Mouse Dspp frameshift model of human dentinogenesis imperfecta.

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-1fs 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 DsppP19L mouse were characterized by morphological assessment, bSEM, nanohardness testing, histological analysis, in situ hybridization and immunohistochemistry. DsppP19L dentin contained dentinal tubules but grew slowly and was softer and less mineralized than the wild-type. DsppP19L incisor enamel was softer than normal, while molar enamel showed reduced rod/interrod definition. Dspp-1fs dentin formation was analogous to reparative dentin: it lacked dentinal tubules, contained cellular debris, and was significantly softer and thinner than Dspp+/+ and DsppP19L dentin. The Dspp-1fs 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.

Bone Morphogenetic Protein 2 Coordinates Early Tooth Mineralization.

Formation of highly organized dental hard tissues is a complex process involving sequential and ordered deposition of an extracellular scaffold, followed by its mineralization. Odontoblast and ameloblast differentiation involves reciprocal and sequential epithelial-mesenchymal interactions. Similar to early tooth development, various Bmps are expressed during this process, although their functions have not been explored in detail. Here, we investigated the role of odontoblast-derived Bmp2 for tooth mineralization using Bmp2 conditional knockout mice. In developing molars, Bmp2LacZ reporter mice revealed restricted expression of Bmp2 in early polarized and functional odontoblasts while it was not expressed in mature odontoblasts. Loss of Bmp2 in neural crest cells, which includes all dental mesenchyme, caused a delay in dentin and enamel deposition. Immunohistochemistry for nestin and dentin sialoprotein (Dsp) revealed polarization defects in odontoblasts, indicative of a role for Bmp2 in odontoblast organization. Surprisingly, pSmad1/5/8, an indicator of Bmp signaling, was predominantly reduced in ameloblasts, with reduced expression of amelogenin ( Amlx), ameloblastin ( Ambn), and matrix metalloproteinase ( Mmp20). Quantitative real-time polymerase chain reaction (RT-qPCR) analysis and immunohistochemistry showed that loss of Bmp2 resulted in increased expression of the Wnt antagonists dickkopf 1 ( Dkk1) in the epithelium and sclerostin ( Sost) in mesenchyme and epithelium. Odontoblasts showed reduced Wnt signaling, which is important for odontoblast differentiation, and a strong reduction in dentin sialophosphoprotein ( Dspp) but not collagen 1 a1 ( Col1a1) expression. Mature Bmp2-deficient teeth, which were obtained by transplanting tooth germs from Bmp2-deficient embryos under a kidney capsule, showed a dentinogenesis imperfecta type II-like appearance. Micro-computed tomography and scanning electron microscopy revealed reduced dentin and enamel thickness, indistinguishable primary and secondary dentin, and deposition of ectopic osteodentin. This establishes that Bmp2 provides an early temporal, nonredundant signal for directed and organized tooth mineralization.

Dentinogenesis imperfecta type II- genotype and phenotype analyses in three Danish families.

BACKGROUND: Dentinogenesis imperfecta (DI) is a rare debilitating hereditary disorder affecting dentin formation and causing loss of the overlying enamel. Clinically, DI sufferers have a discolored and weakened dentition with an increased risk of fracture. The aims of this study were to assess genotype-phenotype findings in three families with DI-II with special reference to mutations in the DSPP gene and clinical, histological, and imaging manifestations. METHODS: Nine patients participated in the study (two from family A, four from family B, and three from family C). Buccal swab samples were collected from all participants and extracted for genomic DNA. Clinical and radiographic examinations had been performed longitudinally, and the dental status was documented using photographic images. Four extracted and decalcified tooth samples were prepared for histological analysis to assess dysplastic manifestations in the dentin. Optical coherence tomography (OCT) was applied to study the health of enamel tissue from in vivo images and the effect of the mutation on the function and structure of the DSPP gene was analyzed using bioinformatics software programs. RESULTS: The direct DNA sequence analysis revealed three distinct mutations, one of which was a novel finding. The mutations caused dominant phenotypes presumably by interference with signal peptide processing and protein secretion. The clinical and radiographic disturbances in the permanent dentition indicated interfamilial variability in DI-II manifestations, however, no significant intrafamilial variability was observed. CONCLUSION: The different mutations in the DSPP gene were accompanied by distinct phenotypes. Enamel defects suggested deficit in preameloblast function during the early stages of amelogenesis.

