member 10A) and LTBP3 (latent transforming growth factor beta binding protein 3). Cases with selective tooth agenesis caused by mutation in genes EDARADD (EDAR-associated death domain), NEMO (nuclear factor-kappaB essential modulator), KRT17 (keratin 17) and TGFA (transforming growth factor-alfa), were also published. All these genes vary both in terms of number of identified mutations and in terms of number of documented patients. These mutations explain the formation of tooth agenesis in only a part of affected individuals. Most patients have no defects in these genes. To select other genes, that are responsible for non-syndromic forms of hypodontia, the identification of genes that cause syndroms with symptoms of hypodontia, seems as reasonable direction of further research.

• Keywords
• hypodoncie, TGFA, KRT17, NEMO, EDARADD, LTBP3, WNT10A, EDA, AXIN2, PAX9, MSX1,
• MeSH
• Anodontia * etiology   genetics   MeSH
• Axin Protein genetics   MeSH
• Ectodysplasins genetics   MeSH
• I-kappa B Kinase genetics   MeSH
• Humans MeSH
• Mutation * MeSH
• Odontogenesis genetics   MeSH
• Edar-Associated Death Domain Protein genetics   MeSH
• Latent TGF-beta Binding Proteins genetics   MeSH
• Wnt Proteins genetics   MeSH
• MSX1 Transcription Factor genetics   MeSH
• PAX9 Transcription Factor genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Příčinou ageneze zubů jsou poruchy buněčné diferenciace v průběhu vývoje dentice.Do současné doby byly nalezeny desítky mutací zasahujících do exprese genů, které se podílejí na diferenciaci buněk dentice. Jedná se především o mutace genů pro PAX9, MSX1 a AXIN2. Výzkum vlivu mutací genů podílejících se na vývoji dentice je založený na sekvenování především translatovaných oblastí. Do současnosti jsou používány běžné kapilární sekvenátory I. generace. Jejich použití je limitováno cenově a pracností analýz. Poslední roky přinášejí nové sekvenačni metody (II. generace), zlevnění analýz a pokrytí větších analyzovaných úseků DNA. Cílem tohoto článkuje shrnutí poznatků o dosavadním způsobu výzkumu vlivu mutací na vývoj dentice.

Disturbances of cell differentiation in dentition development are cause of tooth agenesis. Until now, tens of mutations involved in gene expression related to dentition development were found. They are mutations mainly in PAX9, MSX1 andAXIN2 genes. The research on the influence of gene mutations involved in the dentition development is based on the DNA sequencing of primarily translated sequences. Capillary sequencing instruments of first generation were mainly used in the research until now. Their use is limited by cost and by laboriousness. Last years bring new sequencing methods (II. generation) with cheaper analyses and possibilities to make sequerncing of larger DNA segments. The aim of this paper is a summary of the current knowledge about research manner of influence of gene mutations on dentition development.

• Keywords
• gen, oligodoncie, hypodoncie, ageneze zubů,
• MeSH
• Anodontia * genetics   MeSH
• Child MeSH
• DNA MeSH
• Gene Expression MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Mice, Transgenic anatomy & histology   growth & development   MeSH
• Odontogenesis * physiology   genetics   MeSH
• Polymorphism, Genetic MeSH
• Sequence Analysis, DNA * methods   instrumentation   utilization   MeSH
• MSX1 Transcription Factor genetics   MeSH
• PAX9 Transcription Factor genetics   MeSH
• Tooth growth & development   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Neural crest cells (NCCs) derive early in vertebrate ontogenesis from neural tube as a population of migratory cells with exquisite differentiation potential. Abnormalities in NCC behaviour are cause of debilitating diseases including cancers and a spectrum of neurocristopathies. Thanks to their multilineage differentiation capacity NCCs offer a cell source for regenerative medicine. Both these aspects make NCC biology an important issue to study, which can currently be addressed using methodologies based on pluripotent stem cells. Here we contributed to understanding the biology of human NCCs by refining the protocol for differentiation/propagation of NCClike cells from human embryonic stem cells and by characterizing the molecular and functional phenotype of such cells. Most importantly, we improved formulation of media for NCC culture, we found that poly-L-ornithine combined with fibronectin provide good support for NCC growth, we unravelled the tendency of cultured NCCs to maintain heterogeneity of CD271 expression, and we showed that NCCs derived here possess the capacity to react to BMP4 signals by dramatically up-regulating MSX1, which is linked to odontogenesis.

