Osteogenesis imperfecta molecular features revealed by functional proteomics

Osteogenesis imperfecta (OI), also known as brittle bone disease, is a rare genetic disorder characterized by a high spectrum of pathological manifestations. In most cases, OI involves a dominant mutation in COL1A1 or COL1A2 genes that encode for α1 and α2 chains of type I collagen, respectively. The other known 14 types of OI are recessive or X-linked, and they are due to mutations in non-collagenous genes. These latter encode proteins involved in type I collagen post-translational modifications, folding, intracellular trafficking and extracellular matrix incorporation, or in osteoblast differentiation and function. Applying 2-DE and MALDI-TOF/TOF MS, we analysed fibroblasts from patients affected by recessive OI (types VII, VIII, and IX) and Chihuahua zebrafish, an OI animal model carrying G574D substitution in the α1(I) collagen chain. Fibroblasts from OI dominant patients (types II and III), with lethal and non-lethal outcomes, were investigated by a TMT-labeling/Nano-LCMS/ MS quantitative approach. Data functional processing was then achieved by MetaCore, PANTHER, and REVIGO resources. Reliability of proteomics and bioinformatics results was proved by Western blotting and/or confocal-immunofluorescence. Despite the majority of deregulated proteins identified in dominant OI forms differs from those identified in recessive forms, specific biological processes are characteristically affected in OI, independently on organism, Mendelian mode of transmission, and mutated genes. Cytoskeleton and nuclear lamina disorganization, cell signaling and protein trafficking affection resulted common and critical molecular features in OI. Of grate relevance, they dramatically impact on the survival of dominant OI patients.