Open AccessGermline expression of H‐ Ras G12V causes neurological deficits associated to Costello syndrome
Author(s) -
Viosca J.,
Schuhmacher A. J.,
Guerra C.,
Barco A.
Publication year - 2009
Publication title -
genes, brain and behavior
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.315
H-Index - 91
eISSN - 1601-183X
pISSN - 1601-1848
DOI - 10.1111/j.1601-183x.2008.00443.x
Subject(s) - phenotype , costello syndrome , germline , mutation , cognition , genetics , endocrinology , gene , medicine , biology , neuroscience , kras
Costello syndrome (CS) is a rare congenital disorder caused by germline activation of H‐ Ras oncogenes. A mouse model of CS generated by introduction of an oncogenic Gly12Val mutation in the mouse H‐ Ras locus using homologous recombination in embryonic stem (ES) cells has been recently described. These mice phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. We investigated here their neurological and behavioral phenotype. The analysis of H‐ Ras G12V mice revealed phenotypes that resembled the hyperemotivity, hypersensibility and cognitive impairments observed in children with CS. Stronger neurological deficits were found in the analysis of mice homozygous for this mutation than in the analysis of heterozygous mice, suggesting the existence of a gene dose effect. These mice represent the first mouse model for CS, offering an experimental tool to study the molecular and physiological alterations underlying the neurological manifestations of CS and to test new therapies aimed at preventing or ameliorating the cognitive and emotional impairments associated to this condition.