Biochemical studies in mucolipidoses II and III

L. J. Shapiro, S. Hickman, C. W. Hall, E. F. Neufeld

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2 Scopus citations


Cultured cells from patients with ML II (I cell disease or ICD) and ML III (pseudopolydystrophy) have deficiencies of several lysosomal hydrolyses, which show elevated activities in culture medium and in the patients' body fluids. The basic lesion in ICD is not one of 'leaky lysosomes' because bovine liver glucuronidase survives longer in I cells than in controls and because exogenous human α L iduronidase has a similar half life in Hurler (MPS I) cells and I cells. Although the latter cells secrete excessive amounts of enzymes in the medium they do not correct excessive accumulation of 35SO4 by MPS fibroblasts. They are thus unable to supply the missing enzyme to the MPS mutant cells. For I cell derived α L iduronidase and β glucuronidase the ratios of quantitative corrective activity for mutant fibroblasts to catalytic activity are much less than those of the enzymes from control sources. Failure to exert metabolic complementation is due to the fact that ICD derived enzymes do not enter recipient fibroblasts sufficiently. Between 5 and 25% of exogenous control hexosaminidase is taken up by Sandhoff fibroblasts by specific adsorptive pinocytosis, whereas only 1% of the ICD enzyme enters into these recipient cells probably non selectively. Specific adsorption pinocytosis implies a cell surface receptor and a recognition marker on the enzyme. That the latter is probably of a carbohydrate nature is shown by the finding that sodium metaperiodate treated control hexosaminidase with unaltered catalytic activity is taken up poorly by Sandhoff fibroblasts. Two molecular forms of iduronidase purified from human urine and separated by affinity chromatography show nearly identical enzyme kinetics but differ markedly in their ability to enter to correct MPS I cells. The high uptake, corrective forms binds better to RCA1 lectin than does the low uptake non corrective form and is therefore likely to possess galactose containing oligosaccharide. Lysosomal hydrolases require a structural component which quarantees their uptake by recipient cells and their proper intralysosomal location and function. The mutations in ML II and ML III have a functionally related effect and probably involve the structure of the carbohydrate recognition marker common to several hydrolytic enzymes. The inactivities of either a specific glycosyltransferase necessary for the synthesis of the recognition marker or a glucosidase needed to uncover it, if masked, are among the possible primary defects in ML II and/or ML III. Final discovery of these defects will yield important theoretical and practical information on cell and enzyme physiology. (Leroy - Antwerp)

Original languageEnglish
Pages (from-to)301-305
Number of pages5
JournalBirth Defects: Original Article Series
Issue number6
StatePublished - Dec 1 1975


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