Academic Journal
Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects
| العنوان: | Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects |
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| المؤلفون: | 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 |
| المصدر: | Disease Models & Mechanisms, Vol 4, Iss 3, Pp 393-399 (2011) |
| بيانات النشر: | The Company of Biologists, 2011. |
| سنة النشر: | 2011 |
| المجموعة: | LCC:Medicine LCC:Pathology |
| مصطلحات موضوعية: | Medicine, Pathology, RB1-214 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1754-8403 1754-8411 |
| Relation: | http://dmm.biologists.org/content/4/3/393; https://doaj.org/toc/1754-8403; https://doaj.org/toc/1754-8411 |
| DOI: | 10.1242/dmm.007112 |
| URL الوصول: | https://doaj.org/article/917ce76435664510945a2a7b3336049e |
| رقم الانضمام: | edsdoj.917ce76435664510945a2a7b3336049e |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17548403 17548411 |
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| DOI: | 10.1242/dmm.007112 |