Osteogenesis imperfecta (OI) is a rare genetically heterogeneous connective tissue disorder primarily characterized by bone fragility, along with additional features such as blue sclerae, short stature, and dentinogenesis imperfecta. Although OI mainly presents an autosomal dominant inheritance pattern, over the past two decades, at least 17 genes have been implicated in autosomal recessive OI. In this study, we identified a novel homozygous non-coding variant, c.-167C > T, in the 5' untranslated region (5'UTR) of the SEC24D gene in a family with three affected individuals exhibiting a severe form of OI, craniofacial malformations and skull ossification defects. This is the first reported homozygous pathogenic non-coding variant in SEC24D, expanding the genetic landscape of OI. The variant is located in-frame with the opening reading frame and predicted to introduce a new upstream translation start codon (uATG) in the 5'UTR, disturbing the translational efficiency of the canonical initiation codon, a mechanism with direct implications for RNA-based therapeutic approach. Functional studies in patient-derived fibroblasts confirmed that SEC24D protein expression was significantly reduced while mRNA levels remained unchanged, suggesting a post-transcriptional regulatory mechanism. To address this translational defect, we designed and evaluated antisense oligonucleotides (ASOs) to modulate the translation of SEC24D. ASO treatment successfully increased SEC24D protein levels, demonstrating the potential of RNA-based therapies to modulate translation in genetic disorders caused by non-coding variants. Our findings provide a proof of concept for RNA-targeted therapeutics in OI, reinforcing the importance of investigating non-coding regions in genetic disease mechanisms. These results open new avenues for personalized RNA therapy in conditions linked to translational dysregulation.

Osteogenesis imperfecta (OI) is a rare disorder causing multiple fractures throughout life. No treatment has been shown to reduce the risk of fractures in OI. Here, we present the baseline characteristics of participants in the Treatment of Osteogenesis Imperfecta with Parathyroid Hormone and Zoledronic Acid (TOPaZ) trial. The aim of the trial is to determine whether teriparatide and zoledronic acid are superior to standard care in reducing the risk of clinical fractures. We summarised data on the baseline characteristics of TOPaZ participants, including demographics, genetic diagnosis, clinical features, bone density measurements, previous treatments, and fracture history. We recruited 350 adults with a clinical diagnosis of OI in 27 European referral centres between June 2017 and October 2022. Overall, 266 (76.2%) had type I OI, 55 (15.8%) had type IV, and 19 (5.4%) had type III. The type was unknown in 9 (2.6%). Blue sclera were noted in 80.8%, and 35.8% had dentinogenesis imperfecta. Bisphosphonates had been administered to 28.1% in the 2 years prior to enrolment. Pathogenic variants in COL1A1 or COL1A2 were found in 87.6%. Fractures occurring in the 2 years prior to enrolment were not associated with bone density. The TOPaZ population represents a unique cohort with which to study the genetic epidemiology and outcome of OI in relation to bone density and biochemical markers of bone turnover. When the trial reports, it will also provide new insights into the effect of an anabolic therapy, followed by antiresorptive treatment in the management of OI.

Although the formation, structure, and biomechanical properties of dentin are well-studied, the impact of dentinogenesis imperfecta (DI) on dentin tissue structure and properties remains poorly understood. This perspective paper aims to summarize current knowledge on dentin and discuss the DI-related effects on dentin biological, structural and biomechanical properties. Macroscopically, DI is easily recognizable in clinics, characterized by a blue/gray appearance of the teeth and rapid pulp chamber obliteration after tooth eruption. Microscopically, the porous structure of healthy dentin is absent; tubules are scarce, and some areas are completely atubular. Clinically, the enamel of DI-affected teeth detaches quickly from the dentin, leading to rapid wear of the dentin under normal masticatory forces. The biomechanical properties of DI-affected dentin are poorly studied and challenging to compare with those of healthy dentin. Various factors, such as hydration, tissue heterogeneity, and the scale of analysis, significantly influence the measurement of these properties. An in-depth exploration of the micro- and nano-structure, as well as the biomechanical properties of dentin affected by DI, would provide a better understanding of the behavior of this diseased tissue in patients. This, in turn, would enable the adaptation of dental restoration treatments to meet the mechanical constraints specific to the oral environment. STATEMENT OF SIGNIFICANCE: This manuscript presents a comprehensive perspective on dentin as a biological material. We detail the dentinogenesis processes that govern healthy dentin formation and its microstructural development. We link dentin's functional biomechanics to its hierarchical organization. The work highlights how Dentinogenesis Imperfecta disrupts dentin structure at multiple scales, resulting in altered mechanical properties. Importantly, it draws direct connections between biological alterations and functional consequences, offering critical insights into structure-function relationships in mineralized tissues. This perspective bridges developmental biology, genetic diseases, and a biomaterials-based approach.

