title: Human heart failure is associated with abnormal C-terminal splicing variants in the cardiac sodium channel.
abstract: Heart failure (HF) is associated with reduced cardiac Na+ channel (SCN5A) current. We hypothesized that abnormal transcriptional regulation of this ion channel during HF could help explain the reduced current. Using human hearts explanted at the transplantation, we have identified 3 human C-terminal SCN5A mRNA splicing variants predicted to result in truncated, nonfunctional channels. As compared with normal hearts, the explanted ventricles showed an upregulation of 2 of the variants and a downregulation of the full-length mRNA transcript such that the E28A transcript represented only 48.5% (P<0.01) of the total SCN5A mRNA. This correlated with a 62.8% (P<0.01) reduction in Na+ channel protein. Lymphoblasts and skeletal muscle expressing SCN5A also showed identical C-terminal splicing variants. Variants showed reduced membrane protein and no functional current. Transfection of truncation variants into a cell line stably transfected with the full-length Na+ channel resulted in dose-dependent reductions in channel mRNA and current. Introduction of a premature truncation in the C-terminal region in a single allele of the mouse SCN5A resulted in embryonic lethality. Embryonic stem cell-derived cardiomyocytes expressing the construct showed reductions in Na+ channel-dependent electrophysiological parameters, suggesting that the presence of truncated Na+ channel mRNA at levels seen in HF is likely to be physiologically significant. In summary, chronic HF was associated with an increase in 2 truncated SCN5A variants and a decrease in the native mRNA. These splice variations may help explain a loss of Na+ channel protein and may contribute to the increased arrhythmic risk in clinical HF.
authors: Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, USA.
authors: Lijuan L
authors: LL
authors: Shang
authors: Arnold E
authors: AE
authors: Pfahnl
authors: Shamarendra
authors: S
authors: Sanyal
authors: Zhe
authors: Z
authors: Jiao
authors: Jon
authors: J
authors: Allen
authors: Kathrin
authors: K
authors: Banach
authors: John
authors: J
authors: Fahrenbach
authors: Daiana
authors: D
authors: Weiss
authors: W Robert
authors: WR
authors: Taylor
authors: A Maziar
authors: AM
authors: Zafari
authors: Samuel C
authors: SC
authors: Dudley
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D053595:Embryonic Stem Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006321:Heart; D006333:Heart Failure / Q000209:etiology / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*; D015996:Survival Rate; D014162:Transfection
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels