Mohamed Salah A, Aherrahrou Zouhair, Liptau Henrike, Erasmi Armin W, Hagemann Carolin, Wrobel Sandra, Borzym Katja, Schunkert Heribert, Sievers Hans H, Erdmann Jeanette
Department of Cardiac Surgery, University of Schleswig-Holstein, Campus Luebeck, Germany.
Biochem Biophys Res Commun. 2006 Jul 14;345(4):1460-5. doi: 10.1016/j.bbrc.2006.05.046. Epub 2006 May 15.
The bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, occurring in 1-2% of the population. In a recent report, mutations in NOTCH1 a signaling and transcriptional regulator have been shown to cause BAV in two families. This study provides data on systematic sequencing in search for novel mutations in NOTCH1 gene in a large sample BAV. For the first time, we report results of a systematic mutation-analysis based on DNA-sequencing of all coding exons and adjacent splice consensus sequences of NOTCH1 gene. Our analyses revealed 57 NOTCH1 sequence variants. Twenty-one variants are located within exons and 36 within intronic or 5'-UTR sequences. Thirty-five variants were described previously as polymorphisms. The remaining 22, however, were neither listed in public SNP databases nor in the literature and were therefore considered novel. Seventeen variants were found only once (MAF = 1%), of these 15 were novel. Two sequence variants led to amino acid substitutions (p.T596M and p.P1797H) and are located in highly conserved regions of the NOTCH1 protein. In addition, these two mutations could not be detected in at least 327 healthy controls by using RFLP-analysis. The functional relevance of the other 13 novel and rare variants could not be proven without further functional examination. In this study, we provide a new evidence that the mutations in the NOTCH1 gene may trigger the underlying mechanism causing the valve calcification, especially in BAV. In conclusion, NOTCH1 gene mutations do not only play a role in familiar BAV, but can also be observed in approximately 4% of sporadic cases.
二叶式主动脉瓣（BAV）是最常见的先天性心脏畸形，在人群中的发生率为1%-2%。最近一份报告显示，信号转导和转录调节因子NOTCH1的突变在两个家族中导致了BAV。本研究提供了关于在大样本BAV中系统测序以寻找NOTCH1基因新突变的数据。我们首次报告了基于NOTCH1基因所有编码外显子及相邻剪接共有序列的DNA测序进行系统突变分析的结果。我们的分析揭示了57个NOTCH1序列变异。21个变异位于外显子内，36个位于内含子或5'-UTR序列中。35个变异先前被描述为多态性。然而，其余22个变异既未在公共SNP数据库中列出，也未在文献中报道，因此被认为是新的。17个变异仅被发现一次（MAF = 1%），其中15个是新的。两个序列变异导致氨基酸替换（p.T596M和p.P1797H），且位于NOTCH1蛋白的高度保守区域。此外，通过RFLP分析在至少327名健康对照中未检测到这两个突变。在没有进一步功能检查的情况下，无法证明其他13个新的罕见变异的功能相关性。在本研究中，我们提供了新的证据表明NOTCH1基因突变可能触发导致瓣膜钙化的潜在机制，尤其是在BAV中。总之，NOTCH1基因突变不仅在家族性BAV中起作用，在约4%的散发病例中也可观察到。
