Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects
- Runtuwene, V., van Eekelen, M., Overvoorde, J., Rehmann, H., Yntema, H.G., Nillesen, W.M., van Haeringen, A., van der Burgt, I., Burgering, B., and den Hertog, J.
- Disease models & mechanisms 4(3): 393-399 (Journal)
- Registered Authors
- den Hertog, Jeroen, Overvoorde, John
- MeSH Terms
- Amino Acid Substitution
- Base Sequence
- Cell Movement
- Craniofacial Abnormalities/embryology
- Craniofacial Abnormalities/metabolism
- Craniofacial Abnormalities/pathology
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/pathology
- Molecular Sequence Data
- Noonan Syndrome/genetics*
- Oncogene Proteins/genetics*
- Oncogene Proteins/metabolism
- Protein Transport
- Signal Transduction
- ras Proteins/genetics*
- ras Proteins/metabolism
- 21263000 Full text @ Dis. Model. Mech.
Runtuwene, V., van Eekelen, M., Overvoorde, J., Rehmann, H., Yntema, H.G., Nillesen, W.M., van Haeringen, A., van der Burgt, I., Burgering, B., and den Hertog, J. (2011) Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects. Disease models & mechanisms. 4(3):393-399.
Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras-mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes