Mice that are homozygous for this targeted mutation are fertile, normal in size and do not display any gross physical or behavioral abnormalities. Approximately half of homozygotes exhibit postnatal lethality. The Donating Investigator reports maintaining homozygous pups at a higher temperature (77°F) increases their survival. No gene product (mRNA or protein) is detected by RNA hybridization, real-time PCR analysis of skeletal muscle or liver, or Western blot analysis of brown fat. Histological examination of the brown fat from homozygotes reveals abnormal accumulation of large lipid droplets. Examination of brain tissue shows spongiform lesions and gliosis. When fed a high fat diet homozygotes have increased insulin sensitivity, glucose tolerance and reduced body weight. After 24 hours of fasting, homozygotes develop mild hypoglycemia. Mutants have impaired mitochondrial function and gluconeogenesis and are hypermetabolic as well as hyperactive. Homozygotes are unable to survive exposure to 4°C for more than 6 hours. Exaggerated startle response, stimulus induced myoclonus, dystonic posturing, and limb clasping are also observed. Transverse aortic constriction (TAC) results in dilated cardiomyopathy and development of heart failure. The Donating Investigator reports that heterozygote X heterozygote crosses yields less than the expected Mendelian ratio (the observed ratio is 1 homozygote in 8); and homozygous mice are more likely to have litters disappear or die after birth. This mutant mouse strain may be useful in studies of metabolic homeostasis, resistance to obesity, hyperactivity and behavior, mitochondrial impairment, neurodegeneration, and heart failure.
