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Annals of Translational Medicine Nov 2021Dentinogenesis imperfecta (DGI), Shields type-II is an autosomal dominant genetic disease which severely affects the function of the patients' teeth. The dentin...
BACKGROUND
Dentinogenesis imperfecta (DGI), Shields type-II is an autosomal dominant genetic disease which severely affects the function of the patients' teeth. The dentin sialophosphoprotein () gene is considered to be the pathogenic gene of DGI-II. In this study, a DGI-II family with a novel DSPP mutation were collected, functional characteristics of DGI cells and clinical features were analyzed to better understand the genotype-phenotype relationship of this disease.
METHODS
Clinical data were collected, whole exome sequencing (WES) was conducted, and Sanger sequencing was used to verify the mutation sites. Physical characteristics of the patient's teeth were examined using scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). The localization of green fluorescent protein (GFP)-fused wild-type (WT) dentin sialoprotein (DSP) and its variant were evaluated via an immunocytochemistry (ICC) assay. The behaviors of human dental pulp stem cells (hDPSCs) were investigated by flow cytometry, osteogenic differentiation, and quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS
A novel heterozygous mutation c.53T > G (p. Val18Gly) in was found in this family. The SEM results showed that the participants' teeth had reduced and irregular dentinal tubes. The EDS results showed that the Ca/P ratio of the patients' teeth was significantly higher than that of the control group. The ICC assay showed that the mutant DSP was entrapped in the endoplasmic reticulum (ER), while the WT DSP located mainly in the Golgi apparatus. In comparison with normal cells, the patient's cells exhibited significantly decreased mineralization ability and lower expression levels of and .
CONCLUSIONS
The c.53T > G (p. Val18Gly) variant was shown to present with rare hypoplastic enamel defects. Functional analysis revealed that this novel variant disturbs dentinal characteristics and pulp cell behavior.
PubMed: 34988181
DOI: 10.21037/atm-21-5369 -
Osteoporosis International : a Journal... Dec 2018Osteogenesis imperfecta (OI) is a disease causing bone fragility; however, it potentially affects all organs with a high content of collagen, including ears, teeth, and...
UNLABELLED
Osteogenesis imperfecta (OI) is a disease causing bone fragility; however, it potentially affects all organs with a high content of collagen, including ears, teeth, and eyes. The study is cross-sectional and compares non-skeletal characteristics in adults with OI that clinicians should be aware of when caring for patients with OI.
INTRODUCTION
Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder. The skeletal fragility is pronounced; however, OI leads to a number of extra-skeletal symptoms related to the ubiquity of collagen type 1 throughout the human body. The vast majority of knowledge is derived from studies performed in the pediatric population. Thus, we aimed to investigate the nature and prevalence of ophthalmologic, odontologic, and otologic phenotypes in an adult population with OI.
METHODS
The study population comprises 85 Danish OI patients (age 44.9 ± 15.9 years). Fifty-eight patients had OI type I, 12 OI type III, and 15 OI type IV according to the classification by Sillence. Audiometric evaluations and dental examinations were performed in 62 and 73 patients, respectively. Ophthalmologic investigations were performed in 64 patients, including measurements of the central corneal thickness.
RESULTS
All patients, except two, had corneal thickness below the normal reference value. Patients with OI type I and patients with a quantitative collagen defect had thinner corneas compared to patients with OI type III and other patients with a qualitative collagen defect. One patient in this cohort was diagnosed with and treated for acute glaucoma. Dentinogenesis imperfecta was diagnosed in one fourth of the patients, based on clinical and radiographic findings. This condition was predominately seen in patients with moderate to severe OI. Hearing loss requiring treatment was found in 15 of 62 patients, of whom three were untreated. The most prevalent type of hearing loss (HL) was sensorineural hearing loss, whereas conductive HL was solely seen in patients with OI type III. The patients with the most severe degrees of HL were patients with mild forms of OI. Age was associated with increased HL.
CONCLUSION
Although significant health problems outside the skeleton are frequent in adult patients with OI, the patients are not consistently monitored and treated for their symptoms. Clinicians treating adult patients with OI should be aware of non-skeletal health issues and consider including regular interdisciplinary check-ups in the management plan for adult OI patients.
Topics: Adult; Aged; Denmark; Dentinogenesis Imperfecta; Eye Diseases, Hereditary; Female; Hearing Loss; Humans; Male; Middle Aged; Osteogenesis Imperfecta; Phenotype; Young Adult
PubMed: 30143849
DOI: 10.1007/s00198-018-4663-x -
Journal of International Society of... 2017Dentinogenesis imperfecta is a genetic disorder of the dentin occurring during the tooth development. It leads to many structural changes that can be identified...
