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Sci Rep. 2016 Aug 3;6:30896. doi: 10.1038/srep30896.

Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts.

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Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas-77555, USA.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Physiology, National University of Singapore, Singapore 117597.
Division of Congenital Heart Surgery, Baylor College of Medicine, Houston, TX, 77030, USA.
Pensacola Christian College, 250 Brent Ln, Pensacola, FL 32503, USA.
Department of Surgery, University of New Mexico College of Medicine, Albuquerque, NM, 87131, USA.
Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital Research Institute, The Ohio State University, Columbus, OH 43205, USA.
Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
Program in Developmental Biology, Division of Cardiology, Baylor College of Medicine; Texas Heart Institute, Houston, TX 77030, USA.
Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine University of California, San Diego, La Jolla, CA 92093, USA.
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas-77555, USA.
Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas-77555, USA.


Hypoplastic left heart syndrome (HLHS) is a fatal congenital heart disease in which the left side of the heart is underdeveloped, impairing the systemic circulation. Underdeveloped left ventricle exerts biomechanical stress on the right ventricle that can progress into heart failure. Genome-wide transcriptome changes have been identified at early stages in the right ventricle (RV) of infants with HLHS, although the molecular mechanisms remain unknown. Here, we demonstrate that the RNA binding protein Rbfox2, which is mutated in HLHS patients, is a contributor to transcriptome changes in HLHS patient RVs. Our results indicate that majority of transcripts differentially expressed in HLHS patient hearts have validated Rbfox2 binding sites. We show that Rbfox2 regulates mRNA levels of targets with 3'UTR binding sites contributing to aberrant gene expression in HLHS patients. Strikingly, the Rbfox2 nonsense mutation identified in HLHS patients truncates the protein, impairs its subcellular distribution and adversely affects its function in RNA metabolism. Overall, our findings uncover a novel role for Rbfox2 in controlling transcriptome in HLHS.

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