PDF(Pubmed)
Abstract：
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 (BMP2, -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 BMP2 and BMP4 genes were found. Deregulation of the mRNA expression and co-expression profile of the two genes (BMP2/BMP4) was observed in the affected compared to the normal hearts. BMP2 and -4 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 BMP2 and -4 genes that could support a causal relationship with the congenital defects present in our patients. Importantly, sustained mRNA and protein expression of BMP2 and -4 in CHD cases compared to controls indicates possible temporal epigenetic, microRNA or post-transcriptional regulation mechanisms governing the initial stages of cardiac malformation.
摘要：
先天性心脏畸形（CHMs）占每年人类出生的2％至3％。腔心肌发育需要骨形态发生蛋白（BMP）信号传导。我们通过对所有编码外显子进行测序分析，检查了骨形态发生蛋白2和4（BMP2，-4）基因中可能的分子缺陷，以及通过实时PCR和ELISA可能的转录或蛋白质表达失调，分别,在52例先天性畸形的心脏活检中（房间隔缺损（ASD），室间隔缺损(VSD),法洛四联症（ToF）和复杂病例）与10个非先天性心脏病（CHD）心脏相比。未发现功能缺失突变；仅发现BMP2和BMP4基因中的同义单核苷酸多态性（SNP）。与正常心脏相比，在受影响的心脏中观察到两种基因（BMP2/BMP4）的mRNA表达和共表达谱的失调。BMP2和-4蛋白表达水平在正常和受影响的心脏中相似。这是第一项评估BMP-2和4在先天性心脏畸形中的作用的研究。我们的分析没有揭示BMP2和-4基因中的分子缺陷，这些缺陷可以支持与我们患者中存在的先天性缺陷的因果关系。重要的是,与对照组相比，CHD病例中BMP2和-4的持续mRNA和蛋白表达表明可能的时间表观遗传，微小RNA或转录后调节机制控制心脏畸形的初始阶段。
