Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects
SUMMARY 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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2011-05-01
|
| Series: | Disease Models & Mechanisms |
| Online Access: | http://dmm.biologists.org/content/4/3/393 |
| _version_ | 1818991542597058560 |
|---|---|
| author | Vincent Runtuwene Mark van Eekelen John Overvoorde Holger Rehmann Helger G. Yntema Willy M. Nillesen Arie van Haeringen Ineke van der Burgt Boudewijn Burgering Jeroen den Hertog |
| author_facet | Vincent Runtuwene Mark van Eekelen John Overvoorde Holger Rehmann Helger G. Yntema Willy M. Nillesen Arie van Haeringen Ineke van der Burgt Boudewijn Burgering Jeroen den Hertog |
| author_sort | Vincent Runtuwene |
| collection | DOAJ |
| description | SUMMARY
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. |
| first_indexed | 2024-12-20T20:11:55Z |
| format | Article |
| id | doaj.art-917ce76435664510945a2a7b3336049e |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-20T20:11:55Z |
| publishDate | 2011-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-917ce76435664510945a2a7b3336049e2022-12-21T19:27:48ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112011-05-014339339910.1242/dmm.007112007112Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defectsVincent RuntuweneMark van EekelenJohn OvervoordeHolger RehmannHelger G. YntemaWilly M. NillesenArie van HaeringenIneke van der BurgtBoudewijn BurgeringJeroen den HertogSUMMARY 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.http://dmm.biologists.org/content/4/3/393 |
| spellingShingle | Vincent Runtuwene Mark van Eekelen John Overvoorde Holger Rehmann Helger G. Yntema Willy M. Nillesen Arie van Haeringen Ineke van der Burgt Boudewijn Burgering Jeroen den Hertog Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects Disease Models & Mechanisms |
| title | Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects |
| title_full | Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects |
| title_fullStr | Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects |
| title_full_unstemmed | Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects |
| title_short | Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects |
| title_sort | noonan syndrome gain of function mutations in nras cause zebrafish gastrulation defects |
| url | http://dmm.biologists.org/content/4/3/393 |
| work_keys_str_mv | AT vincentruntuwene noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects AT markvaneekelen noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects AT johnovervoorde noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects AT holgerrehmann noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects AT helgergyntema noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects AT willymnillesen noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects AT arievanhaeringen noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects AT inekevanderburgt noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects AT boudewijnburgering noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects AT jeroendenhertog noonansyndromegainoffunctionmutationsinnrascausezebrafishgastrulationdefects |