Fgfr3 enhancer deletion markedly improves all skeletal features in a mouse model of achondroplasia
Marco Angelozzi, … , Andrew M. Bloh, Véronique Lefebvre
Marco Angelozzi, … , Andrew M. Bloh, Véronique Lefebvre
Published January 16, 2025
Citation Information: J Clin Invest. 2025;135(2):e184929. https://doi.org/10.1172/JCI184929.
View: Text | PDF
Research Article Bone biology Genetics

Fgfr3 enhancer deletion markedly improves all skeletal features in a mouse model of achondroplasia

Abstract

Achondroplasia, the most prevalent short-stature disorder, is caused by missense variants overactivating the fibroblast growth factor receptor 3 (FGFR3). As current surgical and pharmaceutical treatments only partially improve some disease features, we sought to explore a genetic approach. We show that an enhancer located 29 kb upstream of mouse Fgfr3 (–29E) is sufficient to confer a transgenic mouse reporter with a domain of expression in cartilage matching that of Fgfr3. Its CRISPR/Cas9-mediated deletion in otherwise WT mice reduced Fgfr3 expression in this domain by half without causing adverse phenotypes. Importantly, its deletion in mice harboring the ortholog of the most common human achondroplasia variant largely normalized long bone and vertebral body growth, markedly reduced spinal canal and foramen magnum stenosis, and improved craniofacial defects. Consequently, mouse achondroplasia is no longer lethal, and adults are overall healthy. These findings, together with high conservation of –29E in humans, open a path to develop genetic therapies for people with achondroplasia.

Authors

Marco Angelozzi, Arnaud Molin, Anirudha Karvande, Ángela Fernández-Iglesias, Samantha Whipple, Andrew M. Bloh, Véronique Lefebvre

×

Figure 1

Identification of putative enhancers of human FGFR3 and mouse Fgfr3.

Options: View larger image (or click on image) Download as PowerPoint
Identification of putative enhancers of human FGFR3 and mouse Fgfr3. (A)...
(A) From top to bottom, graphical representation of the human chromosome 4 segment containing FGFR3 and neighboring genes; heatmap of chromatin folding from Micro Capture-C assay in H1-hESC cells (UCSC Genome Browser); and ATAC-seq and ChIP-seq data. For Micro Capture-C data, red color density reflects the number of interactions. For CTCF ChIP-seq data in H1-ESC cells (22), vertical lines and arrows indicate peaks and binding motif orientation, respectively. For ATAC-seq data in E67 human femoral and tibial fetal cartilage (24) and for H3K27ac ChIP-seq data in E47 human fetal limbs (25), vertical lines/blocks indicate peaks. Putative enhancers are highlighted in shades of green and the FGFR3 transcription start site (TSS) in light blue. (B) Similar representation as in A but for mouse chromosome 5 segment encompassing Fgfr3 and neighboring genes; CTCF ChIP-seq data in E14.5 fetal limbs (23); ATAC-seq data and ChIP-seq data for H3K4me3, H3K27ac, and SOX9 in P1 chondrocytes (26, 27), and histogram of placental mammal conservation scores (UCSC Genome Browser).