BACKGROUND
Dentinogenesis imperfecta is a genetic disorder of the dentin occurring during the tooth development. It leads to many structural changes that can be identified clinically (brownish colored teeth, cracked enamel) and radiologically (globular crown, cervical constriction, short roots, and obliterated pulp chamber and/or root canals). The aim of this study was to determine by panoramic radiographs assessment the incidence of dentinogenesis imperfecta in a group of patients attending a specialized maxillofacial imaging center in Paris, France.
MATERIAL AND METHODS
A retrospective observational study was conducted using panoramic radiographs of 8830 patients (3723 males and 5107 females), which were used to search the radiological criteria of dentinogenesis imperfecta.
RESULTS
In our sample, the prevalence of dentinogenesis imperfecta was 0.057%. Out of the 8830 subjects, 0.080% of the males presented the radiological signs of the dentinogenesis imperfecta against 0.039% of the females.
CONCLUSION
In our study, we found that dentinogenesis imperfecta is a relatively rare dental anomaly in France, with a rate different from the rates reported in other studies and with no disparity in prevalence among genders.
PubMed: 28462180
DOI: 10.4103/jispcd.JISPCD_48_17 -
Research Square Sep 2023BMP2 signaling plays a pivotal role in odontoblast differentiation and maturation during odontogenesis. Teeth lacking Bmp2 exhibit a morphology reminiscent of...
BMP2 signaling plays a pivotal role in odontoblast differentiation and maturation during odontogenesis. Teeth lacking Bmp2 exhibit a morphology reminiscent of dentinogenesis imperfecta (DGI), associated with mutations in dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) genes. Mechanisms by which BMP2 signaling influences expressions of DSPP and DMP1 and contributes to DGI remain elusive. To study the roles of BMP2 in dentin development, we generated Bmp2 conditional knockout (cKO) mice. Through a comprehensive approach involving RNA-seq, immunohistochemistry, promoter activity, ChIP, and Re-ChIP, we investigated downstream targets of Bmp2. Notably, the absence of Bmp2 in cKO mice led to dentin insufficiency akin to DGI. Disrupted Bmp2 signaling was linked to decreased expression of Dspp and Dmp1, as well as alterations in intracellular translocation of transcription factors Dlx3 and Sp7. Intriguingly, upregulation of Dlx3, Dmp1, Dspp, and Sp7, driven by BMP2, fostered differentiation of dental mesenchymal cells and biomineralization. Mechanistically, BMP2 induced phosphorylation of Dlx3, Sp7, and histone acetyltransferase GCN5 at Thr and Tyr residues, mediated by Akt and Erk kinases. This phosphorylation facilitated protein nuclear translocation, promoting interactions between Sp7 and Dlx3, as well as with GCN5 on Dspp and Dmp1 promoters. The synergy between Dlx3 and Sp7 bolstered transcription of Dspp and Dmp1. Notably, BMP2-driven GCN5 acetylated Sp7 and histone H3, while also recruiting RNA polymerase II to Dmp1 and Dspp chromatins, enhancing their transcriptions. Intriguingly, BMP2 suppressed the expression of histone deacetylases. we unveil hitherto uncharted involvement of BMP2 in dental cell differentiation and dentine development through pAkt/pErk42/44/Dlx3/Sp7/GCN5/Dspp/Dmp1.
PubMed: 37790473
DOI: 10.21203/rs.3.rs-3299295/v1 -
Scientific Reports Oct 2021Non-syndromic inherited defects of tooth dentin are caused by two classes of dominant negative/gain-of-function mutations in dentin sialophosphoprotein (DSPP): 5'...
Non-syndromic inherited defects of tooth dentin are caused by two classes of dominant negative/gain-of-function mutations in dentin sialophosphoprotein (DSPP): 5' mutations affecting an N-terminal targeting sequence and 3' mutations that shift translation into the - 1 reading frame. DSPP defects cause an overlapping spectrum of phenotypes classified as dentin dysplasia type II and dentinogenesis imperfecta types II and III. Using CRISPR/Cas9, we generated a Dspp mouse model by introducing a FLAG-tag followed by a single nucleotide deletion that translated 493 extraneous amino acids before termination. Developing incisors and/or molars from this mouse and a Dspp mouse were characterized by morphological assessment, bSEM, nanohardness testing, histological analysis, in situ hybridization and immunohistochemistry. Dspp dentin contained dentinal tubules but grew slowly and was softer and less mineralized than the wild-type. Dspp incisor enamel was softer than normal, while molar enamel showed reduced rod/interrod definition. Dspp dentin formation was analogous to reparative dentin: it lacked dentinal tubules, contained cellular debris, and was significantly softer and thinner than Dspp and Dspp dentin. The Dspp incisor enamel appeared normal and was comparable to the wild-type in hardness. We conclude that 5' and 3' Dspp mutations cause dental malformations through different pathological mechanisms and can be regarded as distinct disorders.
