title: Diverging alternative splicing fingerprints in the transforming growth factor-β signaling pathway identified in thoracic aortic aneurysms.
abstract: Impaired regulation of the transforming growth factor-β (TGFβ) signaling pathway has been linked to thoracic aortic aneurysm (TAA). Previous work has indicated that differential splicing is a common phenomenon, potentially influencing the function of proteins. In the present study we investigated the occurrence of differential splicing in the TGFβ pathway associated with TAA in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). Affymetrix human exon arrays were applied to 81 intima/media tissue samples from dilated (n = 51) and nondilated (n = 30) aortas of TAV and BAV patients. To analyze the occurrence of alternative splicing in the TGFβ pathway, multivariate techniques, including principal component analysis and OPLS-DA (orthogonal partial least squares to latent structures discriminant analysis), were applied on all exons (n = 614) of the TGFβ pathway. The scores plot, based on the splice index of individual exons, showed separate clusters of patients with both dilated and nondilated aorta, thereby illustrating the potential importance of alternative splicing in TAA. In total, differential splicing was detected in 187 exons. Furthermore, the pattern of alternative splicing is clearly differs between TAV and BAV patients. Differential splicing was specific for BAV and TAV patients in 40 and 86 exons, respectively, and splicings of 61 exons were shared between the two phenotypes. The occurrence of differential splicing was demonstrated in selected genes by reverse transcription-polymerase chain reaction. In summary, alternative splicing is a common feature of TAA formation. Our results suggest that dilatation in TAV and BAV patients has different alternative splicing fingerprints in the TGFβ pathway.
authors: Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. sanela.kurtovic@ki.se
authors: Sanela
authors: S
authors: Kurtovic
authors: Valentina
authors: V
authors: Paloschi
authors: Lasse
authors: L
authors: Folkersen
authors: Johan
authors: J
authors: Gottfries
authors: Anders
authors: A
authors: Franco-Cereceda
authors: Per
authors: P
authors: Eriksson
mesh_terms: D017398:Alternative Splicing; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000473:pathology; D004108:Dilatation, Pathologic / Q000235:genetics; D059472:Exome; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D014644:Genetic Variation; D006801:Humans; D008943:Mitral Valve / Q000378:metabolism / Q000473:pathology; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014261:Tricuspid Valve / Q000378:metabolism / Q000473:pathology
chemical_list: D016212:Transforming Growth Factor beta