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, which 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 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 peripheral nervous systems. The morphological lesions and their topographical distribution, as well as the biochemical alterations, closely resemble those reported for human alpha-mannosidosis. This mouse model will be a valuable tool for studying the pathogenesis of inherited alpha-mannosidosis and may help to evaluate therapeutic approaches for lysosomal storage diseases.
Stinchi
S
S
Dipartimento di Biologia Cellulare e Molecolare, Sezione di Biochimica e Biologia Molecolare, Università degli Studi di Perugia, Via del Giochetto, 06126 Perugia, Italy,
Lüllmann-Rauch
R
R
Hartmann
D
D
Coenen
R
R
Beccari
T
T
Orlacchio
A
A
von Figura
K
K
Saftig
P
P
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D008361:Mannosidases / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009844:Oligosaccharides / Q000378:metabolism / Q000652:urine; D010011:Osteocytes / Q000473:pathology / Q000648:ultrastructure; D013154:Spleen / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D043323:alpha-Mannosidase; D008363:alpha-Mannosidosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
D009844:Oligosaccharides; D008361:Mannosidases; D043323:alpha-Mannosidase