{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:14:05Z","timestamp":1791288845784,"version":"4.3.0"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,3,22]]},"abstract":"<jats:p>\n                    RASopathies are a class of developmental syndromes that result from congenital mutations in key elements of the RAS\/RAF\/MEK signaling pathway. A well-recognized RASopathy is the cardio-facio-cutaneous (CFC) syndrome characterized by a distinctive facial appearance, heart defects, and mental retardation. Clinically diagnosed CFC patients carry germ-line mutations in four different genes, B-\n                    <jats:italic>RAF<\/jats:italic>\n                    ,\n                    <jats:italic>MEK1<\/jats:italic>\n                    ,\n                    <jats:italic>MEK2<\/jats:italic>\n                    , and K-\n                    <jats:italic>RAS<\/jats:italic>\n                    . B-\n                    <jats:italic>RAF<\/jats:italic>\n                    is by far the most commonly mutated locus, displaying mutations that most often result in constitutive activation of the B-RAF kinase. Here, we describe a mouse model for CFC generated by germ-line expression of a B-\n                    <jats:italic>Raf<\/jats:italic>\n                    <jats:sup>LSLV600E<\/jats:sup>\n                    allele. This targeted allele allows low levels of expression of B-Raf\n                    <jats:sup>V600E<\/jats:sup>\n                    , a constitutively active B-Raf kinase first identified in human melanoma. B-Raf\n                    <jats:sup>+\/LSLV600E<\/jats:sup>\n                    mice are viable and display several of the characteristic features observed in CFC patients, including reduced life span, small size, facial dysmorphism, cardiomegaly, and epileptic seizures. These mice also show up-regulation of specific catecholamines and cataracts, two features detected in a low percentage of CFC patients. In addition, B-Raf\n                    <jats:sup>+\/LSLV600E<\/jats:sup>\n                    mice develop neuroendocrine tumors, a pathology not observed in CFC patients. These mice may provide a means of better understanding the pathophysiology of at least some of the clinical features present in CFC patients. Moreover, they may serve as a tool to evaluate the potential therapeutic efficacy of B-RAF inhibitors and establish the precise window at which they could be effective against this congenital syndrome.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1016933108","type":"journal-article","created":{"date-parts":[[2011,3,8]],"date-time":"2011-03-08T07:01:21Z","timestamp":1299567681000},"page":"5015-5020","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":73,"title":["Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome"],"prefix":"10.1073","volume":"108","author":[{"given":"Jelena","family":"Urosevic","sequence":"first","affiliation":[{"name":"Molecular Oncology Program, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), E-28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Sauzeau","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n del C\u00e1ncer and Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer, Consejo Superior de Investigaciones Cientificas-University of Salamanca, E-37007 Salamanca, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda L.","family":"Soto-Montenegro","sequence":"additional","affiliation":[{"name":"Unidad de Medicina y Cirug\u00eda Experimental, Hospital General Universitario \u201cGregorio Mara\u00f1\u00f3n,\u201d Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Salud Mental (CIBERSAM), E-28007 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Reig","sequence":"additional","affiliation":[{"name":"Unidad de Medicina y Cirug\u00eda Experimental, Hospital General Universitario \u201cGregorio Mara\u00f1\u00f3n,\u201d Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Salud Mental (CIBERSAM), E-28007 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Desco","sequence":"additional","affiliation":[{"name":"Unidad de Medicina y Cirug\u00eda Experimental, Hospital General Universitario \u201cGregorio Mara\u00f1\u00f3n,\u201d Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Salud Mental (CIBERSAM), E-28007 Madrid, Spain;"},{"name":"Departamento de Bioingenier\u00eda e Ingenier\u00eda Aerospacial, Universidad Carlos III, E-28991 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma M. Burkitt","family":"Wright","sequence":"additional","affiliation":[{"name":"Genetic Medicine, University of Manchester, Manchester Academic Health Science Centre, Central Manchester University Hospitals National Health Service Foundation Trust, St. Mary's Hospital, Manchester M13 9WL, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Ca\u00f1amero","sequence":"additional","affiliation":[{"name":"Biotechnology Program, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"Mulero","sequence":"additional","affiliation":[{"name":"Biotechnology Program, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagrario","family":"Ortega","sequence":"additional","affiliation":[{"name":"Biotechnology Program, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xos\u00e9 R.","family":"Bustelo","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n del C\u00e1ncer and Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer, Consejo Superior de Investigaciones Cientificas-University of Salamanca, E-37007 Salamanca, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariano","family":"Barbacid","sequence":"additional","affiliation":[{"name":"Molecular Oncology Program, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), E-28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,3,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature00766"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1498"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00215-6"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1749"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124642"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2109"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng2113"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2009.04.001"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2006.042796"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(07)38019-1"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31815"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31658"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.12.040"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1641"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09454"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1002011"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2211"},{"key":"e_1_3_3_18_2","first-page":"2169","article-title":"A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition","volume":"118","author":"Schuhmacher AJ","year":"2008","unstructured":"AJ Schuhmacher, et al., A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition. 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