Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis

Abstract

Costello syndrome is a “RASopathy” that is characterized by growth retardation, dysmorphic facial appearance, hypertrophic cardiomyopathy and tumor predisposition. > 80% of patients with Costello syndrome harbor a heterozygous germline G12S mutation in HRAS. Altered metabolic regulation has been suspected because patients with Costello syndrome exhibit hypoketotic hypoglycemia and increased resting energy expenditure, and their growth is severely retarded. To examine the mechanisms of energy reprogramming by HRAS activation in vivo, we generated knock-in mice expressing a heterozygous Hras G12S mutation (HrasG12S/+ mice) as a mouse model of Costello syndrome. On a high-fat diet, HrasG12S/+ mice developed a lean phenotype with microvesicular hepatic steatosis, resulting in early death compared with wild-type mice. Under starvation conditions, hypoketosis and elevated blood levels of long-chain fatty acylcarnitines were observed, suggesting impaired mitochondrial fatty acid oxidation. Our findings suggest that the oncogenic Hras mutation modulates energy homeostasis in vivo.

Costello syndrome model mice with a Hras G12S mutation are susceptible to develop house dust mite-induced atopic dermatitis

“…Hras G12S/+ mice on a C57BL/6J background have been described previously 13 . Male mice were analyzed in this study.…”

“…We have recently generated a strain of knock-in mice expressing an Hras G12S mutation, the most frequent mutation in Costello syndrome 12 , which exhibited facial dysmorphia, cardiomyocyte hypertrophy, and kidney anomalies. Impaired mitochondrial fatty acid oxidation was observed in Hras G12S/+ mice fed a high-fat diet 13 . Skin abnormalities, including papillomas, have not been observed in young Hras G12S/+ mice (<30 weeks old) under specific pathogen-free conditions.…”

The sixth international RASopathies symposium: Precision medicine—From promise to practice

“…Emma Burkitt-Wright moderated a session with Shin-ichi Inoue presenting on the metabolic phenotyping of a novel HRAS G12S mouse model of Costello syndrome (CS; OMIM# 218040; Oba et al, 2018).…”

“…Emma Burkitt‐Wright moderated a session with Shin‐ichi Inoue presenting on the metabolic phenotyping of a novel HRAS G12S mouse model of Costello syndrome (CS; OMIM# 218040; Oba et al, ). Heterozygous animals have a phenotype reminiscent of human CS, with craniofacial features and cardiomyocyte hypertrophy, as seen in other mouse models of RASopathies (Araki et al, ; Schuhmacher et al, ; Urosevic et al, ).…”

Costello Syndrome: The Challenge of Hypoglycemia and Failure to Thrive

“…Although the HRAS p.G12S mutation represents the most frequent amino acid change causing CS, no one scientific group have developed an Hras G12S knock-in mice so far. Moreover, even though the failure to thrive and hypoglycemia do represent respectively the first severe clinical and metabolic challenge to manage CS-affected individuals soon after birth, no one had studied the metabolic profile and biochemical changes on animal models until the paper presented in this issue by Oba et al (2017) .…”