Novel Molecular Mechanisms Leading to Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is an inherited disorder characterized by increased bone fragility, with severity ranging from very mild to lethal. Mutation in COL1A1 and COL1A2, which code for type I collagen, are identified in the majority (~85%) of patients.
Research to identify the cause of OI in individuals without identified mutations has focused on severe and lethal forms of the disease. By focusing on patients not fulfilling the current definition of “severe” adopted by the NHS funded Highly Specialised OI Service for children with severe, complex and atypical OI, we aimed to contribute to the current knowledge of the molecular basis of OI.
We employed a number of sequencing strategies to achieve this: targeted exome, Sanger and whole exome analysis. Results in this thesis have established that these approaches, together with appropriate functional analysis, can identify novel causes of OI and bone fragility.
We identified four patients with variable presentation and mutations in BMP1 and, importantly, highlight a risk of causing delayed healing, increased stiffness or atypical fractures by anti-resorptive treatment. We report the third occurrence of a c.1178A>G;p.Tyr393Cys P4HB mutation and describe what appears to be an emerging, distinctive radiological phenotype: meta-diaphyseal fractures with metaphyseal sclerosis.
We have expanded the clinical spectrum associated with NBAS mutations to include bone fragility that may present as atypical OI. Submission of a UKGTN gene dossier has ensured rapid transition of this research finding into the patient diagnostic pathway.
In addition, we have identified a number of novel genes and pathways that warrant further investigation, namely SLC38A10, SRCAP, UGGT1, UBASH3B, SULF2-POSTN, and voltage-gated sodium channel genes. Future work will focus on elucidating the significance of these findings and the development of tools to facilitate analysis and interpretation of genetic data as whole genome sequencing becomes more readily available for OI patients