Heart Failure Associated Changes in Alternative Splicing of Sarcomere Genes
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ABSTRACT: Alternative mRNA splicing is an important mechanism for regulation of gene expression. Changes in gene expression contribute to the pathogenesis of heart failure. However, changes in mRNA splicing have not been systematically examined in heart disease. We hypothesized that mRNA splicing is changed in diseased hearts. We used the Affymetrix exon array, which separately measures expression of each known and computationally predicted exon, to globally evaluate changes in mRNA splicing in left ventricular myocardial RNA from control and ischemic cardiomyopathy (ICM) patients. We found that mRNA splicing is systematically changed in heart failure. RTPCR validated 9 previously unreported alternative splicing events. Furthermore, we demonstrated that the splicing of four key sarcomere genes, cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), myosin heavy chain 7 (MYH7), and filamin C (FLNC), was significantly altered in ICM. Altered splicing of these genes in heart disease was confirmed in independent ICM samples, and in dilated cardiomyopathy and aortic stenosis. The minor variant fraction of these five genes was sufficient to classify samples into control or disease groups with 95% accuracy. Our data indicate that alternative splicing is systematically altered in human heart disease, suggesting that disease-associated perturbation of RNA splicing may contribute to the pathogenesis and development of heart failure. Disease-related changes in splicing of sarcomere genes may directly impact cardiomyocyte function.
ORGANISM(S): Homo sapiens
PROVIDER: GSE16499 | GEO | 2010/01/11
SECONDARY ACCESSION(S): PRJNA116119
REPOSITORIES: GEO
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