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Molecular Genetics & Genomic Medicine May 2019Osteogenesis imperfecta (OI), a genetically determined connective tissue disorder, is characterized by increased bone fragility and reduced bone mass. Clinical...
BACKGROUND
Osteogenesis imperfecta (OI), a genetically determined connective tissue disorder, is characterized by increased bone fragility and reduced bone mass. Clinical presentation severity ranges from very mild types with nearly no fractures to intrauterine fractures and perinatal lethality. It can be accompanied by blue sclerae, dentinogenesis imperfecta (DI), hearing loss, muscle weakness, ligament laxity, and skin fragility. This study sought to identify pathogenic gene variants in a four-generation Han Chinese family with OI type I.
METHODS
In order to unveil the molecular genetic factors underlying the disease phenotype, whole exome sequencing in a member, with OI type I, of a Han Chinese family from Hunan, China was performed. The variant identified by whole exome sequencing was further tested by Sanger sequencing in the family members.
RESULTS
A heterozygous missense variant (NM_000089.3: c.3197G>T; NP_000080.2: p.Gly1066Val) in the collagen type I alpha 2 chain gene (COL1A2) was identified in four patients. It co-segregated with the disease in the family.
CONCLUSION
The sequence variant may be a disease-causing factor resulting in abnormal type I procollagen synthesis and leading to OI type I. This finding has significant implications for genetic counseling and clinical monitoring of high-risk families and may be helpful for understanding pathogenic mechanism of OI and developing therapies.
Topics: Adult; Aged; Child; Collagen Type I; Female; Humans; Male; Middle Aged; Mutation, Missense; Osteogenesis Imperfecta; Pedigree
PubMed: 30829463
DOI: 10.1002/mgg3.619 -
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 -
Special Care in Dentistry : Official... Mar 2019Dentinogenesis Imperfecta (DI) forms a group of dental abnormalities frequently found associated with Osteogenesis Imperfecta (OI), a hereditary disease characterized by...
OBJECTIVE
Dentinogenesis Imperfecta (DI) forms a group of dental abnormalities frequently found associated with Osteogenesis Imperfecta (OI), a hereditary disease characterized by bone fragility. The objectives of this study were to quantify the dental caries prevalence and experience among different OI-types in the sample population and quantify how much these values change for the subset with DI.
METHODS
To determine which clinical characteristics were associated with increased Caries Prevalence and Experience (CPE) in patients with OI, the adjusted DFT scores were used to account for frequent hypodontia, impacted teeth and retained teeth in OI population. For each variable measured, frequency distributions, means, proportions and standard deviations were generated. Groups means were analyzed by the unpaired t-test or ANOVA as appropriate. For multivariate analysis, subjects with caries experience of zero were compared with those with caries experience greater than zero using logistic regression.
RESULTS
The stepwise regression analysis while controlling for all other variables demonstrated the presence of DI (OR 2.43; CI 1.37-4.32; P = 0.002) as the significant independent predictor of CPE in the final model.
CONCLUSION
This study found no evidence that CPE of OI subjects differs between the types of OI. The presence of DI when controlled for other factors was found to be the significant predictor of CPE.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cross-Sectional Studies; Dental Caries; Female; Humans; Infant; Male; Middle Aged; Osteogenesis Imperfecta; Prevalence; Risk Factors
PubMed: 30758072
DOI: 10.1111/scd.12368 -
Chinese Medical Journal Jan 2019Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen. This study aimed...
BACKGROUND
Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen. This study aimed to investigate the COL1A1 mutation spectrum and quantitatively assess the genotype-phenotype relationship in a large cohort of Chinese patients with OI.
METHODS
A total of 161 patients who were diagnosed as OI in Department of Endocrinology of Peking Union Medical College Hospital from January 2010 to December 2017 were included in the study. The COL1A1 mutation spectrum was identified by next generation sequencing and confirmed by Sanger sequencing. A new clinical scoring system was developed to quantitatively assess the clinical severity of OI and the genotype-phenotype relationship was analyzed. The independent sample t-test, analysis of variance, Mann-Whitney U-test, Chi-squared test, Pearson correlation, and multiple linear regression were applied for statistical analyses.
