Genetic mutation in bone leads to osteogenesis imperfecta

The weak tendons and fragile bones characteristic of osteogenesis imperfecta, or brittle bone disease, stem from a genetic mutation that causes the incorrect substitution of a single amino acid in the chain of thousands of amino acids making up a collagen molecule, according to new research results.

Scientists at Massachusetts Institute of Technology (MIT) reported that a minuscule encoding error creates a defective collagen molecule that, at the site of the amino acid substitution, repels rather than attracts the collagen molecule alongside it.

In what may be the first detailed molecular-based, multiscale analysis of the role of a material’s failure in human disease, a paper in the Aug. 5 issue of Biophysical Journal describes exactly how the substituted amino acid repels other amino acids rather than forms chemical bonds with them. This creates a radically altered structure at the nanoscale and results in severely compromised tissue at the macroscale, according to an MIT press release.

This approach to the study of disease, referred to as “materiomics” by lead investigator Markus Buehler, PhD, could prove valuable in the study of other diseases — particularly collagen- and other protein-based diseases — where the behavior and breakdown of material play a vital role.

“The consideration of how material properties change in diseases could lead to a new paradigm in the study of genetic disorders that expands beyond the biochemical approach,” Buehler said in the press release.

“We wanted to see how a single-point genetic mutation in a collagen molecule could cause entire tissue to become brittle, soft and even fail. The medical community finds correlations between genetics and patients; our interest is in finding the correlation between genetics and a material's behavior,” he said in the release.

In the new research, Buehler and Sebastian Uzel, a graduate student at MIT, and Alfonso Gautieri, Alberto Redaelli and Simone Vesentini of Politecnico di Milano in Italy, modeled type I collagen’s behavior at the atomistic level all the way up to the scale of the fibrils that make up whole tissue.

Using atomistic modeling, the researchers demonstrated exactly how the substitution of eight different amino acids in place of glycine modifies the electrochemical behavior of the collagen molecules and affects the mechanical properties of the collagen tissue.

They also learned that the mutations creating the most severe form of the disease correlate with the greatest magnitude of adverse effects in creating more pronounced rifts in the tissue, leading to the deterioration and failure of the tissue, according to the press release.

“The study of how the nature of the genetic makeup influences the mechanical behavior of materials … could potentially revolutionize the way we understand, model and treat medical disorders, and may also lead to the development of new biomaterials for applications in tissue engineering and regenerative medicine.” Uzel said in the release.

Reference:
Gautieri A, Uzel S, Vesentini S, et al. Molecular and mesoscale mechanisms of osteogenesis imperfecta disease in collagen fibrils. Biophys J. 97;3:857-865.