RBM20 (RNA binding motif protein 20) is a splicing factor necessary for the correct splicing of a variety of cardiac genes. Mutations in RBM20 can lead to a genetic form of dilated cardiomyopathy (DCM), but the exact mechanism underlying the DCM is as of yet not entirely known. Previously, we could show that loss of RBM20 leads to a drastic isoform switch of the Calcium/Calmodulin-dependent Kinase II δ (CamKIIδ), which is associated with a pro-arrhythmic change in the intracellular calcium handling.

Interestingly, patients with RBM20 cardiomyopathy show a strong gender-dependent severity of the disease: male patients are younger at diagnosis, have a worse heart function and have a greater risk to need a heart transplant at a young age. We have now characterized gender differences in a Rbm20-knockout mouse model. We show that male and female Rbm20-KO mice do not show differences in splicing of the most important Rbm20 target genes. Additionally, while male Rbm20-KO mice show heightened levels of cardiac stress, they do not have a worse heart function in echocardiography compared to their female counterparts, suggesting that the mouse model may not fully represent human RBM20 cardiomyopathy.

Additionally, we show that loss of Rbm20 in mice leads to a change in the phosphorylation state of Rbm20 target proteins. Interestingly, these include e.g. Ttn, Ldb3 and Obscn, which are also associated with the development of DCM. For TTN it is already known that phosphorylation has a strong effect on the elasticity and therefore the function of the protein, and it remains to be seen if phosphorylation changes in Ldb3 and Obscn similarly affect protein function.