RESULTS
Among 161 patients with OI, 32.9% missense mutations, 16.8% non-sense mutations, 24.2% splice-site mutations, 24.8% frameshift mutations, and 1.2% whole-gene deletions were identified, of which 38 variations were novel. These mutations led to 53 patients carrying qualitative defects and 67 patients carrying quantitative defects in type I collagen. Compared to patients with quantitative mutations, patients with qualitative mutations had lower alkaline phosphatase level (296 [132, 346] U/L vs. 218 [136, 284] U/L, P = 0.009) and higher clinical score (12.2 ± 5.3 vs. 7.4 ± 2.4, P < 0.001), denoting more severe phenotypes including shorter stature, lower bone mineral density, higher fracture frequency, more bone deformity, vertebral compressive fractures, limited movement, and dentinogenesis imperfecta (DI). Patients would not present with DI if the glycine substitutions happened before the 79th amino acid in triple helix of α1 chains.
CONCLUSIONS
This presented distinctive COL1A1 mutation spectrum in a large cohort of Chinese patients with OI. This new quantitative analysis of genotype-phenotype correlation would be helpful to predict the prognosis of OI and genetic counseling.
Topics: Adolescent; Adult; Child; Child, Preschool; Collagen Type I; Collagen Type I, alpha 1 Chain; Female; Genetic Association Studies; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Male; Middle Aged; Mutation; Osteogenesis Imperfecta; Young Adult
PubMed: 30614853
DOI: 10.1097/CM9.0000000000000013 -
European Journal of Medical Genetics Dec 2019Osteogenesis imperfecta (OI) type V is an ultrarare heritable bone disorder caused by the heterozygous c.-14C > T mutation in IFITM5. The oro-dental and craniofacial...
Osteogenesis imperfecta (OI) type V is an ultrarare heritable bone disorder caused by the heterozygous c.-14C > T mutation in IFITM5. The oro-dental and craniofacial phenotype has not been described in detail, which we therefore undertook to evaluate in a multicenter study (Brittle Bone Disease Consortium). Fourteen individuals with OI type V (age 3-50 years; 10 females, 4 males) underwent dental and craniofacial assessment. None of the individuals had dentinogenesis imperfecta. Six of the 9 study participants (66%) for whom panoramic radiographs were obtained had at least one missing tooth (range 1-9). Class II molar occlusion was present in 8 (57%) of the 14 study participants. The facial profile was retrusive and lower face height was decreased in 8 (57%) individuals. Cephalometry, performed in three study participants, revealed a severely retrusive maxilla and mandible, and moderately to severly retroclined incisors in a 14-year old girl, a protrusive maxilla and a retrusive mandible in a 14-year old boy. Cone beam computed tomograpy scans were obtained from two study participants and demonstrated intervertebral disc calcification at the C2-C3 level in one individual. Our study observed that OI type V is associated with missing permanent teeth, especially permanent premolar, but not with dentinogenesis imperfecta. The pattern of craniofacial abnormalities in OI type V thus differs from that in other severe OI types, such as OI type III and IV, and could be described as a bimaxillary retrusive malocclusion with reduced lower face height and multiple missing teeth.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Osteogenesis Imperfecta; Phenotype
PubMed: 30593885
DOI: 10.1016/j.ejmg.2018.12.011 -
European Journal of Paediatric Dentistry Dec 2018Dentinogenesis imperfecta (DI) is an autosomal dominant genetic disease that affects both deciduous and permanent teeth, with an incidence of 1 out of 6,000 to 1 out of...
AIM
Dentinogenesis imperfecta (DI) is an autosomal dominant genetic disease that affects both deciduous and permanent teeth, with an incidence of 1 out of 6,000 to 1 out of 8,000. Teeth affected with DI type II present bulbous crowns, short and constricted roots, marked cervical constriction, translucent enamel and amber dentin. Also, they present a partial or total obliteration of pulp space, due to continuous dentin production. SEM analysis has shown an undulated dentin-enamel junction (DEJ) with irregularities and locally wide spaces between the two structures instead of a strict junction and a regular linear surface. Treatment options for patients affected by DI-II are intended to protect and restore function and aesthetics of both posterior and anterior teeth. In literature are presented many different therapies, but mainly centered on cemented prosthetic restorations instead of adhesive restorative procedures. We present in this paper a DI-II case successfully treated in 2005 with extensive adhesive rehabilitation.
CONCLUSION
The 13 years follow-up proves the reliability of adhesion to dentine and enamel for indirect adhesive restorations even on this kind of anomalous substrates.
Topics: Adolescent; Cementation; Composite Resins; Dental Restoration, Permanent; Dentinogenesis Imperfecta; Esthetics, Dental; Humans; Light-Curing of Dental Adhesives; Male; Pit and Fissure Sealants; Pressure; Radiography, Panoramic
PubMed: 30567448
DOI: 10.23804/ejpd.2018.19.04.10 -
Dentistry Journal Dec 2018Phosphophoryn (PP) and dentin sialoprotein (DSP) are two of the most abundant dentin matrix non-collagenous proteins, and are derived from dentin...
Phosphophoryn (PP) and dentin sialoprotein (DSP) are two of the most abundant dentin matrix non-collagenous proteins, and are derived from dentin sialoprotein-phosphophoryn (DSP-PP) mRNA. Mutations in the DSP-PP gene are linked to dentinogenesis imperfecta II and III. Previously, we reported transient DSP-PP expression in preameloblast cells first, followed by co-expression in preameloblasts and young odontoblasts, and finally sustained expression in odontoblasts. This phenomenon raised the possibility that DSP/PP proteins secreted by preameloblasts might promote dental pulp cell migration toward the dental pulp border and promote dental pulp cell differentiation. To examine the effects of DSP/PP proteins on dental pulp cell development, we investigated:(1) native PP effects on dental pulpcell migration and matrix protein expression; and (2) recombinant DSP/PP protein effects on cell proliferation and differentiation. We found that PP promoted cell migration and the expression of high levels of Col type I and PP in dental pulp cells. The addition of recombinant DSP/PP proteins affected cell proliferation and differentiation in a dental pulp cell line. These findings strongly suggest that DSP/PP may modulate cell migration, cell proliferation and differentiation, thus leading to dentin formation. DSP/PP protein may be useful clinically for pulp tissue regeneration.
PubMed: 30544680
DOI: 10.3390/dj6040070 -
Dentistry Journal Nov 2018This qualitative study was conducted to explore parental attitudes and values regarding aesthetics and treatment needs of children in primary dentition affected by AI...
This qualitative study was conducted to explore parental attitudes and values regarding aesthetics and treatment needs of children in primary dentition affected by AI and DI. A purposive sample of parents of young children attended two focus groups: mothers (n = 7) and fathers (n = 6). A topic guide with open-ended questions was formulated and standardised photographs showing primary teeth affected by varying severity of AI/DI and photographs of different aesthetic treatments were utilised to stimulate discussion. Data was audio-recorded and transcribed verbatim. A cross-sectional thematic analysis was performed which identified six main themes; the impact on affected children, the impact on parents, the life course of the disease, coping mechanisms, treatment need, and experience of treatment. Parents believed that young children were aware of their altered dental appearance. A feeling of guilt was evident among fathers affected by the same condition. Most parents sought dental treatment before starting school due to worries of bullying at school. Parents appeared to rely solely on the professional advice of the paediatric dentist in making all treatment related decisions. The personal experience of parents affected by AI/DI played a pivotal role in parent's judgements of their children's teeth and perceived need for treatment.
