Targeted disruption of the lysosomal alpha-mannosidase gene results in mice resembling a mild form of human alpha-mannosidosis

alpha-Mannosidosis is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the lysosomal alpha-mannosidase, whic h is involved in the degradation of asparagine-linked carbohydrate cores of glycoproteins, An alpha-mannosidosis mouse model was generated by targeted disruption of the gene for lysosomal alpha-mannosidase. Homozygous mutant animals exhibit alpha-mannosidase enzyme deficiency and elevated urinary se cretion of mannose-containing oligosaccharides, Thin-layer chromatography r evealed an accumulation of oligosaccharides in liver, kidney, spleen, testi s and brain, The cellular alterations were characterized by multiple membra ne-limited cytoplasmic vacuoles as seen for instance in liver, exocrine pan creas, kidney, thyroid gland, smooth muscle cells, osteocytes and in variou s neurons of the central and peripherial nervous systems. The morphological lesions and their topographical distribution, as well as the biochemical a lterations, closely resemble those reported for human alpha-mannosidosis, T his mouse model will be a valuable tool for studying the pathogenesis of in herited alpha-mannosidosis and may help to evaluate therapeutic approaches for lysosomal storage diseases.