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European Journal of Medical Genetics Nov 2023Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and...
Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management.
Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia. We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision. Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia. In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence.
Topics: Child; Humans; Osteogenesis Imperfecta; Hypophosphatasia; Osteomalacia; Fractures, Multiple; Mutation; Alkaline Phosphatase; Calcinosis; Rickets
PubMed: 37758163
DOI: 10.1016/j.ejmg.2023.104856 -
Journal of the Mechanical Behavior of... Aug 2021The aim of this study was to investigate the wear behavior of Dentinogenesis imperfecta type II (DGI-II) dentin and elucidate the correlation between its tribological...
OBJECTIVES
The aim of this study was to investigate the wear behavior of Dentinogenesis imperfecta type II (DGI-II) dentin and elucidate the correlation between its tribological properties and components.
METHODS
The mid-coronal dentin of normal and DGI-II teeth were divided into two groups: perpendicular and parallel to the dentin tubules. The microstructure of dentin was detected using atomic force microscopy (AFM). The wear behavior of dentin was evaluated by nanoscratch tests and scanning electron microscopy (SEM). Meanwhile, changes in molecular groups and chemical composition were analyzed by Raman and Energy-Dispersive X-ray (EDX) tests, respectively. Nanohardness was also evaluated.
RESULTS
AFM images of DGI-II dentin illustrated a decrease in the number of tubules and the tubule diameter. Nanoscratch test showed a higher friction coefficient and a greater depth-of-scratch in DGI-II dentin. The wear resistance of DGI-II dentin was reduced independent of tubule orientation. EDX results indicated that DGI-II dentin mineral content decreased and Raman spectra results showed DGI-II dentin had a decreased collagen matrix structure stability coupled with hypomineralization. Furthermore, a significant reduction in nanohardness and elastic modulus of DGI-II dentin was observed. Regression analysis revealed a close correlation between dentin components and inferior wear resistance.
CONCLUSIONS
All results indicated the wear behavior of DGI-II dentin was significantly deteriorated, presumably caused by the disorder in microstructures and the reduction of chemical composition.
Topics: Collagen; Dentin; Dentinogenesis Imperfecta; Humans; Microscopy, Electron, Scanning
PubMed: 34010797
DOI: 10.1016/j.jmbbm.2021.104585 -
European Journal of Medical Genetics Nov 2023Osteogenesis imperfecta (OI) type VI is an extremely rare form of OI caused by biallelic variants in the SERPINF1 gene, which codes for the pigment-epithelium derived...
Osteogenesis imperfecta (OI) type VI is an extremely rare form of OI caused by biallelic variants in the SERPINF1 gene, which codes for the pigment-epithelium derived factor (PEDF). We report on four patients (three adults and one adolescent) with a severe deforming form of OI. All patients presented no abnormalities at birth, frequent long bone and vertebrae fractures (mainly during childhood), marked short stature, severe bone deformities, chronic mild to moderate pain, and severe limitation of mobility, with three being completely wheelchair bound. Blue sclera and dentinogenesis imperfecta were absent, although some patients presented tooth, ophthalmological, and/or cardiac features. Radiographic findings included, among others, thin diaphysis and popcorn calcifications, both of which are non-specific to this type of OI. The novel homozygous variants c.816_819del (p.Met272Ilefs*8) and c.283+2T > G in SERPINF1 were identified in three and one patient, respectively. The three patients carrying the frameshift variant were born in nearby regions suggesting a founder effect. Describing the long-term outcomes of four patients with OI type VI, this cohort adds relevant data on the clinical features and prognosis of this type of OI.
Topics: Adolescent; Adult; Humans; Infant, Newborn; Collagen Type I; Frameshift Mutation; Homozygote; Osteogenesis Imperfecta; Serpins
PubMed: 37839784
DOI: 10.1016/j.ejmg.2023.104867 -
Genes May 2022Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II...
Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). DSPP mutations fall into two groups: a 5′-group that affects protein targeting and a 3′-group that shifts translation into the −1 reading frame. Using whole-exome sequence (WES) analyses and Single Molecule Real-Time (SMRT) sequencing, we identified disease-causing DSPP mutations in 12 families. Three of the mutations are novel: c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80). We propose genetic analysis start with WES analysis of proband DNA to identify mutations in COL1A1 and COL1A2 causing dominant forms of osteogenesis imperfecta, 5′-DSPP mutations, and 3′-DSPP frameshifts near the margins of the DSPP repeat region, and SMRT sequencing when the disease-causing mutation is not identified. After reviewing the literature and incorporating new information showing distinct differences in the cell pathology observed between knockin mice with 5′-Dspp or 3′-Dspp mutations, we propose a modified Shields Classification based upon the causative mutation rather than phenotypic severity such that patients identified with 5′-DSPP defects be diagnosed as DGI-III, while those with 3′-DSPP defects be diagnosed as DGI-II.
