title: Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure.
abstract: BACKGROUND
  Human heart failure is associated with decreased cardiac voltage-gated Na+ channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in heart failure. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human heart failure and a specific splicing pathway for SCN5A regulation were explored in this study.
  
  
  RESULTS
  Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell-derived cardiomyocytes. RBM25/LUC7L3-mediated abnormal SCN5A mRNA splicing reduced Na+ channel current 91.1±9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript.
  
  
  CONCLUSIONS
  Of the 17 mRNA splicing factors upregulated in heart failure, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full-length Na+ channel transcript. Because the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure.
authors.affiliation: Section of Cardiology, University of Illinois at Chicago, 840 S Wood St, MC 715, Chicago, IL 60612, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.forename: An
authors.initials: A
authors.lastname: Xie
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Huang
authors.forename: Anyu
authors.initials: A
authors.lastname: Zhou
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Herman
authors.forename: Sassan
authors.initials: S
authors.lastname: Ghassemzadeh
authors.forename: Euy-Myoung
authors.initials: EM
authors.lastname: Jeong
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Kasturirangan
authors.forename: Mihai
authors.initials: M
authors.lastname: Raicu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sobieski
authors.forename: Geetha
authors.initials: G
authors.lastname: Bhat
authors.forename: Antone
authors.initials: A
authors.lastname: Tatooles
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Benz
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kamp
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009687:Nuclear Proteins; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics*; D017381:Spliceosomes / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C404083:LUC7L3 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels