K-Ras V14I recapitulates Noonan syndrome in mice
Open accessAbstract
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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V14 is an important hub in the KRAS hydrophobic interaction network.
“Supporting the fact that V14 is an important hub in the KRAS hydrophobic interaction network”
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- Authors
- Hernández-Porras, I., Fabbiano, S., Schuhmacher, A. J., Aicher, A., Cañamero, M., Cámara, J. A., Cussó, L., Desco, M., Heeschen, C., Mulero, F., Bustelo, X. R., Guerra, C., & Barbacid, M.
- Affiliations
- Molecular Oncology (United States) (US)
- Universidad de Salamanca (ES)
- Molecular Pathology, and
- Spanish National Cancer Research Centre (ES)
- Centro de Investigación Biomédica en Red de Salud Mental (ES)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-10-30
- Volume
- 111
- Issue
- 46
- Pages
- 16395-16400
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4246321
- OpenAlex
- W2015288448
- Cited by
- 96
- References
- 23
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 20 · 2023: 5 · 2022: 13 · 2021: 9 · 2020: 8 · 2019: 8 · 2018: 6 · 2017: 3 · 2016: 7 · 2015: 4
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundación Ramón Areces (FRA 01-09-001)
- Comunidad de Madrid (S2006/BIO-0232, GR/SAL/0349/2004)
- European Commission (RD06/0020, 260791, 259770)
- Ministerio de Economía y Competitividad (RD12/0036/0002, SAF2012, RD06/0020)
- Ministerio de Ciencia e Innovación
- Instituto de Salud Carlos III (RD06/0020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Noonan syndrome, mouse model, juvenile myelomonocytic leukemia, myeloproliferative neoplasms, craniofacial dysmorphism, congenital heart disease, growth delay, MEK inhibition, perinatal lethality, developmental defects
- MeSH terms
- Abnormalities, Multiple, Alleles, Animals, Crosses, Genetic, Disease Models, Animal, Dwarfism, Epistasis, Genetic, Face, Female, Genes, Dominant, Genotype, Heart Defects, Congenital, Hematopoiesis, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Myeloproliferative Disorders, Neoplastic Syndromes, Hereditary, Noonan Syndrome, Phenotype, Pregnancy, Prenatal Exposure Delayed Effects, Radiation Chimera, Genes, ras, Signal Transduction, Proto-Oncogene Proteins p21(ras), Point Mutation, Cell Lineage, Amino Acid Substitution, Mutation, Missense, MAP Kinase Kinase Kinases, Protein Kinase Inhibitors, Body Size, Mice, Leukemia, Myelomonocytic, Juvenile
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