Mannosidosis is an inherited deficiency of lysosomal alpha- mannosidase that leads to the massive accumulation and excretion of oligoasccharides resulting from the partial degradation of glycoprotein saccharide chains. This leads to mental retardation, neurological and skeletal abnormalities, hearing loss, and recurrent infections. The disease occurs in humans, cattle, and cats, and a similar condition can be induced in any animal by the ingestion of plants containing swainsonine, a potent inhibitor of alpha-mannosidase. Surprisingly, the pattern of oligosaccharide excretion in humans is quite different from that in other animals, especially for the oligosaccharides containing 2 to 5 mannose residues. Also, the presence of some oligosaccharide species, and absence of others, is difficult to explain on the basis of what is known about the substrate specificity of lysosomal alpha- mannosidase, the structures of glycoprotein saccharide chains, and the """"""""processing"""""""" pathway of N-glycoproteins during their biosynethesis. Investigation of the detailed substrate specificity of lysosomal alpha-mannosidase preparations for natural substrates, under conditions of incomplete digestion, will help to explain the storage and excretion patterns in human and non-human mannosidosis. We are uniquely qualified to perform such a study for the following reasons: (a) our detailed knowledge of the structures of oligosaccharides stored in tissues and excreted in urine of humans and animals with natural and swainsonine-induced mannosidosis; (b) the availability in our laboratories of a wide variety of suitable substrates with known structures, (c) our experience of purifying the various forms of alpha-D-mannosidase from human and bovine tissues and investigating their activities in vitro and in cultured cells towards natural and synthetic substrates and (d) our capability for rapid structural analysis of the incubation products by combinations of H.P.L.C., chemical, enzymic and spectroscopic methods. These investigations on the origin and the catabolism of the oligosaccharides in mannosidosis will contribute to our understanding of the normal catabolism of glycoproteins and of the molecular pathology of mannosidosis and related glycoproteinoses.
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