Dentinogenesis Imperfecta: A Case Report of Five Patients in the Same Family Group / Dentinogenesis Imperfecta: Un Reporte de Caso de Cinco Pacientes en el Mismo Grupo Familiar

Dentinogenesis imperfecta (DI) is a type of dentin dysplasia that affects the dentin structure of one or both dentitions, which may be classified in three types. The aim of this report was to show the clinical and radiographic features of the four cases of DI in the same family group. Five brothers were checked clinically and radiographically. Two individuals were diagnosed, by their phenotypic features and medical history, with DI type I; two of them with DI type II and one case without signs of DI. It is important to know the features of dentinogenesis imperfecta to perform a comprehensive dental care, including the right diagnosis and an effective treatment plan.

La dentinogénesis imperfecta (DI) es un tipo de displasia de la dentina que afecta su estructura en una o ambas denticiones. La DI puede clasificarse en tres tipos. El objetivo de este informe fue demostrar las características clínicas y radiológicas de los cuatro casos de DI en un mismo grupo familiar. Cinco hermanos fueron controlados clínica y radiográficamente. Dos individuos fueron diagnosticados, por sus características fenotípicas y antecedentes clínicos, con el tipo de DI I; dos de ellos con DI de tipo II y un caso sin signos de DI. Es importante conocer las características de la dentinogénesis imperfecta para poder realizar una atención odontológica integral, lo que permitirá desarrollar un diagnóstico correcto y un plan de tratamiento efectivo.

Dentinogenesis imperfecta - hardness and Young's modulus of teeth.

Dentinogenesis imperfecta type II (DI-II) is the most common dental genetic disease with reported incidence 1 in 8000. Elasticity and hardness of the enamel of teeth are important values which are connected with their resistance to attrition. It is hypothesized that values of physical properties for healthy teeth and teeth with DI-II are different. The aim of the study was to investigate some physical properties of teeth extracted from patients with DI-II in comparison with normal teeth. The material of the study was six teeth: three lower molars, with clinical signs of DI-II, which were extracted due to complications of pulp inflammation and three other lower molars which were extracted for orthodontic reasons - well formed, without any signs of pathology. The surfaces of DI-II and normal teeth were tested on the CSM Instruments Scratch Tester machine (producer CSEM Switzerland) by Oliver and Pharr method. The indenter used was Vicker's VG-73 diamond indenter. Additionally, the Scanning Electron Microscopy (SEM) analysis of the surface of the teeth with DI-II was made. Vickers hardness of the teeth with dental pathology (DI-II) was seven times smaller, and Young's modulus six times smaller than those of healthy teeth. The parameters of hardness and elasticity of enamel of teeth with clinical diagnosis of DI-II were very much smaller than in normal teeth and because of that can be responsible for attrition.

Dentinogenesis imperfecta: a case report.

Dentinogenesis imperfecta is an autosomal dominant disorder of tooth development characterized by the presence of opalescent dentin, resulting in a dusky blue to brownish discoloration of the teeth. This condition is genetically and clinically heterogeneous; it may affect only the teeth or it may be associated with the osteogenesis imperfecta. Dentinogenesis imperfecta has been subdivided into three types: type I is associated with osteogenesis imperfecta; in type II there is no associated osteogenesis imperfecta; and when the condition is associated with the Brandywine triracial isolate and large pulp chambers it is classified as type III. This report describes a 16-year-old female patient who showed the characteristic dental features of dentinogenesis imperfecta type II. The etiology and prevalence of the disorder, and a comprehensive treatment plan, will be briefly reviewed.

