RNA-binding protein with multiple splicing (Rbpms) contributes to noncompaction cardiomyopathy by regulating cardiomyocyte cytokinesis and binucleation

Noncompaction cardiomyopathy is a common congenital cardiomyopathy associated with a deficiency of ventricular cardiomyocytes and impaired pump function. The genetic basis and underlying mechanisms of this disorder remain elusive. Polyploidization is an intrinsic feature of mammalian cardiomyocytes, which occurs shortly after birth and is accompanied by cardiomyocyte cell cycle arrest. We show that genetic deletion of the RNA binding protein with multiple splicing (Rbpms) in mice results in premature onset of cardiomyocyte polyploidization (binucleation) and consequent noncompaction cardiomyopathy. A similar blockade to cytokinesis occurs in human iPSC-derived cardiomyocytes with RBPMS gene deletion. Paired-end RNA sequencing analysis revealed that Rbpms plays an essential role in RNA splicing and mediates isoform switching from the short to the long form of Pdlim5, a heart-specific LIM domain protein that connects the sarcomere with various signaling proteins during heart development. The loss of Rbpms leads to abnormal accumulation of short Pdlim5 isoforms that disrupt cardiomyocyte cytokinesis. Our results link premature cardiomyocyte binucleation to noncompaction cardiomyopathy and highlight the central role of Rbpms in this process. Overall design: RNA was isolated from heart ventricle of 1-day old WT or Rbpms KO mice. Stranded mRNA-seq was performed to profile gene expression changes upon Rbpms KO.