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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 -
International Journal of Dentistry 2021Dentinogenesis imperfecta (DI) and amelogenesis imperfecta (AI) are hereditary abnormalities of dental hard tissues. Dental abnormalities may also be accompanied by... (Review)
Review
Dentinogenesis imperfecta (DI) and amelogenesis imperfecta (AI) are hereditary abnormalities of dental hard tissues. Dental abnormalities may also be accompanied by symptoms of disorders such as osteogenesis imperfecta. AI and DI have a significant burden on socializing, function, and comfort; therefore, frequent screening and accurate diagnosis is the cornerstone of managing such conditions. Both AI and DI could be treated with many strategies, including restorative, prosthetic, periodontal, surgical, and orthodontics treatment. The interdisciplinary combination of orthodontic, prosthodontic, and periodontic treatment has been proven to improve the prognosis of AI and DI. Regarding orthodontic treatment, the most difficult element of orthodontic therapy may be maintaining a high level of motivation for what might be a prolonged form of treatment spanning several years. There are many forms of orthodontic management for AI and DI, including removable appliances, functional appliances, and fixed appliances. Clear aligner therapy (CAT) contains a broad range of equipment that works in different ways, has different construction processes, and is compatible with different malocclusion procedures. The application of CAT in patients with AI and DI is favorable over the fixed applicants. However, the available evidence regarding the application of CAT in AI is weak and heterogeneous. In this review, we discussed the current evidence regarding the application of clear CAT in patients with AI and DI.
PubMed: 34976063
DOI: 10.1155/2021/7343094 -
Molecular Syndromology Oct 2021We report on 2 cousins, a girl and a boy, born to first-cousin Lebanese parents with Hamamy syndrome, exhibiting developmental delay, intellectual disability, severe...
We report on 2 cousins, a girl and a boy, born to first-cousin Lebanese parents with Hamamy syndrome, exhibiting developmental delay, intellectual disability, severe telecanthus, abnormal ears, dentinogenesis imperfecta, and bone fragility. Whole-exome sequencing studies performed on the 2 affected individuals and one obligate carrier revealed the presence of a homozygous c.503G>A (p.Arg168His) missense mutation in in both sibs, not reported in any other family. Review of the literature and differential diagnoses are discussed.
PubMed: 34899143
DOI: 10.1159/000517253 -
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 -
European Archives of Paediatric... Apr 2022Osteogenesis imperfecta (OI) results from mutations in the genes involved in the modification or biosynthesis of collagen. This study aimed to assess the oral...
PURPOSE
Osteogenesis imperfecta (OI) results from mutations in the genes involved in the modification or biosynthesis of collagen. This study aimed to assess the oral health-related quality of life (OHRQoL) in children with OI.
METHODOLOGY
Participants were recruited from a highly specialised OI centre for children. The Child Oral-Health Impact Profile-Short Form (COHIP-SF) was used, adding demographic and qualitative questions. Children aged 8-16 years participated between January and October 2019. Statistical analysis was carried out. A higher COHIP-SF score indicates better OHRQoL (maximum score, 76).
RESULTS
One hundred and six (106) children participated (44 female, mean age 11.93 years). COHIP-SF median score was 59. Children reporting mild OI (n = 55) had higher median scores (62) compared to severe OI (n = 7) with median scores of 55 (P = 0.087). When comparing mixed (< 12 years, n = 46) and permanent dentition (≥ 12, n = 60), no significant difference in OHRQoL was seen (P = 0.977). There was no significant difference between severities for each COHIP-SF domain. Limited data on the presence of dentinogenesis imperfecta did not impact overall score (P = 0.109), but was significant in the oral-health domain (P = 0.033).
QUALITATIVE
Common themes were the need for braces, discolouration, pain and function.
CONCLUSION
This study confirmed that children with OI have dental concerns in areas including oral health, functional well-being and socio-emotional well-being. This was related to severity of OI.
Topics: Child; Dentition, Permanent; Female; Humans; Oral Health; Osteogenesis Imperfecta; Quality of Life; Surveys and Questionnaires
PubMed: 34799841
DOI: 10.1007/s40368-021-00664-9 -
Journal of Clinical and Experimental... Oct 2021Osteogenesis imperfecta (OI) is a disease characterized by decreased bone mineral density, causing susceptibility to bone fractures by mild trauma and bone deformities....
Osteogenesis imperfecta (OI) is a disease characterized by decreased bone mineral density, causing susceptibility to bone fractures by mild trauma and bone deformities. The aim of this study was to describe an osteogenesis imperfecta type III clinical case, its craniofacial and oral changes as well as its atypical radiographic findings. An eighteen-year-old, male patient diagnosed with osteogenesis imperfecta type III was referred for dental evaluation; the clinical examination showed the craniofacial and oral changes of the disease such as triangular face, class III malocclusion, anterior open bite and posterior crossbite, dentinogenesis imperfecta presenting amber discoloration. The radiographic examination revealed teeth with pulp chamber obliteration and root canals, however unusual findings were also observed such as: bilateral increase of the mandibular canals and preservation of the pulp chamber and third molar root canals. Our findings show that is essential an adequate knowledge of anatomy, a careful anamnestic evaluation and a complete radiological evaluation of the patient with OI. Dental anomalies, developmental disability, rare disorders.
