title: K-RasV14I recapitulates Noonan syndrome in mice.
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.
authors.affiliation: Molecular Oncology.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández-Porras
authors.affiliation: Centro de Investigación del Cáncer, Universidad de Salamanca, E-37007 Salamanca, Spain;
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fabbiano
authors.affiliation: Molecular Oncology.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Schuhmacher
authors.affiliation: Molecular Pathology, and.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aicher
authors.affiliation: Biotechnology Programs, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain;
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.affiliation: Biotechnology Programs, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain;
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Cámara
authors.affiliation: 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.
authors.forename: Lorena
authors.initials: L
authors.lastname: Cussó
authors.affiliation: 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.
authors.forename: Manuel
authors.initials: M
authors.lastname: Desco
authors.affiliation: Molecular Pathology, and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
authors.affiliation: Biotechnology Programs, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain;
authors.forename: Francisca
authors.initials: F
authors.lastname: Mulero
authors.affiliation: Centro de Investigación del Cáncer, Universidad de Salamanca, E-37007 Salamanca, Spain;
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
authors.affiliation: Molecular Oncology, mcguerra@cnio.es mbarbacid@cnio.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerra
authors.affiliation: Molecular Oncology, mcguerra@cnio.es mbarbacid@cnio.es.
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics / Q000517:prevention & control; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D049628:Body Size / Q000235:genetics; D019070:Cell Lineage; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004392:Dwarfism / Q000235:genetics; D004843:Epistasis, Genetic; D005145:Face / Q000002:abnormalities; D005260:Female; D005799:Genes, Dominant; D011905:Genes, ras; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000235:genetics; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000196:embryology / Q000235:genetics; D009634:Noonan Syndrome / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000502:physiology; D011828:Radiation Chimera; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D020930:MAP Kinase Kinase Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: MEK inhibitors; RASopathies; developmental disorders; heart defects; myeloproliferative disorders