Identification of novel disease genes for Noonan-related syndromes

Costello综合征和CFC综合征是罕见的多发性先天性异常综合征，其特征是独特的面部外观，心脏缺陷，肌肉皮肤异常和智力迟钝。这两种综合征的临床特征与努南综合征的临床特征重叠。在大约50%的临床诊断为Noonan综合征的个体中发现了PTPN11的功能获得突变（Tartaglia 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，与生长因子、细胞因子、激素和细胞外基质引发的信号转导途径有关。在患有Costello综合征或CFC综合征的个体中未发现PTPN11突变，这些疾病的遗传原因尚不清楚。我们假设在Costello综合征和ptpn11阴性Noonan综合征中突变的基因编码在信号通路中SHP-2的上游或下游起作用的分子。在这些分子中，他们对13例Costello综合征和28例PTPN//-阴性Noonan综合征的基因组DNA中的4个RAS （KRAS， HRAS和NRAS，以及最近发现的ERAS基因）的整个编码区进行了测序。我们在Costello综合征（一种先天性异常/智力低下综合征）患者中发现了HRAS种系突变（Aoki et al. 2005）。这一发现为识别心-面-皮（CFC）综合征患者的KRAS、BRAF和MAP2K1/2突变的种系突变提供了线索（Niihori et al. 2006和Narumi et al. 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CFC是由RAS/RAF/MEK/ERK通路调控异常引起的新概念。

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.