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

我们在180名Noonan综合征患者中的17名患者中发现了编码RAS亚家族成员的RIT1共有9个错义非同义突变。70%的突变阳性个体表现为肥厚性心肌病；这一频率相对于努南综合征患者20%的总体发病率来说是很高的。这些RIT1的改变增强了ELK1的活化。将突变体RIT1的mrna引入到1细胞期的斑马鱼胚胎中，发现会导致颅面异常、环不完整、心脏腔发育不全和卵黄囊拉长的胚胎显著增加。这些结果表明，RIT1的功能获得突变导致Noonan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.