Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome
Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome
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DOI：
10.1038/ng1939
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发表时间：
2007-01-01
期刊：
影响因子：
30.8
通讯作者：
Gelb, Bruce D.
中科院分区：
文献类型：
--
作者：
Tartaglia, Marco;Pennacchio, Len A.;Gelb, Bruce D.
努南综合征是一种以身材矮小、面部畸形、先天性心脏缺陷和骨骼异常为特征的发育障碍(1)。由于PTPN11和KRAS突变导致的ras -丝裂原活化蛋白激酶（MAPK）信号的增加导致50%的Noonan综合征病例（2-6）。在这里，我们报告了129例Noonan综合征患者中没有PTPN11或KRAS突变的22例在编码ras特异性鸟嘌呤核苷酸交换因子的SOS1中存在错义突变。SOS1突变聚集在编码残基的密码子上，这些残基与维持SOS1的自抑制形式有关。此外，两种Noonan综合征相关突变体的异位表达可诱导RAS和ERK活化增强。与SOS1缺陷相关的表型属于Noonan综合征谱系，但具有独特性，外胚层异常的患病率很高，但通常正常发育和线性生长。我们的研究结果首次揭示了疾病中RAS鸟嘌呤核苷酸交换因子的功能获得突变，并定义了RAS通路上调可以深刻改变人类发育的新机制。
Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies(1). Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome(2-6). Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.