Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

Dis Model Mech. 2011 May;4(3):393-9. doi: 10.1242/dmm.007112. Epub 2011 Jan 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Gastrulation / genetics*
  • Humans
  • Molecular Sequence Data
  • Mutation / genetics*
  • Noonan Syndrome / genetics*
  • Oncogene Proteins / genetics*
  • Oncogene Proteins / metabolism
  • Protein Transport
  • Signal Transduction
  • Zebrafish / embryology*
  • Zebrafish / metabolism
  • ras Proteins / genetics*
  • ras Proteins / metabolism

Substances

  • Oncogene Proteins
  • ras Proteins