Topics: Animals; Dentinogenesis Imperfecta; Extracellular Matrix Proteins; Humans; Mice; Mutation; Pedigree; Phosphoproteins; Sialoglycoproteins
PubMed: 35627243
DOI: 10.3390/genes13050858 -
A homozygous mutation causes osteogenesis and dentinogenesis imperfecta with craniofacial anomalies.JBMR Plus May 2024Osteogenesis imperfecta (OI) is a heterogeneous spectrum of hereditary genetic disorders that cause bone fragility, through various quantitative and qualitative defects...
Osteogenesis imperfecta (OI) is a heterogeneous spectrum of hereditary genetic disorders that cause bone fragility, through various quantitative and qualitative defects of type 1 collagen, a triple helix composed of two α1 and one α2 chains encoded by and , respectively. The main extra-skeletal manifestations of OI include blue sclerae, opalescent teeth, and hearing impairment. Moreover, multiple genes involved in osteoblast maturation and type 1 collagen biosynthesis are now known to cause recessive forms of OI. In this study a multiplex consanguineous family of two affected males with OI was recruited for genetic screening. To determine the causative, pathogenic variant(s), genomic DNA from two affected family members were analyzed using whole exome sequencing, autozygosity mapping, and then validated with Sanger sequencing. The analysis led to the mapping of a homozygous variant previously reported in SP7/OSX, a gene encoding for Osterix, a transcription factor that activates a repertoire of genes involved in osteoblast and osteocyte differentiation and function. The identified variant (c.946C > T; p.Arg316Cys) in exon 2 of results in a pathogenic amino acid change in two affected male siblings and develops OI, dentinogenesis imperfecta, and craniofacial anomaly. On the basis of the findings of the present study, :c. 946C > T is a rare homozygous variant causing OI with extra-skeletal features in inbred Arab populations.
PubMed: 38562913
DOI: 10.1093/jbmrpl/ziae026 -
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 -
International Journal of Nanomedicine 2019Dentinogenesis imperfecta type 1 (OIDI) is considered a relatively rare genetic disorder (1:5000 to 1:45,000) associated with osteogenesis imperfecta. OIDI impacts the...
INTRODUCTION
Dentinogenesis imperfecta type 1 (OIDI) is considered a relatively rare genetic disorder (1:5000 to 1:45,000) associated with osteogenesis imperfecta. OIDI impacts the formation of collagen fibrils in dentin, leading to morphological and structural changes that affect the strength and appearance of teeth. However, there is still a lack of understanding regarding the nanoscale characterization of the disease, in terms of collagen ultrastructure and mechanical properties. Therefore, this research presents a qualitative and quantitative report into the phenotype and characterization of OIDI in dentin, by using a combination of imaging, nanomechanical approaches.
METHODS
For this study, 8 primary molars from OIDI patients and 8 primary control molars were collected, embedded in acrylic resin and cut into longitudinal sections. Sections were then demineralized in 37% phosphoric acid using a protocol developed in-house. Initial experiments demonstrated the effectiveness of the demineralization protocol, as the ATR-FTIR spectral fingerprints showed an increase in the amide bands together with a decrease in phosphate content. Structural and mechanical analyses were performed directly on both the mineralized and demineralized samples using a combination of scanning electron microscopy, atomic force microscopy, and Wallace indentation.
RESULTS
Mesoscale imaging showed alterations in dentinal tubule morphology in OIDI patients, with a reduced number of tubules and a decreased tubule diameter compared to healthy controls. Nanoscale collagen ultrastructure presented a similar D-banding periodicity between OIDI and controls. Reduced collagen fibrils diameter was also recorded for the OIDI group. The hardness of the (mineralized) control dentin was found to be significantly higher (p<0.05) than that of the OIDI (mineralized) dentine. Both the exposed peri- and intratubular dentinal collagen presented bimodal elastic behaviors (Young's moduli). The control samples presented a stiffening of the intratubular collagen when compared to the peritubular collagen. In case of the OIDI, this stiffening in the collagen between peri- and intratubular dentinal collagen was not observed and the exposed collagen presented overall a lower elasticity than the control samples.
CONCLUSION
This study presents a systematic approach to the characterization of collagen structure and properties in OIDI as diagnosed in dentin. Structural markers for OIDI at the mesoscale and nanoscale were found and correlated with an observed lack of increased elastic moduli of the collagen fibrils in the intratubular OIDI dentin. These findings offer an explanation of how structural changes in the dentin could be responsible for the failure of some adhesive restorative materials as observed in patients affected by OIDI.
Topics: Collagen; Dentin; Dentinogenesis Imperfecta; Elasticity; Hardness; Humans; Molar; Osteogenesis Imperfecta; Phenotype; Radiography, Bitewing; Spectroscopy, Fourier Transform Infrared; Tooth Demineralization
PubMed: 31819441
DOI: 10.2147/IJN.S217420 -
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 -
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