Rbm20-flox Mouse

Rbm20, the RNA-binding motif protein 20, is a vertebrate-and muscle-specific RNA-binding protein belonging to the serine-arginine-rich family of splicing factors [2]. It is crucial for heart-specific alternative splicing, with one of its major targets being the TTN gene. The alternative splicing of TTN pre-mRNA by Rbm20 is vital for the passive stiffness and diastolic function of the heart as TTN encodes titin, a key sarcomeric structural protein for passive tension in cardiomyocytes [3].

Mutations in Rbm20 are a common cause of familial dilated cardiomyopathy (DCM) [1]. Many pathogenic variants cluster within an arginine/serine-rich (RS-rich) domain which mediates nuclear localization. These mutations lead to Rbm20 mis-localization to form aberrant ribonucleoprotein (RNP) granules in the cytoplasm of cardiomyocytes and abnormal alternative splicing of cardiac genes [1]. Rbm20 knockout rodents have implicated disrupted splicing of Rbm20 target genes as a causative mechanism for DCM [2]. In Rbm20R636Q mutant mice, homozygous mice develop severe cardiac dysfunction, heart failure, and premature death, while systemic delivery of adenine base editing components can restore cardiac function and extend lifespan [1].

In conclusion, Rbm20 is essential for heart-specific alternative splicing, especially of the TTN gene, influencing myocardial passive stiffness and diastolic function. Studies using Rbm20-related genetic mouse models, such as knockouts and mutant mice, have revealed its significant role in the development of DCM, providing insights into potential therapeutic strategies for this disease.