Topics: Animals; Dental Enamel; Dentin; Dentinogenesis Imperfecta; Disease Models, Animal; Extracellular Matrix Proteins; Female; Frameshift Mutation; Humans; Male; Mice; Mice, Transgenic; Phenotype; Phosphoproteins; Sialoglycoproteins; Tooth
PubMed: 34667213
DOI: 10.1038/s41598-021-00219-4 -
Congenital Anomalies Jul 2016Odontoblasts are specialized cells that produce dentin and exhibit unique morphological characteristics; i.e., they extend cytoplasmic processes into dentinal tubules.... (Review)
Review
Odontoblasts are specialized cells that produce dentin and exhibit unique morphological characteristics; i.e., they extend cytoplasmic processes into dentinal tubules. While osteoblasts, which are typical hard-tissue-forming cells, are generated from mesenchymal stem cells during normal and pathological bone metabolism, the induction of odontoblasts only occurs once during tooth development, and odontoblasts survive throughout the lives of healthy teeth. During the differentiation of odontoblasts, signaling molecules from the inner enamel epithelium are considered necessary for the differentiation of odontoblast precursors, i.e., peripheral dental papilla cells. If odontoblasts are destroyed by severe external stimuli, such as deep caries, the differentiation of dental pulp stem cells into odontoblast-like cells is induced. Various bioactive molecules, such as non-collagenous proteins, might be involved in this process, although the precise mechanisms responsible for odontoblast differentiation have not been fully elucidated. Recently, our knowledge about the other functional activities of odontoblasts (apart from dentin formation) has increased. For example, it has been suggested that odontoblasts might act as nociceptive receptors, and surveillance cells that detect the invasion of exogenous pathogens. The regeneration of the dentin-pulp complex has recently gained much attention as a promising future treatment modality that could increase the longevity of pulpless teeth. Finally, congenital dentin anomalies, which are concerned with the disturbance of odontoblast functions, are summarized.
Topics: Animals; Biomarkers; Cell Differentiation; Congenital Abnormalities; Dental Pulp; Dentin; Dentinogenesis; Extracellular Matrix; Host-Pathogen Interactions; Humans; Morphogenesis; Odontoblasts; Odontogenesis; Protein Transport; Regeneration; Signal Transduction; Stem Cells
PubMed: 27131345
DOI: 10.1111/cga.12169 -
The Chinese Journal of Dental Research Mar 2024The dentine sialophosphoprotein (DSPP) gene is the only identified causative gene for dentinogenesis imperfecta type 2 (DGI-II), dentinogenesis imperfecta type 3... (Review)
Review
The dentine sialophosphoprotein (DSPP) gene is the only identified causative gene for dentinogenesis imperfecta type 2 (DGI-II), dentinogenesis imperfecta type 3 (DGI-III) and dentine dysplasia type 2 (DD-II). These three disorders may have similar molecular mechanisms involved in bridging the DSPP mutations and the resulting abnormal dentine mineralisation. The DSPP encoding proteins DSP (dentine sialoprotein) and DPP (dentine phosphoprotein) are positive regulators of dentine formation and perform a function during dentinogenesis. The present review focused on the recent findings and viewpoints regarding the relationship between DSPP and dentinogenesis as well as mineralisation from multiple perspectives, involving studies relating to spatial structure and tissue localisation of DSPP, DSP and DPP, the biochemical characteristics and biological function of these molecules, and the causative role of the proteins in phenotypes of the knockout mouse model and in hereditary dentine defects.
Topics: Animals; Mice; Calcification, Physiologic; Calcinosis; Dentin; Dentinogenesis Imperfecta; Disease Models, Animal; Mice, Knockout; Humans; Sialoglycoproteins; Phosphoproteins
PubMed: 38546516
DOI: 10.3290/j.cjdr.b5136791 -
Journal of Oral and Maxillofacial... Mar 2021Dentinogenesis imperfecta (DGI) type II affects both primary and permanent dentitions and has the autosomal mode of inheritance. The affected teeth may appear as amber...
Dentinogenesis imperfecta (DGI) type II affects both primary and permanent dentitions and has the autosomal mode of inheritance. The affected teeth may appear as amber or gray because of chipping of enamel shortly after their eruption. Correct diagnosis and management are highly needed to restore the quality of oral health and to improve esthetics and masticatory functions. We present here a case of systematic and conservative dental approach in the management of a 7-year-old child having Dentinogenesis Imperfecta Type II (DGI Type II) with 1 ½ follow-up.
