title: A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition.
abstract: Germline activation of H-RAS oncogenes is the primary cause of Costello syndrome (CS), a neuro-cardio-facio-cutaneous developmental syndrome. Here we describe the generation of a mouse model of CS by introduction of an oncogenic Gly12Val mutation in the mouse H-Ras locus using homologous recombination in ES cells. Germline expression of the endogenous H-RasG12V oncogene, even in homozygosis, resulted in hyperplasia of the mammary gland. However, development of tumors in these mice was rare. H-RasG12V mutant mice closely phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. These mice also displayed alterations in the homeostasis of the cardiovascular system, including development of systemic hypertension, extensive vascular remodeling, and fibrosis in both the heart and the kidneys. This phenotype was age dependent and was a consequence of the abnormal upregulation of the renin-Ang II system. Treatment with captopril, an inhibitor of Ang II biosynthesis, prevented development of the hypertension condition, vascular remodeling, and heart and kidney fibrosis. In addition, it partially alleviated the observed cardiomyopathies. These mice should help in elucidating the etiology of CS symptoms, identifying additional defects, and evaluating potential therapeutic strategies.
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Schuhmacher
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerra
authors.forename: Vincent
authors.initials: V
authors.lastname: Sauzeau
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006973:Hypertension / Q000378:metabolism*; D008607:Intellectual Disability / Q000235:genetics*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010641:Phenotype; D011995:Recombination, Genetic; D015398:Signal Transduction; D013577:Syndrome; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000804:Angiotensin II; D002216:Captopril; D018631:ras Proteins