Myocardial alternative RNA splicing and gene expression profiling in early stage hypoplastic left heart syndrome.
Hypoplastic Left Heart Syndrome (HLHS) is a congenital defect characterized by underdevelopment of the left ventricle and pathological compensation of the right ventricle. If untreated, HLHS is invariably lethal due to the extensive increase in right ventricular workload and eventual failure. Despite the clinical significance, little is known about the molecular pathobiological state of HLHS. Splicing of mRNA transcripts is an important regulatory mechanism of gene expression. Tissue specific alterations of this process have been associated with several cardiac diseases, however, transcriptional signature profiles related to HLHS are unknown. In this study, we performed genome-wide exon array analysis to determine differentially expressed genes and alternatively spliced transcripts in the right ventricle (RV) of six neonates with HLHS, compared to the RV and left ventricle (LV) from non-diseased control subjects. In HLHS, over 180 genes were differentially expressed and 1800 were differentially spliced, leading to changes in a variety of biological processes involving cell metabolism, cytoskeleton, and cell adherence. Additional hierarchical clustering analysis revealed that differential gene expression and mRNA splicing patterns identified in HLHS are unique compared to non-diseased tissue. Our findings suggest that gene expression and mRNA splicing are broadly dysregulated in the RV myocardium of HLHS neonates. In addition, our analysis identified transcriptome profiles representative of molecular biomarkers of HLHS that could be used in the future for diagnostic and prognostic stratification to improve patient outcome.
Division of Cardiothoracic Surgery, University of Miami Miller School of Medicine and Holtz Children's Hospital/Jackson Memorial Hospital, Miami, Florida, United States of America. mricci@med.miami.edu
Marco
M
Ricci
Yanji
Y
Xu
Harriet L
HL
Hammond
David A
DA
Willoughby
Lubov
L
Nathanson
Maria M
MM
Rodriguez
Matteo
M
Vatta
Steven E
SE
Lipshultz
Joy
J
Lincoln
D017398:Alternative Splicing / Q000235:genetics*; D016022:Case-Control Studies; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005865:Gestational Age; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D007231:Infant, Newborn; D008297:Male; D046228:Microarray Analysis; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054928:Validation Studies as Topic
D012333:RNA, Messenger