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Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16395-400. doi: 10.1073/pnas.1418126111. Epub 2014 Oct 30.

K-RasV14I recapitulates Noonan syndrome in mice.

Author information

1
Molecular Oncology.
2
Centro de Investigación del Cáncer, Universidad de Salamanca, E-37007 Salamanca, Spain;
3
Molecular Pathology, and.
4
Biotechnology Programs, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain;
5
Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III, E-28911 Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, E-28007 Madrid, Spain; and Centro de Investigación Biomédica en Red de Salud Mental, E-28029 Madrid, Spain.
6
Molecular Oncology, mcguerra@cnio.es mbarbacid@cnio.es.

Abstract

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.

KEYWORDS:

MEK inhibitors; RASopathies; developmental disorders; heart defects; myeloproliferative disorders

PMID:
25359213
PMCID:
PMC4246321
DOI:
10.1073/pnas.1418126111
[Indexed for MEDLINE]
Free PMC Article

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