Germline expression of H-RasG12V causes neurological deficits associated to Costello syndrome

Authors

  • J. Viosca,

    1. Instituto de Neurociencias de Alicante (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Campus de Sant Joan, Apt. 18, Sant Joan d’Alacant, 03550 Alicante, Spain
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    • 1

      These two authors contributed equally to this work.

  • A. J. Schuhmacher,

    1. Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), E-28029 Madrid, Spain
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    • 1

      These two authors contributed equally to this work.

  • C. Guerra,

    Corresponding author
    1. Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), E-28029 Madrid, Spain
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  • A. Barco

    Corresponding author
    1. Instituto de Neurociencias de Alicante (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Campus de Sant Joan, Apt. 18, Sant Joan d’Alacant, 03550 Alicante, Spain
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*A. Barco, Instituto de Neurociencias de Alicante (UMH-CSIC), Campus de Sant Joan, Apt. 18, Sant Joan d’Alacant 03550, Alicante, Spain. E-mail: abarco@umh.es; C. Guerra, Centro Nacional de Investigaciones Oncológicas (CNIO), E-28029 Madrid, Spain. E-mail: cguerra@cnio.es

Abstract

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-RasG12V 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.

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