Molecular analysis of congenital anomaly syndromes caused by intracellular signal transduction defects

我们在180名努南综合征患者中的17名中发现了9个编码RAS亚家族成员的RIT 1的错义、非同义突变。70%的突变阳性个体表现为肥厚型心肌病;相对于努南综合征个体20%的发病率，该频率较高。这些RIT 1改变增强ELK 1反式激活。将突变RIT 1的mRNA引入1细胞期斑马鱼胚胎中，发现导致胚胎颅面异常，不完整的循环，心脏发育不全室和延长的卵黄囊的显着增加。这些结果表明，RIT 1中的功能获得性突变导致努南综合征，并显示出与其他RASopathy相关基因突变相似的生物学效应。

We identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals with Noonan syndrome. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidencein individuals with Noonan syndrome. These RIT1 alterations enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.