Molecular analysis of congenital anomaly syndromes due to mutations in signal transduction pathways

我们一直在寻找多发性先天性畸形/智力低下综合征的遗传异常。最近，我们在Noonan相关综合征中发现了Ras/MAPK信号通路的突变，即Costello综合征和心面神经综合征(CFC)综合征。本研究的目的是确定与各种信号转导途径相关的新的致病基因，建立基因检测方案，并进行功能研究，以更好地了解这些疾病的发病机制。首先，我们收集了Noonan综合征、Costello综合征、CFC综合征患者以及临床症状相似的患者的DNA样本和细胞培养。我们对之前报道的致病基因进行了全面的突变分析，并将结果发表在《人类突变》(在线发布：2008年5月9日)的综述中。候选基因分析显示了新基因的突变。对已鉴定的突变进行了功能研究，以表征它们对信号通路的影响。我们还开始培育携带突变HRAS基因的转基因小鼠，作为Costello综合征的疾病模型。整个研究得到了东北大学医学部伦理委员会的批准，并根据相关指南进行了遗传分析。

We have been searching for genetic abnormalities in multiple congenital anomalies/mental retardation syndromes. Recently we identified mutations in the Ras/MAPK signaling pathways among Noonan-related syndromes, namely Costello syndrome and cardiofaciocutaenous (CFC) syndrome. The purpose of the current study is to identify novel disease-causing genes related to various signal transduction pathways, to establish genetic testing protocols, and to perform functional studies to better understand the pathogenesis of these disorders. At first, we collected DNA samples and cell cultures from patients with Noonan syndrome, Costello syndrome, CFC syndrome and patients with similar clinical pictures. We performed comprehensive mutation analysis of the previously reported disease-causing genes and reported the results in a review in Human Mutation (Published Online: May 9 2008). Candidate gene analysis revealed mutations in novel genes. Functional studies of the identified mutations were performed to characterize their effects on the signaling pathway. We also started to create transgenic mice harboring mutated HRAS gene as a disease model for Costello syndrome.The entire study was approved by the Ethics Committee of Tohoku University School of Medicine and the genetic analysis was done according to the relevant guidelines.