Increased Young's modulus and hardness of Col1a2oim dentin.

Mice harboring the Col1a2(oim) mutation (oim) express dentinogenesis imperfecta. To determine the effect of Col1a2 genotype on tissue mechanical properties, we compared Young's modulus and hardness of dentin in the 3 Col1a2 genotypes. Upper incisors were tested by nanoindentation. Genotype had a significant effect on Young's modulus, but there was not a simple mutant allele dosage relationship. The effect of genotype on hardness did not reach significance. Hardness and Young's modulus were greater near the dento-enamel junction than near the pulp chamber. Greater hardness and Young's modulus values near the dento-enamel junction reflected continued mineralization of the dentin following its initial synthesis. Analysis showed the mechanical data to be consistent with Fourier transform infrared and backscattered electron microscopy studies that revealed increased mineralization in oim bone. Analysis of the data suggests that clinical fragility of teeth in oim mice is not due to deficiencies of hardness or Young's modulus, but may be due to defects in post-yield behavior or resistance to fatigue damage.

Phenotypic variation in dentinogenesis imperfecta/dentin dysplasia linked to 4q21.

Dentinogenesis imperfecta (DGI) and dentin dysplasia (DD) are allelic disorders that primarily affect the formation of tooth dentin. Both conditions are autosomal-dominant and can be caused by mutations in the dentin sialophosphoprotein gene (DSPP, 4q21.3). We recruited 23 members of a four-generation kindred, including ten persons with dentin defects, and tested the hypothesis that these defects are linked to DSPP. The primary dentition showed amber discoloration, pulp obliteration, and severe attrition. The secondary dentition showed either pulp obliteration with bulbous crowns and gray discoloration or thistle-tube pulp configurations, normal crowns, and mild gray discoloration. Haplotype analyses showed no recombination between three 4q21-q24 markers and the disease locus. Mutational analyses identified no coding or intron junction sequence variations associated with affection status in DMP1, MEPE, or the DSP portion of DSPP. The defects in the permanent dentition were typically mild and consistent with a diagnosis of DD-II, but some dental features associated with DGI-II were also present. We conclude that DD-II and DGI-II are milder and more severe forms, respectively, of the same disease.

Evaluation of oral problems in an osteogenesis imperfecta population.

OBJECTIVE: The incidence of craniofacial and dental anomalies in children with the more severe nonlethal forms of osteogenesis imperfecta was evaluated. STUDY DESIGN: The study evaluated 40 children (age range, 1-17.5 years) with types III and IV osteogenesis imperfecta. In each case, the dentition was evaluated for the presence of dentinogenesis imperfecta, attrition, and caries, as well as for radiographic appearance, dental development, and malocclusion. RESULTS: The incidence of dentinogenesis imperfecta was greater than 80% in the primary dentition. Clinically, the color of the dentition was of predictive value in appropriate management of the primary dentition. Tooth discoloration and attrition did not occur to the same extent in the permanent dentition as in the primary dentition in either group. Class III dental malocclusion occurred in 70% to 80% of this osteogenesis imperfecta population, with a high incidence of anterior and posterior cross bites and open bites. A delay in dental development was observed in 21% of patients type III osteogenesis imperfecta, whereas accelerated development was noted in 23% of the patients with type IV. In addition, ectopic eruption occurred in 13 patients. CONCLUSIONS: In addition to dentinogenesis imperfecta, significant oral problems occur in types III and IV osteogenesis imperfecta. Other features that impact the dental management of this population are highlighted.

[Disorders of growth and development in patients with osteogenesis imperfecta and their effects on the orofacial system]. / Wachstums- und Entwicklungsstörungen bei Patienten mit Osteogenesis imperfecta und deren Auswirkungen auf das oro-faziale System.

The results of stomatological examinations covering 16 children with osteogenesis imperfecta are reported. This disease is accompanied by typical symptoms in the oro-facial region. Dentinogenesis imperfecta occurred in 5 patients and can be considered an optional symptom of osteogenesis imperfecta.