PubMed: 34083977
DOI: 10.4103/jomfp.JOMFP_172_20 -
Acta Medica Academica Aug 2021The aim of this paper is to describe the varying clinical and imaging manifestations of Osteogenesis Imperfecta (OI) in the fetus, the child, and the adult. OI is a...
The aim of this paper is to describe the varying clinical and imaging manifestations of Osteogenesis Imperfecta (OI) in the fetus, the child, and the adult. OI is a genetic disorder with mutation of Type 1 and non-type 1 collagen genes that results in disruption of multiple collagen based organ systems, most notably bones, often leading to "brittle bones". Additional features such as blue sclera, dentinogenesis imperfecta, joint and ligamentous hyperlaxity, hearing loss and cardiac defects may be present. Currently, there are at least 30 recognized genetic forms of OI. Given the multiple genes involved, variable genetic inheritance, and the wide range in phenotype, diagnosis can be challenging. While OI may sometimes be diagnosed in the fetus, patients with mild forms of OI may be diagnosed in childhood or even in adulthood. Imaging, including ultrasound, radiography, computed tomography, and magnetic resonance imaging, plays an important role in the diagnoses of OI in the fetus, the child, and the adult. Imaging is also crucial in identifying the many multisystem manifestations of OI. In particular, imaging can help differentiate manifestations of OI from injuries sustained in non-accidental trauma. Age, severity and manner of presentation of OI vary broadly depending on the specific genetic mutation involved, mode of inheritance, and age of the patient. Successful diagnosis of OI hinges on a detailed knowledge of the variable presentation and complications that may be encountered with this disease. CONCLUSION: In conclusion, OI comprises a heterogeneous group of genetic disorders responsible for bone fragility and additional connective tissue disorders, which can result in specific clinical and imaging findings in the fetus, the child, and the adult.
Topics: Adult; Fetus; Humans; Joint Instability; Mutation; Osteogenesis Imperfecta; Radiography
PubMed: 34847680
DOI: 10.5644/ama2006-124.343 -
Stem Cells and Development May 2019Tooth development is regulated by sequential and reciprocal epithelium-mesenchymal interactions and their related molecular signaling pathways, such as bone...
Tooth development is regulated by sequential and reciprocal epithelium-mesenchymal interactions and their related molecular signaling pathways, such as bone morphogenetic proteins (BMPs). Among the 14 types of BMPs, BMP9 (also known as growth differentiation factor 2) is one of the most potent BMPs to induce osteogenic differentiation of mesenchymal stem cells. The purpose of this study was to examine potential roles of BMP9 signaling in tooth development. First, we detected the expression pattern of BMP9 in tooth germ during postnatal tooth development, and we found that BMP9 was widely expressed in odontoblasts, ameloblasts, dental pulp cells, and osteoblasts in alveolar bones. Then, we established a -KO mouse model. Gross morphological examination revealed that the tooth cusps of -KO mice were significantly abraded with shorter roots. Micro-computed tomography and three-dimensional reconstruction analysis indicated that the first molars of the -KO mice exhibited a reduced thickness dentin, enlarged pulp canals, and shortened roots, resembling the phenotypes of the common hereditary dental disease dentinogenesis imperfecta. Further, the alveolar bone of the -KO mutants was found to be shorter and had a decreased mineral density and trabecular thickness and bone volume fraction compared with that of the wild-type control. Mechanistically, we demonstrated that both dentin sialophosphoprotein and dentin matrix protein 1 were induced in dental stem cells by BMP9, whereas their expression was reduced when BMP9 was silenced. Further studies are required to determine whether loss of or decreased BMP9 expression is clinically associated with dentinogenesis imperfecta. Collectively, our results strongly suggest that BMP9 may play an important role in regulating dentinogenesis and tooth development. Further research is recommended into the therapeutic uses of BMP9 to regenerate traumatized and diseased tissues and for the bioengineering of replacement teeth.
Topics: Ameloblasts; Animals; Cell Differentiation; Dental Pulp; Dentin; Dentinogenesis Imperfecta; Epithelial-Mesenchymal Transition; Extracellular Matrix Proteins; Gene Expression Regulation; Growth Differentiation Factor 2; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Odontoblasts; Odontogenesis; Osteoblasts; Osteogenesis; Phosphoproteins; Sialoglycoproteins; Tooth; Tooth Germ
PubMed: 30816068
DOI: 10.1089/scd.2018.0230