Investigation of the Role of and in ASD, VSD and Complex Congenital Heart Disease.

Congenital heart malformations (CHMs) make up between 2 and 3% of annual human births. Bone morphogenetic proteins (BMPs) signalling is required for chamber myocardium development. We examined for possible molecular defects in the bone morphogenetic protein 2 and 4 ( genes by sequencing analysis of all coding exons, as well as possible transcription or protein expression deregulation by real-time PCR and ELISA, respectively, in 52 heart biopsies with congenital malformations (atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy ofFallot (ToF) and complex cases) compared to 10 non-congenital heart disease (CHD) hearts. No loss of function mutations was found; only synonymous single nucleotide polymorphisms (SNPs) in the and genes were found. Deregulation of the mRNA expression and co-expression profile of the two genes () was observed in the affected compared to the normal hearts. and protein expression levels were similar in normal and affected hearts. This is the first study assessing the role of BMP-2 and 4 in congenital heart malformations. Our analysis did not reveal molecular defects in the and genes that could support a causal relationship with the congenital defects present in our patients. Importantly, sustained mRNA and protein expression of and in CHD cases compared to controls indicates possible temporal epigenetic, microRNA or post-transcriptional regulation mechanisms governing the initial stages of cardiac malformation.