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

我们一直在寻找多种先天性异常/精神发育迟滞综合征的遗传异常。最近，我们发现突变的Ras/MAPK信号通路之间努南相关的综合征，即Costello综合征和cardiofaciocutaenous（CFC）综合征。目前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，我们收集了努南综合征，卡斯特罗综合征，CFC综合征和类似的临床表现的患者的DNA样品和细胞培养物。我们对先前报道的致病基因进行了全面的突变分析，并在《人类突变》（在线发表：2008年5月9日）的一篇综述中报道了结果。候选基因分析揭示了新基因的突变。对鉴定的突变进行功能研究以表征其对信号传导途径的影响。此外，作为Costello综合征的疾病模型，我们开始了HRAS基因突变的转基因小鼠的制作。整个研究得到了东北大学医学部伦理委员会的批准，并按照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.