Unraveling the mechanism of rare collagen diseases by means of a bottom-up and interdisciplinary approach


People involved: Simone Vesentini, Alfonso Gautieri, Monica Soncini

Funding source: 5x1000 Junior(Politecnico di Milano)

Funding period: 2010 - 2011

Partners: Bioengineering Department, Politecnico di Milano; Civil and Environmental Department, MIT; Department of Human Morphology, University of Insubria; Department of Biochemistry, University of Pavia; Faculty of Science et Technology, University of Twente; Energy Department, Politecnico di Milano.

In many hereditary connective-tissue disorders, collagen's regular repeating sequence of amino acids is disrupted.Ostoegenesis imperfecta (OI) or “brittle bone” disease is associated with mutations in the genes for type I collagen chains and produces variable phenotypes, ranging from lethal cases at birth to mild cases with increased bone fractures.

Collagen’s molecular structure consists of three helical polypeptide chains coiled around each other to form a triple helix. The close packing of these chains creates a precise stagger in their alignment and requires that the smallest amino acid, glycine, occupies every third position in each peptide. The most common OI mutations are single base substitutions leading to replacement of glycine by another residue, breaking the typical (Gly-X-Y)n repeating sequence pattern of the collagen triple-helix.Although the existence of a connection between certain collagen mutations and the diseases has been well established, the mechanism by which mutations cause the disease is still poorly understood. In order to obtain these information an interdisciplinary and international team is envisioned where experimental and theoretical competences converge to establish how a single point mutation would produce such a remarkable effect on the final connective tissue.

The project is divided into two phases. The first part will involve the development of micro and meso-scale theoretical models, based on preliminary results obtained in previous collaborative works. The second part will involve the macro-scale simulations as well as the validation of the models using pathological collagen tissue extracted from transgenic OI mice, as well as the subsequent mechanical experimental studies at the different hierarchical scales. This new insight on the molecular mechanism of the collagen molecule assembly would possibly reflect in many other disorders which also arise from glycine mutations in collagen, such as Alport syndrome which is due to mutations in type IV collagen, and Ehlers–Danlos syndrome which is related with mutations in type III collagen.