Abstract 1945 A Novel Analysis of the Relationship between TENT5A mutations and Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a group of bone disorders characterized by fragile bones, caused by abnormal bone formation. Mutations in TENT5A, a nucleotidyl transferase, have been associated with OI. Exon 2 in TENT5A plays an important role in the polyadenylation of mRNA, though the method of this interaction is unknown. Polyadenylation stabilizes and protects mRNA as it travels through the body, and also fuels the synthesis of collagen and the expression of collagen-producing genes. Therefore, when TENT5A properly adenylates the body's mRNA, collagen production and bone growth are stimulated. TENT5A also binds with SMADs (Suppressor of Mothers against Decapentaplegic) 1 and 4 of the SMAD signaling pathway, promoting Bone Morphogenetic Protein 1 (BMP1) expression, which is important for maintaining tissue homeostasis. A missense mutation in exon 2 of TENT5A, H127R, which replaces histidine with arginine is believed to cause OI. When this mutation occurs, hydrogen bonds between histidine 127 and serine 123 are broken, and the structure they form--made up of the β turn between a beta sheet and an alpha helix--is not maintained. Additionally, the hydrogen bonds between H127 and arginine 73 are broken, destabilizing the parallel adjacent alpha helix. We hypothesize that this causes TENT5A to not properly interact with mRNA in exon 2 or the Smad pathway, leading mRNA to not be polyadenylated and BMP1 to not be expressed. Our research will focus on the downstream effects of H127R on collagen expression and bone and cartilage development, and how they lead to OI. The Mahtomedi MAPS Team in collaboration with the Center for BioMolecular Modeling at 3D Molecular Designs used 3D modeling and printing technology to investigate this research.