期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 46, 页码 16395-16400出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1418126111
关键词
RASopathies; developmental disorders; heart defects; myeloproliferative disorders; MEK inhibitors
资金
- Histopathology and Transgenic Units
- European Research Council [ERC-AG/250297-RAS AHEAD]
- European Union [LSHG-CT-2007-037665, HEALTH-F2-2010-259770, HEALTH-2010-260791]
- Spanish Ministry of Science and Innovation [SAF2006-11773, CSD2007-00017]
- Spanish Ministry of Economy and Competitiveness [SAF2011-30173, SAF2009-07172, SAF2012-3171, RD06/0020/0001, RD12/0036/0002]
- Autonomous Community of Madrid [GR/SAL/0587/2004, S2006/BIO-0232, GR/SAL/0349/2004]
- Fundacion de la Mutua Madrilena del Automovil
- Castilla-Leon Autonomous Government [CSI039A12-1]
- Asociacion Espanola Contra el Cancer (AECC)
- Fondo de Investigacion Sanitaria [PI042124, PI08-1623, PI11-02529]
- Fundacion Ramon Areces [FRA 01-09-001]
- Instituto de Salud Carlos III
- Spanish Ministry of Economy and Competitiveness
Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. NS also is associated with a risk for developing myeloproliferative disorders (MPD), including juvenile myelomonocytic leukemia (JMML). Mutations responsible for NS occur in at least 11 different loci including KRAS. Here we describe a mouse model for NS induced by K-Ras(V14I), a recurrent KRAS mutation in NS patients. K-Ras(V14I)-mutant mice displayed multiple NS-associated developmental defects such as growth delay, craniofacial dysmorphia, cardiac defects, and hematologic abnormalities including a severe form of MPD that resembles human JMML. Homozygous animals had perinatal lethality whose penetrance varied with genetic background. Exposure of pregnant mothers to a MEK inhibitor rescued perinatal lethality and prevented craniofacial dysmorphia and cardiac defects. However, Mek inhibition was not sufficient to correct these defects when mice were treated after weaning. Interestingly, Mek inhibition did not correct the neoplastic MPD characteristic of these mutant mice, regardless of the timing at which the mice were treated, thus suggesting that MPD is driven by additional signaling pathways. These genetically engineered K-Ras(V14I)-mutant mice offer an experimental tool for studying the molecular mechanisms underlying the clinical manifestations of NS. Perhaps more importantly, they should be useful as a preclinical model to test new therapies aimed at preventing or ameliorating those deficits associated with this syndrome.
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