Rbm20, short for 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 plays a crucial role in determining the physiological mRNA landscape formation, especially in the heart, by regulating heart-specific alternative splicing [3]. One of its major targets is the TTN gene, and its regulation of TTN pre-mRNA splicing is vital for the passive stiffness and diastolic function of the heart [4].

Mutations in Rbm20 are a common cause of familial dilated cardiomyopathy (DCM) [1]. Rbm20 knockout rodents have shown that disrupted splicing of Rbm20 target genes is a causative mechanism for DCM [2]. Pathogenic variants in Rbm20, especially those in the arginine/serine-rich (RS-rich) domain, not only disrupt splicing but also hinder nucleocytoplasmic transport and lead to the formation of Rbm20 biomolecular condensates in the sarcoplasm [2]. For example, homozygous R636Q/R636Q mutant mice developed severe cardiac dysfunction, heart failure, and premature death, while systemic delivery of adenine base editing components restored cardiac function and extended lifespan [1].

In conclusion, Rbm20 is essential for regulating alternative splicing in the heart, particularly of the TTN gene, which is crucial for cardiac function. Studies using gene knockout mouse models have significantly enhanced our understanding of how Rbm20 mutations contribute to DCM, highlighting its potential as a therapeutic target for treating this disease [1,2,4].

References:

1. Nishiyama, Takahiko, Zhang, Yu, Cui, Miao, Bassel-Duby, Rhonda, Olson, Eric N. 2022. Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy. In Science translational medicine, 14, eade1633. doi:10.1126/scitranslmed.ade1633. https://pubmed.ncbi.nlm.nih.gov/36417486/

2. Gregorich, Zachery R, Zhang, Yanghai, Kamp, Timothy J, Granzier, Henk L, Guo, Wei. 2024. Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems. In Circulation. Genomic and precision medicine, 17, e004355. doi:10.1161/CIRCGEN.123.004355. https://pubmed.ncbi.nlm.nih.gov/38288598/

3. Koelemen, Jan, Gotthardt, Michael, Steinmetz, Lars M, Meder, Benjamin. 2021. RBM20-Related Cardiomyopathy: Current Understanding and Future Options. In Journal of clinical medicine, 10, . doi:10.3390/jcm10184101. https://pubmed.ncbi.nlm.nih.gov/34575212/

4. Watanabe, Takeshi, Kimura, Akinori, Kuroyanagi, Hidehito. 2018. Alternative Splicing Regulator RBM20 and Cardiomyopathy. In Frontiers in molecular biosciences, 5, 105. doi:10.3389/fmolb.2018.00105. https://pubmed.ncbi.nlm.nih.gov/30547036/