Alterations in the growth hormone/insulin-like growth factor I pathways infeline GM1 gangliosidosis

Cats affected with feline GM1 gangliosidosis, an autosomal, recessively inh erited, lysosomal enzymopathy, have progressive neurological dysfunction, p remature thymic involution, stunted growth, and premature death. Although i ncreased membrane GM1 gangliosides can result in increased apoptosis of thy mocytes, there is not a direct correlation between thymocyte surface GM1 an d thymic apoptosis in vivo, suggesting that other factors may he important to the pathogenesis of thymic involution in affected cats. Because GH and i nsulin-like growth factor I(IGF-I) are important hormonal peptides supporti ng thymic function and affecting growth throughout the body, particularly i n the prepubescent period, several components of the GH/IGF-I pathway were compared in GM1 mutant and normal age-matched cats. GM1 mutant cat serum IG F-I concentrations were reduced significantly compared with those in normal cats by 150 days of age, and GM1 mutant cats had no peripuberal increase i n serum IGF-I. Additionally, IGF-binding protein-3 was reduced, and IGF-bin ding protein-2 was elevated significantly in GM1 mutant cats more than 200 days of age. Liver IGF-I messenger RNA and pituitary GH messenger RNA both were reduced significantly in GM1 mutant cats. After stimulation by exogeno us recombinant canine GH, serum IGF-I levels increased significantly in GM1 mutant cats, indicating that GH/IGF-I signaling pathways within the liver remain intact and suggesting that alterations are external to the liver.