• MeSH
• Adapalene MeSH
• Biomarkers metabolism   MeSH
• Cell Differentiation * drug effects   MeSH
• Neural Crest cytology   drug effects   metabolism   MeSH
• Embryonic Stem Cells cytology   drug effects   metabolism   MeSH
• Phenotype MeSH
• Bone Morphogenetic Protein 4 pharmacology   MeSH
• Humans MeSH
• Naphthalenes metabolism   MeSH
• Polymerase Chain Reaction MeSH
• Flow Cytometry MeSH
• MSX1 Transcription Factor metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Tooth agenesis is one of the most common developmental anomalies in humans. To date, many mutations involving paired box 9 (PAX9), msh homeobox 1 (MSX1), and axin 2 (AXIN2) genes have been identified. The aim of the present study was to perform screening for mutations and/or polymorphisms using the capillary sequencing method in the critical regions of PAX9 and MSX1 genes in a group of 270 individuals with tooth agenesis and in 30 healthy subjects of Czech origin. This screening revealed a previously unknown heterozygous g.9527G>T mutation in the PAX9 gene in monozygotic twins with oligodontia and three additional affected family members. The same variant was not found in healthy relatives. This mutation is located in intron 2, in the region recognized as the splice site between exon 2 and intron 2. We hypothesize that the error in pre-mRNA splicing may lead to lower expression of PAX9 protein and could have contributed to the development of tooth agenesis in the affected subjects.

• MeSH
• Anodontia genetics   MeSH
• Child MeSH
• Twins, Monozygotic genetics   MeSH
• Exons genetics   MeSH
• Genetic Variation genetics   MeSH
• Guanine MeSH
• Heterozygote MeSH
• Introns genetics   MeSH
• Cohort Studies MeSH
• Humans MeSH
• RNA Splice Sites genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation genetics   MeSH
• Diseases in Twins genetics   MeSH
• Untranslated Regions genetics   MeSH
• Open Reading Frames genetics   MeSH
• Mass Screening MeSH
• Polymorphism, Genetic genetics   MeSH
• Thymine MeSH
• MSX1 Transcription Factor genetics   MeSH
• PAX9 Transcription Factor genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

Caspase-3 and -7 are generally known for their central role in the execution of apoptosis. However, their function is not limited to apoptosis and under specific conditions activation has been linked to proliferation or differentiation of specialised cell types. In the present study, we followed the localisation of the activated form of caspase-7 during intramembranous (alveolar and mandibular bones) and endochondral (long bones of limbs) ossification in mice. In both bone types, the activated form of caspase-7 was detected from the beginning of ossification during embryonic development and persisted postnatally. The bone status was investigated by microCT in both wild-type and caspase-7-deficient adult mice. Intramembranous bone in mutant mice displayed a statistically significant decrease in volume while the mineral density was not altered. Conversely, endochondral bone showed constant volume but a significant decrease in mineral density in caspase-7 knock-out mice. Cleaved caspase-7 was present in a number of cells that did not show signs of apoptosis. PCR array analysis of the mandibular bone of caspase-7-deficient versus wild-type mice pointed to a significant decrease in mRNA levels for Msx1 and Smad1 in early bone formation. These observations might explain the decrease in the alveolar bone volume of adult knock-out mice. In conclusion, this study is the first to report a non-apoptotic function of caspase-7 in osteogenesis and also demonstrates further specificities in endochondral versus intramembranous ossification.

• MeSH
• Apoptosis MeSH
• Embryonic Development MeSH
• Caspase 3 metabolism   MeSH
• Caspase 7 genetics   metabolism   MeSH
• Bone and Bones metabolism   pathology   radiography   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Osteogenesis * MeSH
• Osteocalcin metabolism   MeSH
• Tomography, X-Ray Computed MeSH
• Smad1 Protein genetics   metabolism   MeSH
• MSX1 Transcription Factor genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Like all developmental processes, odontogenesis is highly complex and dynamically regulated, with hundreds of genes co-expressed in reciprocal networks. Tooth agenesis (missing one or more/all teeth) is a common human craniofacial anomaly and may be caused by genetic variations and/or environmental factors. Variants in PAX9, MSX1, AXIN2, EDA, EDAR, and WNT10A genes are associated with tooth agenesis. Currently, variants in ATF1, DUSP10, CASC8, IRF6, KDF1, GREM2, LTBP3, and components and regulators of WNT signaling WNT10B, LRP6, DKK, and KREMEN1 are at the forefront of interest. Due to the interconnectedness of the signaling pathways of carcinogenesis and odontogenesis, tooth agenesis could be a suitable marker for early detection of cancer predisposition. Variants in genes associated with tooth agenesis could serve as prognostic or therapeutic targets in cancer. This review aims to summarize existing knowledge of development and clinical genetics of teeth. Concurrently, the review proposes possible approaches for future research in this area, with particular attention to roles in monitoring, early diagnosis and therapy of tumors associated with defective tooth development.

• MeSH
• Anodontia epidemiology   genetics   MeSH
• Early Detection of Cancer MeSH
• Neoplastic Syndromes, Hereditary epidemiology   genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Association Studies MeSH
• Carcinogenesis MeSH
• Carcinoma epidemiology   genetics   MeSH
• Colorectal Neoplasms epidemiology   genetics   MeSH
• Humans MeSH
• Biomarkers, Tumor MeSH
• Ovarian Neoplasms epidemiology   genetics   MeSH
• Stomach Neoplasms epidemiology   genetics   MeSH
• Neoplasms epidemiology   genetics   MeSH
• Odontogenesis MeSH
• Wnt Signaling Pathway genetics   MeSH
• Signal Transduction genetics   MeSH
• MSX1 Transcription Factor genetics   MeSH
• PAX9 Transcription Factor genetics   MeSH
• Tooth Discoloration MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH