A NOTCH2 Mutation Causes Osteogenesis Imperfecta

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PROJECT SUMMARY/ABSTRACT Notch receptors play a critical role in cell fate decisions and in the regulation of bone remodeling, either directly or through the induction of their target genes, namely Hairy Enhancer of Split (HES) and Hes-related with YRPW motif (HEY). A 2 month old female child harboring a NOTCH2 pathogenic variant (e4006G>C) in exon 25 leading to a G1336R change in epidermal growth factor (EGF) repeat 34 presented with skeletal fragility and fractures. Never before has a mutation in Notch signaling been associated with osteogenesis imperfecta (OI). Whereas significant knowledge has been generated about the function of Notch receptors in the skeleton, little is known regarding mechanisms that control the activation of Notch and that are dependent on the interaction of its extracellular domain with Notch ligands. We created a Notch24006G>C mouse model (Notch2em1Ecan) that harbors a 4006G>C mutation in exon 25 of Notch2 and exhibits small and fragile bones replicating the genetic and functional outcomes of the human disorder. This reveals that a previously unrecognized mutation in the extracellular domain of NOTCH2 causes a skeletal syndrome; however, the mechanisms responsible for the skeletal manifestations are not established, and will be explored as part of the proposed research. Our specific aims are: Aim 1) To characterize the skeletal phenotype of Notch2em1Ecan mutants. Our goals are to establish the phenotype and cell lineage affected in Notch2 mutant mice and mechanisms responsible for the skeletal phenotype; Aim 2) To establish the mechanisms responsible for changes in Notch24006G>C mutant function. We will determine whether NOTCH2 mutants have altered affinity and binding to Notch ligands of the Jagged and Delta-like families and whether this results in changes in Notch activation and signaling in Notch2em1Ecan mutants. The goals of the proposed work are to understand novel functions of the NOTCH2 extracellular domain and the skeletal manifestations of diseases associated with a newly discovered NOTCH2 mutation.