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-faciocutaneous 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-Ras G12V oncogene, even in homozygosis, resulted in hyperplasia of the mammary gland. However, development of tumors in these mice was rare. H-Ras G12V 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.

Endogenous expression of Hras G12V induces developmental defects and neoplasms with copy number imbalances of the oncogene

“…Moreover, Hras G12V -IRES-␤-geo mice developed age-dependent systemic hypertension, cardiac fibrosis, and vascular remodeling, particularly in homozygotes (20). There was no increase in pERK or pAKT in cardiac tissue of CC/FRHras G12V mice.…”

“…Accordingly, there has only been one child reported with a germline HRAS G12V mutation, which was associated with a severe form of CS that resulted in death at 18 months of age, suggesting that this mutation may not be well tolerated in humans (11). Unexpectedly, a mouse germline knock-in of a bicistronic Hras G12V allele (Hras G12V -IRES-␤-geo) was associated with a mild phenotype (20). Mice were viable, fertile, and survived normally.…”

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

“…There were no reports of microdissection of the conduction system to validate Mori et al's [1996] observation of ''degeneration of the conduction system'' in which abnormalities of the conduction pathways led to the atrioventricular node. The existing mouse model does not exhibit tachycardia [Schuhmacher et al, 2008;Chen et al, 2009]. Atrial tachycardia may be a functional consequence of diastolic dysfunction in adults with HCM where increased filling pressure is associated with increased atrial stretch leading to dysrhythmia [Brembilla-Perrot et al, 1997].…”

“…Congenital heart defects (CHDs), cardiac hypertrophy, usually described as hypertrophic cardiomyopathy (HCM) and arrhythmia (especially non-reentrant atrial tachycardia) were each found in approximately one-third of Costello syndrome patients. The knock-in G12V Hras mouse model, though a rare mutation in Costello syndrome, does not appear to completely recapitulate cardiac issues seen in humans [Schuhmacher et al, 2008;Chen et al, 2009].…”

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome

“…One patient had hypertension, which was also observed in a mouse model of CS. 39 One patient had glycogen storage disease type III, as previously reported by Kaji et al, 40 accompanied by a p.G12S mutation. Bladder cancer was observed in one patient.…”