Genetic ataxia telangiectasia porcine model phenocopies the multisystemic features of the human disease

摘要

Abstract Ataxia telangiectasia (AT) is a progressive multisystem autosomal recessive disorder caused by mutations in the AT-mutated ( ATM ) gene. Early onset AT in children is characterized by cerebellar degeneration, leading to motor impairment. Lung disease and cancer are the two most common causes of death in AT patients. Accelerated thymic involution may contribute to the cancer, and recurrent and/or chronic respiratory infections may be a contributing factor to lung disease in AT. AT patients have fertility issues, are highly sensitive to ionizing radiation and they present oculocutaneous telangiectasia. Current treatments only slightly ameliorate disease symptoms; therapy that alters or reverses the course of the disease has not yet been discovered. Previously, we have shown that ATM ?/? pigs, a novel model of AT, present with a loss of Purkinje cells, altered cerebellar cytoarchitecture and motor coordination deficits. ATM ?/? porcine model not only recapitulates the neurological phenotype, but also other multifaceted clinical features of the human disease. Our current study shows that ATM ?/? female pigs are infertile, with anatomical and functional signs of an immature reproductive system. Both male and female ATM ?/? pigs show abnormal thymus structure with decreased cell cycle and apoptosis markers in the gland. Moreover, ATM ?/? pigs have an altered immune system with decreased CD8 + and increased natural killer and CD4 + CD8 + double-positive cells. Nevertheless, ATM ?/? pigs manifest a deficient IgG response after a viral infection. Based on the neurological and peripheral phenotypes, the ATM ?/? pig is a novel genetic model that may be used for therapeutic assessments and to identify pathomechanisms of this disease. Highlights ? The A-T porcine model recapitulates multi-system abnormalities similar to the human disease. ? AT porcine model shows infertility associated with a low estradiol level in blood ? AT porcine model shows a reduced immunological response to PRRS viral infection ? Apoptosis and P53 are involved in the thymus pathology in AT pigs ? Altered cell cycle is involved in the thymus pathology of AT pigs