Abstract 16144: Alternative Splicing in Myocardium from Infants with Tetralogy of Fallot
Messenger RNA splicing plays a fundamental role in regulating development and differentiation. Although it is clear that alternative splicing (AS) contributes to heart developmental organization, there is a paucity of information regarding the association of AS with congenital heart defects. We recently reported that specific small nucleolar RNAs (snoRNAs) that guide the biochemical modification of spliceosomal RNAs are reduced in myocardium of infants with tetralogy of Fallot (TOF). Two spliceosomal RNAs, U2 and U6, targeted by these snoRNAs are significantly reduced nearly two-fold in the myocardium from infants with TOF, suggesting the possibility that splicing might be affected. We evaluated genome wide transcript splicing patterns in tissue derived from human heart myocardium from a cohort of children with idiopathic TOF without chromosome abnormalities (i.e., 22q11.2 deletion) (n=16; 11 males, 5 females; ages 98-510 days) and compared to myocardium from fetuses (n= 3; 53 days gestation and n=3; 90 days gestation) and infants with normally developing hearts (n=8; 3 males, 5 females; ages 28-382 days). Our analysis revealed a substantial number of alternative splicing events that were enriched for genes from networks known to be important for heart formation. Alternative splicing events were enriched in five networks composed of 229 genes that are critical for mammalian heart development. Over 50% of the genes in these five networks had alternative splicing variants and interestingly, >25% of the splice variants were in common between TOF and fetal tissues compared to myocardium from normally developing infants of approximately six months of age. Moreover, the targeted spliceosomal RNAs are members of the U2 spliceosome, not the minor U12 spliceosome. Exons from genes with U12 type splicing sequences had significantly less alternative splicing (7.5%) than were U2 type exons in the five critical cardiac networks (51%, p< 0.0001). We propose that temporal and spatially-specific splicing patterns failed to progress adequately during early embryonic development leading to a breakdown in communication between the first and second heart fields, resulting in conotruncal misalignment.
- © 2012 by American Heart Association, Inc.