PubMed: 34667502
DOI: 10.4317/jced.58263 -
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 -
Frontiers in Physiology 2021Dentin sialophosphoprotein (DSPP) is an extracellular matrix protein that is highly expressed in odontoblasts, but only transiently expressed in presecretory ameloblasts...
Dentin sialophosphoprotein (DSPP) is an extracellular matrix protein that is highly expressed in odontoblasts, but only transiently expressed in presecretory ameloblasts during tooth development. We previously generated a knockin mouse model expressing a mouse equivalent (DSPP, p.P19L) of human mutant DSPP (p.P17L; referred to as " "), and reported that and mice manifested a dentin phenotype resembling human dentinogenesis imperfecta (DGI). In this study, we analyzed pathogenic effects of mutant P19L-DSPP on enamel development in and mice. Micro-Computed Tomography (μCT) analyses of 7-week-old mouse mandibular incisors showed that mice had significantly decreased enamel volume and/or enamel density at different stages of amelogenesis examined. Acid-etched scanning electron microscopy (SEM) analyses of mouse incisors demonstrated that, at the mid-late maturation stage of amelogenesis, the enamel of wild-type mice already had apparent decussating pattern of enamel rods, whereas only minute particulates were found in mice, and no discernible structures in mouse enamel. However, by the time that incisor enamel was about to erupt into oral cavity, distinct decussating enamel rods were evident in mice, but only poorly-defined enamel rods were revealed in mice. Moreover, μCT analyses of the mandibular first molars showed that and mice had a significant reduction in enamel volume and enamel density at the ages of 2, 3, and 24weeks after birth. Backscattered and acid-etched SEM analyses revealed that while 3-week-old mice had similar pattern of enamel rods in the mandibular first molars as age-matched wild-type mice, no distinct enamel rods were observed in mice. Yet neither nor mice showed well-defined enamel rods in the mandibular first molars by the age of 24weeks, as judged by backscattered and acid-etched SEM. hybridization showed that mRNA level was markedly reduced in the presecretory ameloblasts, but immunohistochemistry revealed that DSP/DSPP immunostaining signals were much stronger within the presecretory ameloblasts in mutant mice than in wild-type mice. These results suggest that mutant P19L-DSPP protein caused developmental enamel defects in mice, which may be associated with intracellular retention of mutant DSPP in the presecretory ameloblasts.
PubMed: 34630144
DOI: 10.3389/fphys.2021.724098 -
Global Medical Genetics Sep 2021Dentin sialophosphoprotein ( ) gene mutations cause autosomal dominantly inherited diseases. gene mutations lead to abnormal expression of DSPP, resulting in a series... (Review)
Review
Dentin sialophosphoprotein ( ) gene mutations cause autosomal dominantly inherited diseases. gene mutations lead to abnormal expression of DSPP, resulting in a series of histological, morphological, and clinical abnormalities. A large number of previous studies demonstrated that DSPP is a dentinal-specific protein, and gene mutations lead to dentin dysplasia and dentinogenesis imperfecta. Recent studies have found that DSPP is also expressed in bone, periodontal tissues, and salivary glands. DSPP is involved in the formation of the periodontium as well as tooth structures. DSPP deficient mice present furcation involvement, cementum, and alveolar bone defect. We speculate that similar periodontal damage may occur in patients with mutations. This article reviewed the effects of gene mutations on periodontal status. However, almost all of the research is about animal study, there is no evidence that mutations cause periodontium defects in patients yet. We need to conduct systematic clinical studies on mutation families in the future to elucidate the effect of gene on human periodontium.
PubMed: 34430959
DOI: 10.1055/s-0041-1726416 -
Bone Reports Dec 2021Osteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; extra-skeletal features in OI include blue sclerae, dentinogenesis...
OBJECTIVES
Osteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; extra-skeletal features in OI include blue sclerae, dentinogenesis imperfecta, skin laxity and joint hyper-extensibility. Most patients with OI are thought to have a low bone mass but contrary to expectations there are certain forms of OI with high bone mass which this study explores in further detail.
METHOD
A cohort of n = 6 individuals with pathogenic variants in and the C-propeptide cleavage variants in were included in this study. Detailed clinical and radiological phenotyping was done and correlated with genotype to identify patterns of clinical presentation and fracture history in this cohort of patients. This data was compared to previously reported literature in this group.
RESULTS
2 patients with and 4 patients with pathogenic variants in C-propeptide region in were deep-phenotyped as part of this study and 1 patient with C-propeptide variant in , showed low bone mineral density. In those with an elevated bone mineral density, this became even more apparent on bisphosphonate therapy. Patients in this cohort had variable clinical presentation ranging from antenatal presentation to more of an insidious course resulting in later confirmation of genetic diagnosis up to 19 years of age.
CONCLUSIONS
Patients with pathogenic variants in the C-propeptide region of and appear to have a high bone mass phenotype with increased sensitivity to bisphosphonate therapy. It is important to closely monitor patients with these genotypes to assess their response to therapy and tailor their treatment regime accordingly.
PubMed: 34277895
DOI: 10.1016/j.bonr.2021.101102