Disrupting Effects of Osteogenesis Imperfecta Mutations Could Be Predicted by Local Hydrogen Bonding Energy

Abstract

Osteogenesis imperfecta(OI) is a disease caused by substitution in glycine residues with different amino acids in type I collagen (Gly-Xaa-Yaa)n. Collagen model peptides can capture the thermal stability loss of the helix after Gly mutations, most of which are homotrimers. However, a majority of natural collagen exists in heterotrimers. To investigate the effects of chain specific mutations in the natural state of collagen more accurately, here we introduce various lengths of side-chain amino acids into ABC-type heterotrimers. The disruptive effects of the mutations were characterized both experimentally and computationally. We found the stability decrease in the mutants was mainly caused by the disruption of backbone hydrogen bonds. Meanwhile, we found a threshold value of local hydrogen bonding energy that could predict triple helix folding or unfolding. Val caused the unfolding of triple helices, whereas Ser with a similar side-chain length did not. Structural details suggested that the side-chain hydroxyl group in Ser forms hydrogen bonds with the backbone, thereby compensating for the mutants’ decreased stability. Our study contributes to a better understanding of how OI mutations destabilize collagen triple helices and the molecular mechanisms underlying OI.

Genotype–phenotype relationship and comparison between eastern and western patients with osteogenesis imperfecta

“…The α1 and α2 chains of collagen type I both contain a central triple-helical domain, which is composed of uninterrupted repeats of the Gly-X–Y tripeptide [ 19 ]. As glycine is the only small residue to be accommodated inside the helix, triple-helix formation can proceed normally only if a glycine residue is present [ 26 ]. In this large cohort of OI, we not only detected many kinds of pathogenic mutations leading to haploinsufficiency and substitution of glycine but also identified 10 biallelic mutational genes that impair multiple aspects of type I collagen, including translation, posttranslational folding, modification, and assembly.…”

Micro Ribonucleic Acid−29a (miR−29a) Antagonist Normalizes Bone Metabolism in Osteogenesis Imperfecta (OI) Mice Model

“…Osteogenesis imperfecta (OI) is a group of autosomal dominant genetic diseases associated with pathogenic variants of the COL1A1 and COL1A2 genes [1,2]. COL1A1 and COL1A2 encode the alpha chains of collagen type 1, the major constituting component of bones [3,4]. The aberrant expression of COL1A1 and COL1A2 could contribute to defects in bone formation, and OI patients could present with bone deformities, compromised bone strength, and other connective tissue presentations such as soft teeth scleral discoloration [1].…”