Abstract 19326: Microrna Regulating Protein Bicc1 Causes Dilated Cardiomyopathy Through Modulation of Polycystin-2
An ENU-induced mutation in the RNA binding protein Bicc1 was recovered in a mutant named Destro. Destro exhibits complex congenital cardiovascular defects (CHD) associated with heterotaxy, with some mutants also exhibiting kidney, biliary ductal and pancreatic cysts. The mutation was identified by whole genome sequencing as Bicc1c.606+2T>C, which caused an 18 amino acid in-frame deletion in the K homology domain required for RNA recognition. Previous studies showed Bicc1 mutations can cause polycystic kidney disease (PKD) via its role in regulating microRNA-17 (miR-17) activity, and the altered expression of polycystin-2 (Pkd2), a known miR-17 target. Destro mutants without CHD or laterality defects are postnatal viable, but die prematurely at 4-5 months of age with severe runting, even in the absence of PKD. Transthoracic echocardiography showed cardiac function in such animals declined markedly with age. This was associated with increase in LV chamber size/body weight ratio and the elevated expression of heart failure markers such as Nppa, Nppb, and osteopontin. As Pkd2 was recently shown to interact with ryanodine receptor, RyR2 to modulate Ca(2+) signaling in cardiomyocytes, we propose Bicc1 mutation can cause cardiomyopathy independent of defects associated with the kidney. Consistent with this hypothesis, we noted all homozygous Bicc1 mutants surviving to adulthood succumb to heart failure associated with dilated cardiomyopathy, but yet show no evidence of PKD. Overall, these findings indicate a novel role for the RNA binding protein Bicc1 in cardiac pathology involving dilated cardiomyopathy. Experiments are underway to examine the role of microRNA regulation of Pkd2 on cardiac pathology in the Bicc1 mutants. Based on these observations, we suggest patients with PKD may have additional risk for cardiomyopathy of an independent etiology from any underlying kidney disease.
- © 2012 by American Heart Association, Inc.