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Identification of novel disease genes for Noonan-related syndromes

努南相关综合征的新疾病基因的鉴定

基本信息

批准号：
17591068
负责人：
AOKI Yoko
金额：
$ 2.24万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591068/
关键词：
Multiple congenital anomaly proto-oncogene Ras Tyrosine phosphatase RAF

项目摘要

Costello syndrome and CFC syndrome are rare, multiple congenital anomaly syndrome characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities and mental retardation. Clinical features with both syndromes overlap with those with Noonan syndrome. Gain-of-function mutations in PTPN11 have been identified in approximately 50% of individuals with clinically diagnosed Noonan syndrome(Tartaglia et al., 2001) SHP-2, the product of PTPN11, is a widely expressed cytoplasmic tyrosine phosphatase and has been implicated in signal transduction pathways elicited by growth factors, cytokines, hormones and extracellular matrix. No PTPN11 mutations have been found in individuals with Costello or CFC syndrome and genetic causes for these disorders had been unknown.We hypothesized that genes mutated in Costello syndrome and in PTPN11-negative Noonan syndrome encode molecules that function upstream or downstream of SHP-2 in signal pathways. Among these molecules, they sequenced the entire coding region of 4 RAS (KRAS, HRAS and NRAS, as well as the recently identified ERAS genes) in genomic DNA from 13 individuals with Costello syndrome and 28 individuals with PTPN//-negative Noonan syndrome. We discovered HRAS germline mutations in patients with Costello syndrome, a congenital anomaly/mental retardation syndrome (Aoki et al. 2005). This discovery provided a clue to identification of germline mutations in KRAS, BRAF and MAP2K1/2 mutations in patients with cardio-facio-cutaneous (CFC) syndrome (Niihori et al. 2006 and Narumi et al. 2007). These genes encode molecules in the RAS/RAF/MEK/ERK pathway, proposing a new concept that clinically related disorders, Noonan, Costello and CFC are caused by dys-regulation of RAS/RAF/MEK/ERK pathway.

Costello综合征和CFC综合征是一种罕见的多发性先天性畸形综合征，其特征是面部外观独特、心脏缺陷、肌肉皮肤异常和智力低下。这两种综合征的临床特征与Noonan综合征的临床特征重叠。在大约50%的临床诊断为Noonan综合征的患者中发现了PTPN11的功能获得突变(Taraglia et al.，2001)，PTPN11的产物SHP-2是一种广泛表达的细胞质酪氨酸磷酸酶，参与了由生长因子、细胞因子、激素和细胞外基质诱导的信号转导通路。在Costello或CFC综合征患者中没有发现PTPN11突变，这些疾病的遗传原因尚不清楚。我们假设Costello综合征和PTPN11阴性的Noonan综合征患者的基因突变编码分子，这些分子在信号通路中作用于SHP-2的上游或下游。在这些分子中，他们对13名Costello综合征患者和28名PTPN//阴性Noonan综合征患者的基因组DNA中4个RAS(KRAS、HRAS和NRAS，以及最近发现的era基因)的完整编码区进行了测序。我们在Costello综合征患者中发现了HRAS胚系突变，这是一种先天性异常/智力低下综合征(Aoki等人。2005)。这一发现为鉴定心面部皮肤综合征患者KRAS、BRAF和MAP2K1/2突变的种系突变提供了线索(Niihori等人。2006和Narumi等人。2007)。这些基因编码RAS/RAF/MEK/ERK通路中的分子，提出了临床相关疾病Noonan、Costello和CFs的新概念，这些疾病是由于RAS/RAF/MEK/ERK通路的异常调节引起的。