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.
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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

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Figure 4

–29E deletion largely restores skeletal growth of achondroplastic mice.

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–29E deletion largely restores skeletal growth of achondroplastic mice....
(A) Weights of WT mice, achondroplastic mice, and achondroplastic mice with –29E deletion in the ACH allele or both alleles at 3 ages. Bars and brackets represent means and SDs, respectively. Each symbol corresponds to a distinct mouse. Blue dots, males; pink triangles, females. The percentages of average values for each genotype group relative to WT mice are indicated. Statistical analysis was performed using 1-way ANOVA followed by Tukey’s multiple comparison tests. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001. NA, not available (–29E+/+Fgfr3ACH/+ mice die around P25). (B) X-rays of the skeleton of representative mice. Scale bar: 1 cm. (C) Naso-anal lengths of mice from the same group as in A. (D) X-rays of the skulls of representative mice. Red arrows indicate jaw misalignment. Scale bar: 5 mm. (E) Long bone lengths of the same mice as in A.