2026-05-22T19:19:29Zhttps://repisalud.isciii.es/rest/oai/request
oai:repisalud.isciii.es:20.500.12105/230662024-11-29T10:12:07Zcom_20.500.12105_2173com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19597col_20.500.12105_16978
Repisalud author Hernández-Porras, Isabel author Fabbiano, Salvatore author Schuhmacher, Alberto J author Aicher, Alexandra author Cañamero, Marta author Cámara, Juan Antonio author Cussó, Lorena author Desco, Manuel author Heeschen, Christopher author Mulero, Francisca author Bustelo, Xosé R author Guerra, Carmen author Barbacid, Mariano funder Unión Europea. Comisión Europea. European Research Council (ERC) funder Ministerio de Economía y Competitividad (España) funder Comunidad de Madrid (España) funder Fundación Mutua Madrileña funder Junta de Castilla y León (España) funder Asociación Española Contra el Cáncer 2024-09-16T08:16:53Z 2024-09-16T08:16:53Z 2014-11-18 Proc Natl Acad Sci U S A . 2014;111(46):16395-400. 10.1073/pnas.1418126111 1091-6490 Proceedings of the National Academy of Sciences of the United States of America https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246321/ 25359213 https://hdl.handle.net/20.500.12105/23066 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. eng K-RasV14I recapitulates Noonan syndrome in mice. research article