Back to Search
Start Over
Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects.
- Source :
-
Disease models & mechanisms [Dis Model Mech] 2011 May; Vol. 4 (3), pp. 393-9. Date of Electronic Publication: 2011 Jan 24. - Publication Year :
- 2011
-
Abstract
- 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.
- Subjects :
- Amino Acid Substitution
Animals
Base Sequence
Cell Movement
Craniofacial Abnormalities embryology
Craniofacial Abnormalities metabolism
Craniofacial Abnormalities pathology
Embryo, Nonmammalian abnormalities
Embryo, Nonmammalian metabolism
Embryo, Nonmammalian pathology
Humans
Molecular Sequence Data
Oncogene Proteins metabolism
Protein Transport
Signal Transduction
Zebrafish metabolism
ras Proteins metabolism
Gastrulation genetics
Mutation genetics
Noonan Syndrome genetics
Oncogene Proteins genetics
Zebrafish embryology
ras Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1754-8411
- Volume :
- 4
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Disease models & mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- 21263000
- Full Text :
- https://doi.org/10.1242/dmm.007112