Dentinogenesis imperfecta is a rare genetic disorder impacting dentin structure, with an incidence of 1 in 6000 to 1 in 8000 individuals. This condition alters the tooth's color and structure, affecting patients aesthetically, functionally, and socially. Advances in adhesive dentistry offer new therapeutic possibilities, although challenges remain. This article describes the full-mouth adhesive rehabilitation of a 24-year-old male patient diagnosed with DGI, who presented with generalized enamel fractures, shortened crowns, and chronic apical infections. Clinical and radiographic examinations revealed typical features of DGI, including bulbous crowns, short roots, cervical constrictions, and pulpal obliterations. Microscopic analysis of an extracted molar confirmed enamel and dentin structural anomalies, including a smooth dentin-enamel junction (DEJ) and obliterated dentinal tubules. Given the compromised DEJ and high risk of enamel fracture, a minimally invasive, full adhesive treatment plan was developed. The protocol involved resin infiltration (Icon, DMG) to enhance enamel bonding, followed by the placement of lithium disilicate ceramic crowns in the anterior region and monolithic zirconia bridges posteriorly. Vertical dimension of occlusion was increased using composite abutments and a digital workflow ensured accurate, tissue-preserving preparations. The treatment significantly improved the patient's quality of life, with the General Oral Health Assessment Index (GOHAI) increasing from 36/60 to 58/60. A one-year follow-up showed no prosthetic or biological complications. Further research and long-term monitoring are necessary to confirm the clinical stability and effectiveness of this approach in managing dentinogenesis imperfecta.

Background: Osteogenesis imperfecta (OI) is marked by clinical and genetic heterogeneity, and the genotype-phenotype correlation remains not very clear. We conducted a clinical and genetic study in a Chinese OI cohort to determine the spectra of phenotypes and pathogenic variants. Methods: In this study, 298 Chinese families were recruited from 2019 to 2024. Clinical phenotypes including fractures, short stature, skeletal deformities, blue sclera, dentinogenesis imperfecta, and hearing loss were recorded and analyzed. Next-generation sequencing combined with PCR-based techniques was used to detect candidate pathogenic variants. Variant pathogenicity was evaluated via conservation analysis, bioinformatics analysis, and functional studies at the cellular level. In this OI cohort, the spectra of pathogenic variants, clinical phenotypes, and genotype-phenotype correlations were analyzed. Results: Our OI cohort included 71 type I (23.83%), 122 type III (40.94%), 90 type IV (30.20%), and 15 type V (5.03%) probands. The cohort consisted of 196 children (65.77%) and 102 adults (34.23%). For the first time, phenotypic differences between different age groups were confirmed. In total, we identified 231 variants, including 47 novel pathogenic variants. Notable variants include two atypical splicing variants, one small deletion, two small duplications, one gross deletion, and one gross duplication. New genotype-phenotype correlations were observed: patients with SERPINF1 variants had the highest fracture frequency, followed by those with WNT1 variants, compared to patients with other gene variants. Conclusions: We performed the clinical and genetic analysis in a large Chinese OI cohort. The expanded spectra of genetic variants and clinical phenotypes were constructed by identifying 47 novel pathogenic variants and summarizing the skeletal and extra-skeletal manifestations. The current paper will provide important evidence for the precise diagnosis of the disease.