RESUMO
Rad9 and Atm regulate multiple cellular responses to DNA damage, including cell cycle checkpoints, DNA repair and apoptosis. However, the impact of dual heterozygosity for Atm and Rad9 is unknown. Using 50 cGy of X rays as an environmental insult and cataractogenesis as an end point, this study examined the effect of heterozygosity for one or both genes in mice. Posterior subcapsular cataracts, characteristic of radiation exposure, developed earlier in X-irradiated double heterozygotes than in single heterozygotes, which were more prone to cataractogenesis than wild-type controls. Cataract onset time and progression in single or double heterozygotes were accelerated even in unirradiated eyes. These findings indicate that the cataractogenic effect of combined heterozygosity is greater than for each gene alone and are the first to demonstrate the impact of multiple haploinsufficiency on radiation effects in an intact mammal. These observations may help explain observed interindividual differential radiosensitivity in human populations and have important implications for those undergoing radiotherapy or exposed to elevated levels of cosmic radiation, such as the astronaut corps. These findings demonstrate that Mrad9 and Atm are important determinants of lens opacification and, given the roles of Atm and Rad9 in maintaining genomic stability, are consistent with a genotoxic basis for radiation cataractogenesis.
Assuntos
Ataxia Telangiectasia/genética , Catarata/etiologia , Catarata/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Lesões por Radiação/etiologia , Lesões por Radiação/genética , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Catarata/metabolismo , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Camundongos , Proteínas Serina-Treonina Quinases/genética , Doses de Radiação , Lesões por Radiação/metabolismo , Proteínas Supressoras de Tumor/genética , Raios XRESUMO
Anterior lenticonus is an ocular abnormality that can occur in Alport's syndrome. In this study, Scheimpflug slit imaging analyses were employed for quantitative and objective evaluation of lens changes associated with Alport's syndrome. It was determined that while the apices of the lenticular protrusions are central in the vertical plane, they are nasally displaced in the horizontal meridian. The eccentricity and dimensions of the diameters and thicknesses of the conical aberration are highly correlated in both eyes. Lens thickness and anterior chamber depth do not differ between eyes. Densitometrically similar differences are apparent in the cortex and nuclear regions although evidence of overt opacification may or may not be present. The data strongly suggest that the physical parameters of the lenticonus are consistent with the constraints imposed by the pupil. Changes observed in the cornea and the vitreous may be associated with the syndrome.
