It is now known that the monomeric end-products of lysosomal digestion (e.g., amino acids, monosaccharides, etc.) transit the lysosomal membrane to the cytoplasm through the agency of specific porters or carriers, none of which have to date been isolated or characterized. In two instances, inherited defects in lysosomal carrier function are known to result in human disorders with severe clinical consequences viz., cystinosis and sialic acid storage disease. These distict disorders are characterized, respectively, by abnormal intra-lysosomal accumulations of the amino acid cystine and of the acidic monosaccharides sialic acid and D-glucuronic acid. Since L-iduronic acid, a structural analog of D- glucuronic acid, is a common component of oligosaccharides known to be hydrolytically processed within cellular lysosomes, we have examined cultured skin fibroblasts from patients with sialic acid storage disease for evidence of abnormal accumulation of this hexuronic acid. Such an observed accumulation could be considered presumptive evidence that iduronic and sialic acids share a common lysosomal membrane carrier. HPLC analysis of protein-free extracts of the two variant human forms of sialic acid storage disease (i.e., Salla Disease and infantile sialic acid storage disease) failed to indicate increased endogenous levels of free L-iduronic acid relative to extracts from normal cells, in contrast to the gross elevations noted for sialic acid. However, in two instances mutant cells incubated in the presence of heparin, an oligosaccharide rich in iduronic acid residues, where noted to contain distinctively elevated concentrations of the free acidic monosaccharide. These observations are consistent with the notion that either iduronate utilizes a distant membrane carrier for lysosomal egress or that, if a common porter exists for sialic and L-iduronic acids, the mutant forms chraracteristic of the sialic acid storage diseases may be """"""""leaky"""""""" with respect to the latter sugar, which can accumulate only when the cells are presented with an excess exogenous source of the hexuronic acid.
