Aoki Yoko, Niihori Tetsuya, Narumi Yoko, Kure Shigeo, Matsubara Yoichi
Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Hum Mutat. 2008 Aug;29(8):992-1006. doi: 10.1002/humu.20748.
The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. A variety of mutations in protein tyrosine phosphatase, non-receptor type 11(PTPN11) has been identified in 50% of Noonan patients. Specific mutations in PTPN11 have been identified in LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In 2005, we discovered Harvey-RAS (HRAS) germline mutations in patients with Costello syndrome. This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome. These genes encode molecules in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway, leading to a new concept that clinically related disorders, i.e., Noonan, Costello, and CFC syndromes are caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. In the present review, we summarize mutations in HRAS, KRAS, BRAF, MAP2K1/2, and PTPN11, the phenotypes of patients with these mutations, the functional properties of mutants and animal models. Finally we suggest that disorders with mutations of molecules in the RAS/MAPK cascade (Noonan, LEOPARD, Costello, and CFC syndromes and neurofibromatosis type I) may be comprehensively termed "the RAS/MAPK syndromes." Details on mutations will be updated in the RAS/MAPK Syndromes Homepage (www.medgen.med.tohoku.ac.jp/RasMapk syndromes.html).
RAS蛋白及其下游信号通路在细胞增殖、分化、存活和细胞死亡中起关键作用，但其在人类发育中的生理作用尚不清楚。努南综合征、科斯特洛综合征和心脏-颜面-皮肤综合征（CFC综合征）是常染色体显性遗传的多发性先天性异常综合征，其特征为独特的面部外观、心脏缺陷、肌肉皮肤异常和智力发育迟缓。在50%的努南综合征患者中已发现蛋白酪氨酸磷酸酶非受体11型（PTPN11）存在多种突变。在豹皮综合征（多发性雀斑样痣、心电图传导异常、眼距过宽、肺动脉狭窄、生殖器异常、生长发育迟缓及感觉神经性耳聋）中已鉴定出PTPN11的特定突变。2005年，我们在科斯特洛综合征患者中发现了哈维-RAS（HRAS）种系突变。这一发现为鉴定CFC综合征患者中柯尔斯顿-RAS（KRAS）、BRAF以及丝裂原活化蛋白激酶激酶1和2（MAP2K1/MAP2K2）的种系突变提供了线索。这些基因编码RAS/RAF/MEK/细胞外信号调节激酶（ERK）信号通路中的分子，从而引出了一个新的概念，即临床上相关的疾病，如努南综合征、科斯特洛综合征和CFC综合征是由RAS/丝裂原活化蛋白激酶（MAPK）信号通路失调引起的。在本综述中，我们总结了HRAS、KRAS、BRAF、MAP2K1/2和PTPN11中的突变、具有这些突变的患者的表型、突变体的功能特性以及动物模型。最后，我们建议将RAS/MAPK级联分子发生突变的疾病（努南综合征、豹皮综合征、科斯特洛综合征、CFC综合征和I型神经纤维瘤病）统称为“RAS/MAPK综合征”。突变的详细信息将在RAS/MAPK综合征主页（www.medgen.med.tohoku.ac.jp/RasMapk syndromes.html）上更新。
