A Transgenic Mouse Model of OI Type V Supports a Neomorphic Mechanism of the IFITM5 Mutation. (March 2015)

• Record Type: Journal Article
• Authors: Lietman, Caressa D; Marom, Ronit; Munivez, Elda; Bertin, Terry K; Jiang, Ming‐Ming; Chen, Yuqing; Dawson, Brian; Weis, Mary Ann; Eyre, David; Lee, Brendan
• Is Part Of: Journal of bone and mineral research. Volume 30:Number 3(2015:Mar.)
• Page Start: 498
• Page End: 507
• Publication Date: 2015-03
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2363
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2363-sec-0001" sec-type="section"> <p>Osteogenesis imperfecta (OI) type V is characterized by increased bone fragility, long bone deformities, hyperplastic callus formation, and calcification of interosseous membranes. It is caused by a recurrent mutation in the 5' UTR of the <italic>IFITM5</italic> gene (c.‐14C > T). This mutation introduces an alternative start codon, adding 5 amino acid residues to the N‐terminus of the protein. The mechanism whereby this novel IFITM5 protein causes OI type V is yet to be defined. To address this, we created transgenic mice expressing either the wild‐type or the OI type V mutant IFITM5 under the control of an osteoblast‐specific Col1a1 2.3‐kb promoter. These mutant IFITM5 transgenic mice exhibited perinatal lethality, whereas wild‐type IFITM5 transgenic mice showed normal growth and development. Skeletal preparations and radiographs performed on E15.5 and E18.5 OI type V transgenic embryos revealed delayed/abnormal mineralization and skeletal defects, including abnormal rib cage formation, long bone deformities, and fractures. Primary osteoblast cultures, derived from mutant mice calvaria at E18.5, showed decreased mineralization by Alizarin red staining, and RNA isolated from calvaria showed reduced expression of osteoblast differentiation markers such as <italic>Osteocalcin</italic>, compared with nontransgenic littermates and wild‐type mice calvaria, consistent with the <italic>in vivo</italic> phenotype. Importantly, overexpression of wild‐type <italic>Ifitm5</italic> did not manifest a significant bone phenotype. Collectively, our results suggest that expression of mutant IFITM5 causes abnormal skeletal development, low bone mass, and abnormal osteoblast differentiation. Given that neither overexpression of the wild‐type <italic>Ifitm5</italic>, as shown in our model, nor knock‐out of <italic>Ifitm5</italic>, as previously published, showed significant bone abnormalities, we conclude that the <italic>IFITM5</italic> mutation in OI type V acts in a neomorphic fashion. © 2014 American Society for Bone and Mineral Research.</p> </sec> </abstract>