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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 -
Journal of Personalized Medicine Jun 2021Hereditary dentin defects can be categorized as a syndromic form predominantly related to osteogenesis imperfecta (OI) or isolated forms without other non-oral...
Hereditary dentin defects can be categorized as a syndromic form predominantly related to osteogenesis imperfecta (OI) or isolated forms without other non-oral phenotypes. Mutations in the gene encoding dentin sialophosphoprotein (DSPP) have been identified to cause dentinogenesis imperfecta (DGI) Types II and III and dentin dysplasia (DD) Type II. While DGI Type I is an OI-related syndromic phenotype caused mostly by monoallelic mutations in the genes encoding collagen type I alpha 1 chain () and collagen type I alpha 2 chain (). In this study, we recruited families with non-syndromic dentin defects and performed candidate gene sequencing for exons and exon/intron boundaries. Three unrelated Korean families were further analyzed by whole-exome sequencing due to the lack of the mutation, and heterozygous mutations were identified: c.3233G>A, p.(Gly1078Asp) in Family 1 and c.1171G>A, p.(Gly391Ser) in Family 2 and 3. Haplotype analysis revealed different disease alleles in Families 2 and 3, suggesting a mutational hotspot. We suggest expanding the molecular genetic etiology to include for isolated dentin defects in addition to .
PubMed: 34201399
DOI: 10.3390/jpm11060526 -
Journal of Clinical Research in... Dec 2022Odontochondrodysplasia (ODCD, OMIM #184260) is a rare, non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones,...
Odontochondrodysplasia (ODCD, OMIM #184260) is a rare, non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. ODCD is inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11 gene (; OMIM *604505). The gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), which is an indispensable protein for the function of the Golgi apparatus. Mutations in also cause achondrogenesis type 1A (ACG1A). Null mutations of lead to ACG1A, also known as a lethal skeletal dysplasia, while hypomorphic mutations cause ODCD. Here we report a male child diagnosed as ODCD with a novel compound heterozygous mutation who presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial dysmorphism resembling achondroplasia and hypochondroplasia.
PubMed: 34111908
DOI: 10.4274/jcrpe.galenos.2021.2021.0099 -
Prenatal Diagnosis Oct 2021To investigate the genetic etiology of skeletal dysplasia in highly selected fetuses during the first and second trimesters using deep phenotyping and exome sequencing...
OBJECTIVE
To investigate the genetic etiology of skeletal dysplasia in highly selected fetuses during the first and second trimesters using deep phenotyping and exome sequencing (ES).
METHOD
Fetuses with short femurs were identified using the established prenatal diagnostic approach. A multidisciplinary team reviewed fetal phenotypic information (prenatal ultrasound findings, fetal postmortem, and radiographs) in a cohort of highly selected fetuses with skeletal dysplasia during the first and second trimesters. The affected families underwent multiplatform genetic tests.
RESULTS
Of the 27 affected fetuses, 21 (77.8%) had pathogenic or potential pathogenic variations in the following genes: COL1A1, FGFR3, COL2A1, COL1A2, FLNB, DYNC2LI1, and TRIP11. Two fetuses had compound heterozygous mutations in DYNC2LI1 and TRIP11, respectively, and the other 19 carried de novo autosomal dominant variants. Novel variants were identified in COL1A1, COL2A1, COL1A2, DYNC2LI1, and TRIP11 in 11 fetuses. We also included the first description of the phenotype of odontochondrodysplasia in a prenatal setting.
CONCLUSIONS
ES or panel sequencing offers a high diagnostic yield for fetal skeletal dysplasia during the first and second trimesters. Comprehensive and complete phenotypic information is indispensable for genetic analysis and the expansion of genotype-phenotype correlations in fetal skeletal abnormalities.
Topics: Adult; Dentinogenesis Imperfecta; Female; Fetus; Gestational Age; Humans; Osteochondrodysplasias; Phenotype; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Ultrasonography, Prenatal; Exome Sequencing
PubMed: 34091931
DOI: 10.1002/pd.5974 -
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 -
PloS One 2021Dentin Sialoprotein (DSP) and phosphophoryn (PP) are two most dominant non-collagenous proteins in dentin, which are the cleavage products of the DSPP (dentin...
Dentin Sialoprotein (DSP) and phosphophoryn (PP) are two most dominant non-collagenous proteins in dentin, which are the cleavage products of the DSPP (dentin sialophosphoprotein) precursor protein. The absence of the DSPP gene in DSPP knock-out (KO) mice results in characteristics that are consistent with dentinogenesis imperfecta type III in humans. Symptoms include thin dentin, bigger pulp chamber with frequent pulp exposure as well as abnormal epithelial-mesenchymal interactions, and the appearance of chondrocyte-like cells in dental pulp. To better understand how DSPP influences tooth development and dentin formation, we used a bacterial artificial chromosome transgene construct (BAC-DSPP) that contained the complete DSPP gene and promoter to generate BAC-DSPP transgenic mice directly in a mouse DSPP KO background. Two BAC-DSPP transgenic mouse strains were generated and characterized. DSPP mRNA expression in BAC-DSPP Strain A incisors was similar to that from wild-type (wt) mice. DSPP mRNA expression in BAC-DSPP Strain B animals was only 10% that of wt mice. PP protein content in Strain A incisors was 25% of that found in wt mice, which was sufficient to completely rescue the DSPP KO defect in mineral density, since microCT dentin mineral density analysis in 21-day postnatal animal molars showed essentially identical mineral density in both strain A and wt mice. Strain B mouse incisors, with 5% PP expression, only partially rescued the DSPP KO defect in mineral density, as microCT scans of 21-day postnatal animal molars indicated a reduced dentin mineral density compared to wt mice, though the mineral density was still increased over that of DSPP KO. Furthermore, our findings showed that DSPP dosage in Strain A was sufficient to rescue the DSPP KO defect in terms of epithelial-mesenchymal interactions, odontoblast lineage maintenance, along with normal dentin thickness and normal mineral density while DSPP gene dosage in Strain B only partially rescued the aforementioned DSPP KO defect.
Topics: Animals; Chromosomes, Artificial, Bacterial; Collagen Type II; Dentin; Extracellular Matrix Proteins; Incisor; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Minerals; Phosphoproteins; RNA, Messenger; Sialoglycoproteins; Tooth; X-Ray Microtomography
PubMed: 34038418
DOI: 10.1371/journal.pone.0250429