PubMed: 30453633
DOI: 10.3390/dj6040065 -
BMC Oral Health Oct 2018To report on dental characteristics and treatment load in Danish adult patients with osteogenesis imperfecta (OI).
BACKGROUND
To report on dental characteristics and treatment load in Danish adult patients with osteogenesis imperfecta (OI).
METHODS
Oral examination of 73 patients with OI was performed and OI type I, III, and IV were represented by 75.3%, 8.2%, and 16.4%, respectively. Patients were diagnosed as having dentinogenesis imperfecta (DI) if they had clinical and radiological signs of DI. In the data analysis, mild OI (type I) was compared to moderate-severe OI (type III and IV).
RESULTS
Discoloration of teeth was prevalent in patients with moderate-severe compared to mild OI (83.3% vs. 5.5%, p < 0.001). Cervical constriction and pulpal obliteration were frequent findings in patients with moderate-severe OI (61.1% and 88.9%, respectively), whereas pulp stones and taurodontism were diagnosed in patients with mild OI only (29.1% and 9.1%, respectively). DI was found in 24.7% of OI patients and considerably more frequent in patients with moderate-severe (94.4%) compared to mild OI (1.8%) (p < 0.001). The number of teeth with artificial crowns was significantly higher in patients with moderate-severe OI than in patients with mild OI (median 1.5, range 0-23 vs. median 0, range 0-14) (p < 0.001). The number of teeth with fillings in patients with mild OI was significantly higher than in patients with moderate-severe OI (mean 9.7, SD 5.1, median 9.0, range 1-21 vs. mean 5.0, SD 4.4, median 4.0, range 0-16) (p < 0.001).
CONCLUSIONS
One fourth of patients with OI had DI, and the vast majority of them had moderate-severe OI. Whereas discoloration of teeth, cervical constriction and pulp obliteration were frequent findings in patients with moderate-severe OI, pulp stones and taurodontism were found in patients with mild OI only. In patients with moderate-severe OI, the dental treatment load was dominated by prosthetic treatment, whereas restorative treatment with fillings was more prevalent in patients with mild OI.
Topics: Adult; Cross-Sectional Studies; Denmark; Dentinogenesis Imperfecta; Female; Humans; Male; Middle Aged; Prevalence; Severity of Illness Index
PubMed: 30355314
DOI: 10.1186/s12903-018-0639-7 -
American Journal of Medical Genetics.... Jan 2019Severe forms of osteogenesis imperfecta (OI) are usually caused by mutations in genes that code for collagen Type I and frequently are associated with craniofacial...
Severe forms of osteogenesis imperfecta (OI) are usually caused by mutations in genes that code for collagen Type I and frequently are associated with craniofacial abnormalities. However, the dental and craniofacial characteristics of OI caused by the p.Ser40Leu mutation in the IFITM5 gene have not been reported. We investigated a 15-year-old girl with severe OI caused by this mutation. She had marked deformations of extremity long bones. There were no clinical or radiological signs of dentinogenesis imperfecta, but one tooth was missing and several teeth were impacted. Cone beam computed tomography revealed a generalized osteopenic appearance of the craniofacial skeleton, bilateral enlargement of mandibular bodies, and areas of cortical erosions. The cranial base and skull showed a generalized granular bone pattern with a mixture of osteosclerosis and osteolysis. Sphenoid and frontal sinuses were congenitally missing. Cephalometric analysis indicated a Class III growth pattern. In this case, the IFITM5 p.Ser40Leu mutation did not affect tooth structure but was associated with deformities in craniofacial bones that resemble those in the other parts of the skeleton.
Topics: Adolescent; Cephalometry; Craniofacial Abnormalities; Female; Humans; Male; Membrane Proteins; Mutation; Osteogenesis Imperfecta; Phenotype
PubMed: 30289614
DOI: 10.1002/ajmg.a.40383