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Mucopolysaccharidosis IVA is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), a lysosomal enzyme required for the stepwise degradation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). To generate a model for studies of the pathophysiology and of potential therapies, we disrupted exon 2 of Galns, the homologous murine gene. Homozygous Galns-/- mice have no detectable GALNS enzyme activity and show increased urinary glycosaminoglycan (GAGs) levels. These mice accumulate GAGs in multiple tissues including liver, kidney, spleen, heart, brain and bone marrow. At 2 months old, lysosomal storage is present primarily within reticuloendothelial cells such as Kupffer cells and cells of the sinusoidal lining of the spleen. Additionally, by 12 months old, vacuolar change is observed in the visceral epithelial cells of glomeruli and cells at the base of heart valves but it is not present in parenchymal cells such as hepatocytes and renal tubular epithelial cells. In the brain, hippocampal and neocortical neurons and meningeal cells had lysosomal storage. KS and C6S were more abundant in the cytoplasm of corneal epithelial cells of Galns-/- mice compared with wild-type mice by immunohistochemistry. Radiographs revealed no change in the skeletal bones of mice up to 12 months old. Thus, targeted disruption of the murine Galns gene has produced a murine model, which shows visceral storage of GAGs but lacks the skeletal features. The complete absence of GALNS in mutant mice makes them useful for studies of pharmacokinetics and tissue targeting of recombinant GALNS designed for enzyme replacement.

human molecular genetics online/human molecular genetics

Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns-/-) produced by targeted disruption of the gene defective in Morquio A disease