Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.
Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.
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RRAS 的激活突变是 RAS 病谱中表型的基础，并有助于白血病的发生。
DOI：
10.1093/hmg/ddu148
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发表时间：
2014-08-15
影响因子：
3.5
通讯作者：
Tartaglia M
中科院分区：
文献类型：
--
作者：
Flex E;Jaiswal M;Pantaleoni F;Martinelli S;Strullu M;Fansa EK;Caye A;De Luca A;Lepri F;Dvorsky R;Pannone L;Paolacci S;Zhang SC;Fodale V;Bocchinfuso G;Rossi C;Burkitt-Wright EM;Farrotti A;Stellacci E;Cecchetti S;Ferese R;Bottero L;Castro S;Fenneteau O;Brethon B;Sanchez M;Roberts AE;Yntema HG;Van Der Burgt I;Cianci P;Bondeson ML;Cristina Digilio M;Zampino G;Kerr B;Aoki Y;Loh ML;Palleschi A;Di Schiavi E;Carè A;Selicorni A;Dallapiccola B;Cirstea IC;Stella L;Zenker M;Gelb BD;Cavé H;Ahmadian MR;Tartaglia M
RASopathies是一个以心脏缺陷、生长缺陷、面部畸形、可变认知缺陷和某些恶性肿瘤易感性为特征的疾病家族，由主要通过RAF/MEK/ERK（MAPK）级联的RAS信号传导的体质失调引起。我们报告了RRAS中的两个生殖系突变（p.Gly39dup和p.Val55Met），RRAS是一种编码控制细胞粘附、扩散和迁移的小单体GT3的基因，是一种罕见的（分析的504例患者中有2例受试者）和可变表型的基础，其特征部分重叠努南综合征，最常见的RAS病。我们还确定了体细胞RRAS突变（p.Gly39dup和p.Gln87Leu）在2/110例非综合征型青少年骨髓单核细胞白血病，一种由RAS信号上调引起的儿童骨髓增生性/骨髓增生异常疾病，定义了这种血液疾病的非典型形式，迅速进展为急性髓性白血病。三个确定的突变中的两个影响RAS基因的已知致癌热点，并赋予RRAS功能增强和刺激依赖性MAPK激活。在秀丽隐杆线虫中表达RRAS突变体同源物增强了RAS信号传导并产生了突出的外阴，这是一种先前与RASopathy引起的SHOC 2S 2G突变体相关的表型。总体而言，这些发现提供了RRAS和MAPK信号传导之间的功能联系的证据，并揭示了RRAS功能增强在人类疾病中的不可预测的作用。
RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.
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影响因子：
30.8
作者：
Cordeddu, Viviana;Di Schiavi, Elia;Pennacchio, Len A.;Ma'ayan, Avi;Sarkozy, Anna;Fodale, Valentina;Cecchetti, Serena;Cardinale, Alessio;Martin, Joel;Schackwitz, Wendy;Lipzen, Anna;Zampino, Giuseppe;Mazzanti, Laura;Digilio, Maria C.;Martinelli, Simone;Flex, Elisabetta;Lepri, Francesca;Bartholdi, Deborah;Kutsche, Kerstin;Ferrero, Giovanni B.;Anichini, Cecilia;Selicorni, Angelo;Rossi, Cesare;Tenconi, Romano;Zenker, Martin;Merlo, Daniela;Dallapiccola, Bruno;Iyengar, Ravi;Bazzicalupo, Paolo;Gelb, Bruce D.;Tartaglia, Marco
通讯作者：
Tartaglia, Marco
SHP2敲低和NOONAN/LEOPARD突变体SHP2诱导的胃部缺陷。
影响因子：
4.5
作者：
Jopling, Chris;van Geemen, Daphne;den Hertog, Jeroen
通讯作者：
den Hertog, Jeroen
影响因子：
15.9
作者：
Chen, Peng-Chieh;Wakimoto, Hiroko;Kucherlapati, Raju
通讯作者：
Kucherlapati, Raju
影响因子：
2.7
作者：
Kishore, RS;Sundaram, MV
通讯作者：
Sundaram, MV
影响因子：
4.8
作者：
Hall, BE;Yang, SS;Bar-Sagi, D
通讯作者：
Bar-Sagi, D