Human Molecular Genetics Advance Access published online on December 23, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi465
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1 Department of Microbiology and Molecular Genetics, Michigan State University East Lansing, Michigan
* To whom correspondence should be addressed.
Received November 7, 2005
Revised December 16, 2005
Accepted December 16, 2005
Article
Mei Zhu 1,
Kathryn L. Lovell 2,
Jon S. Patterson 3,
Thomas L. Saunders 4,
Elizabeth D. Hughes 4,
and
Karen H. Friderici Ph.D. Associate Professor 5 *
-Mannosidosis mice: a model for the human lysosomal storage disease
2 Department of Neurology and Ophthalmology, and Neuroscience Program, Michigan State University, East Lansing, Michigan
3 Pathobiology & Diagnostic Investigation, College of Veterinary Medicine , Michigan State University, East Lansing, Michigan
4 Department of Internal Medicine and Transgenic Animal Model Core, University of Michigan, Ann Arbor, Michigan
5 Department of Microbiology and Molecular Genetics, Michigan State University East Lansing, Michigan; Department of Pediatrics and Human Development, 5163 biomedical Physical Sciences Bldg. Michigan State University, East Lansing, Michigan 48824
Karen H. Friderici, E-mail: frideric{at}msu.edu
Abstract 
-Mannosidase, a lysosomal enzyme which acts exclusively at the last step of oligosaccharide catabolism in glycoprotein degradation, functions to cleave the unique -linked mannose sugar found in all N-linked oligosaccharides of glycoproteins. Deficiency of this enzyme results in -mannosidosis, a lysosomal storage disease characterized by the cellular accumulation of small oligosaccharides. In human -mannosidosis the clinical presentation is variable and can be mild, even when caused by functionally null mutations. In contrast, two existing ruminant animal models have disease that is consistent and severe. To further explore the molecular pathology of this disease and to investigate potential treatment strategies we produced a -mannosidase knockout mouse. Homozygous mutant mice have undetectable -mannosidase activity. General appearance and growth of the knockout mice are similar to the wild-type littermates. At greater than one year of age these mice exhibit no dysmorphology or overt neurological problems. The mutant animals have consistent cytoplasmic vacuolation in the central nervous system and minimal vacuolation in most visceral organs. Thin-layer chromatography demonstrated an accumulation of disaccharide in epididymis and brain. This mouse model closely resembles human -mannosidosis and provides a useful tool for studying the phenotypic variation in different species and will facilitate the study of potential therapies for lysosomal storage diseases.
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