Pathogenic role of Arhgef18 in cardiomyopathies

Cardiomyopathies (CMs), including dilated, hypertrophic and left-ventricular noncompaction types, are common yet poorly understood myocardial diseases in children, with genetic factors explaining only a third of cases. A study in Disease Models & Mechanisms investigates the role of Rho/Rac guanine nucleotide exchange factor 18 (Arhgef18), a gene previously identified as having a potential role in CM pathogenesis, by developing a cardiomyocyte-specific Arhgef18 conditional knockout (cKO) mouse model using the Cre/LoxP system. These mice exhibited hallmark CM phenotypes, including ventricular dilation wall thinning, and reduced cardiac function compared to control animals. Notably, cytoskeletal remodeling and loss of cardiomyocyte polarity were observed, suggesting that Arhgef18 is critical for maintaining myocardial structure and organization. Tissue-specific analysis confirmed that Arhgef18 was specifically knocked down in heart tissue, with no change in other organs. The findings highlight Arhgef18 as a potential pathogenic gene contributing to CM through its role in cytoskeletal integrity and polarity regulation. This model provides a stable and reliable platform for exploring CM mechanisms and offers foundational insights for developing targeted diagnostic and therapeutic strategies for pediatric cardiomyopathies.

Original reference: Fu, X. et al. Dis. Model. & Mech. 18, dmm052172 (2025)