Genetic mannosidosis

Genetic mannosidosis has been described in man, Angus cattle and Murray Gray cattle, and is characterized by a deficiency of a-mannosidase leading to storage of excess mannose-rich oligosaccharides in lysosomes. Pathologically, there is vacuolation of reticuloendothelial cells in the liver and lymph nodes, pancreatic exocrine cells, and neurons. Affected cattle are ataxic, uncoordinated, fail to thrive, and die in the first year of life. 

Locoweed poisoning mimics exactly the genetic mannosidosis. Thus, the availability of specific inhibitors (plant toxins) of these enzymes provides a mechanism for induction of phenocopies of these genetic diseases in animal... 

Genetic Deficiencies of Glycoprotein Lysosomal Hydrolases Cause Diseases Such as a-Mannosidosis... 

A search for lysosomal hydrolases and related enzymes has been made in haemolysates from human and rabbit red cells. Apart from acid phosphatases, significant activities were found only for a-D-mannosidase, neutral o-D-glucosidase, and -D-2-acetamido-2-deoxyhexosidase. a-D-Mannosidase activity per cell in human red blood cells was 200-times lower than in white cells. The optimal pH was 5.5-6.0. Electrophoresis on cellulose acetate showed three bands. Haemolysates from four patients with mannosidosis were not deficient in a-D-mannosidase. Curves of pH activity and electrophoretic patterns were similar to those of controls. From its biochemical and genetic properties, it is concluded that red cell a-D-mannosidase differs from the lysosomal acid a-D-mannosidase. 

The activities and properties of an a-D-mannosidase of diploid Wl-38 fibroblasts from embryonic human-lung tissues have been reported. Mannosidosis is a genetic disorder that can be recognized by a deficiency of a specific a-D-mannosid-ase in cultured fibroblasts. ... 

The genetic defect in patients with a-mannosidosis generally do not appear to involve the alterations in the transcription or translation of the mannosidase polypeptide [162], but recent data indicate that a human mutations can include splicing, missense, or nonsense mutations, as well as small insertions or deletions [177-179], Animal models for the enzyme deficiency have also been identified in Persian cats [158] and in Angus and Galloway cattle [159]. The defect in the feline disease results from a 4 bp deletion resulting in a frame shift at codon 583 and a premature termination at codon 645 [158], Each of the bovine mutations involve different missense mutations causing amino acid substitutions that influence the either the level of protein expression or enzyme stability [159],... 

Gotoda, Y., N. Wakamatsu, H. Kawai, Y. Nishida, and T. Matsumoto, Missense and nonsense mutations in the lysosomal a-mannosidase gene (MANB) in severe and mild forms of a-mannosidosis. Am. J. Hum. Genet., 1998, 63, 1015-1024. 

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