Whole Exome Sequencing Identifies a Novel COL1A1 Missense Mutation Causing Dentinogenesis Imperfecta Type I Without Skeletal Abnormalities

Abstract Background：Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility, blue sclerae and dentinogenesis imperfecta (DGI), which are mainly caused by a mutation of the COL1A1 or COL1A2 genes that encode type I procollagen.Methods: The ultrastructure of dentin was analyzed by micro-CT, scanning electron microscopy, energy-dispersive spectroscopy analysis, nanoindentation test and Toluidine Blue Staining. Whole-exome sequencing (WES) was performed to identify the pathogenic gene. The function of the mutant COL1A1 was studied by real-time PCR, western blotting, subcellular localization. Functional analysis in dental pulp stem cells (DPSCs) was also performed to explore the impact of the identified mutation on this phenotype. Results: WES identified a missense mutation (c.1463G > C) in exon 22 of the COL1A1 gene. However, the cases reported herein only exhibited DGI-I in the clinical phenotype, there is no bone disease and any other common abnormal symptom caused by COL1A1 mutation. In addition, ultrastructural analysis of the tooth affected with non-syndromic DGI-I showed that the abnormal dentin was accompanied by disruption of odontoblast polarization, reduced numbers of odontoblasts, loss of dentinal tubules, and reduction in hardness and elasticity, suggesting severe developmental disturbance. What’s more, the odontoblast differentiation ability based on DPSCs that were isolated and cultured from the DGI-I patient was enhanced compared with those from an age-matched, healthy control.Conclusion: This study helped the family members to understand the disease progression and provided new insights into the phenotype-genotype association in collagen-associated diseases and improve clinical diagnosis of OI/DGI-I.