Targeted Disruption of the Lysosomal -Mannosidase Gene Results in Mice Resembling a Mild form of Human -Mannosidosis

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Abstract
α-Mannosidosis is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the lysosomal α-mannosidase, which is involved in the degradation of asparagine-linked carbohydrate cores of glycoproteins. An α-mannosidosis mouse model was generated by targeted disruption of the gene for lysosomal α-mannosidase. Homozygous mutant animals exhibit α-mannosidase enzyme deficiency and elevated urinary secretion of mannose-containing oligosaccharides. Thin-layer chromatography revealed an accumulation of oligosaccharides in liver, kidney, spleen, testis and brain. The cellular alterations were characterized by multiple membrane-limited cytoplasmic vacuoles as seen for instance in liver, exocrine pancreas, kidney, thyroid gland, smooth muscle cells, osteocytes and in various neurons of the central and peripherial nervous systems. The morphological lesions and their topographical distribution, as well as the biochemical alterations, closely resemble those reported for human α-mannosidosis. This mouse model will be a valuable tool for studying the pathogenesis of inherited α-mannosidosis and may help to evaluate therapeutic approaches for lysosomal storage diseases.