title: Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas-77555, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Verma
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Deshmukh
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas-77555, USA.
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Nutter
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas-77555, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jaworski
authors.affiliation: Department of Physiology, National University of Singapore, Singapore 117597.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Jin
authors.affiliation: Division of Congenital Heart Surgery, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Lalita
authors.initials: L
authors.lastname: Wadhwa
authors.affiliation: Pensacola Christian College, 250 Brent Ln, Pensacola, FL 32503, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Abata
authors.affiliation: Department of Surgery, University of New Mexico College of Medicine, Albuquerque, NM, 87131, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Ricci
authors.affiliation: 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.
authors.forename: Joy
authors.initials: J
authors.lastname: Lincoln
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.|Program in Developmental Biology, Division of Cardiology, Baylor College of Medicine; Texas Heart Institute, Houston, TX 77030, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
authors.affiliation: Department of Physiology, National University of Singapore, Singapore 117597.|Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas-77555, 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.
authors.forename: Muge N
authors.initials: MN
authors.lastname: Kuyumcu-Martinez
mesh_terms: D017398:Alternative Splicing; D018389:Codon, Nonsense; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007231:Infant, Newborn; D000072260:RNA Splicing Factors / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018389:Codon, Nonsense; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D012097:Repressor Proteins