# A NOTCH2 Mutation Causes Osteogenesis Imperfecta

> **NIH NIH R21** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $182,188

## Abstract

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.

## Key facts

- **NIH application ID:** 10552122
- **Project number:** 1R21AR080642-01A1
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Ernesto Canalis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $182,188
- **Award type:** 1
- **Project period:** 2023-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10552122

## Citation

> US National Institutes of Health, RePORTER application 10552122, A NOTCH2 Mutation Causes Osteogenesis Imperfecta (1R21AR080642-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10552122. Licensed CC0.

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