Animal models of inherited metabolic diseases : proceedings of the International Symposium on Animal Models of Inherited Metabolic Disease held in Bethesda, Maryland, October 19-20, 1981 / editors: Robert J. Desnick, Donald F. Patterson, Dante G. Scarpelli.
- International Symposium on Animal Models of Inherited Metabolic Disease (1981 : Bethesda, Md.)
- Date:
- [1982]
Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Credit: Animal models of inherited metabolic diseases : proceedings of the International Symposium on Animal Models of Inherited Metabolic Disease held in Bethesda, Maryland, October 19-20, 1981 / editors: Robert J. Desnick, Donald F. Patterson, Dante G. Scarpelli. Source: Wellcome Collection.
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![The finding that zinc cations stimulated normal plant, mammalian and human acid a-mannosidase activity (Snaith, 1975; Phillips et_ al_., 1974), as well as residual a-manno sidase in tissues and fluids from bovine and human manno- sidosis (Desnick et_ al_., 1976; Jolly et_ a]_., 1980), stim ulated the trial of cofactor supplernentaton in bovine mannosidosis. Following oral zinc supplementation, a modest increase in the activity of the residual acid a-man nosidase was observed in bovine liver, kidney and pancreas (organs in which zinc accumulates). A concomitant decrease in the levels of mannosyl-oligosaccharides also was ob served in these tissues. However, in the brain of the treated calf, the residual enzymatic activity and oligo saccharide content were not changed. These findings in dicated that the effect of zinc supplementation may be confined to tissues that accumulate zinc and that inad equate zinc uptake by tissues of the nervous system may have precluded a therapeutic effect. As described above, characterization of the physical and kinetic properties of the residual ASB activity in feline MPS VI indicated that the mutation in the structural gene for the feline enzyme altered the gene product such that it was unable to maintain its normal dimeric conforma tion (Vine ejt al_., 1981, 1982; McGovern et^ al_., 1982). Al though the defective enzyme retained partial activity, the inability for subunit association presumably rendered the enzyme protein more defective catalytically and markedly unstable. These findings stimulated the evaluation of thiol-active reagents as stabilizers. In the presence of dithiothreitol (DTT) or cysteamine, the residual feline MPS VI activity was dimerized (Vine et^ al_., 1982) resulting in increased activity. Since DTT and cysteamine have been safely administered as experimental therapeutic agents in patients with cystinosis (Thoene ejt aj_., 1976; Aaron et. al., 1971; Goldman et_ al_., 1971; Depape-Brigger et al., 1977; Girardin et_ al_., 1979; Yudkoff ejt a]_., 1981), the therapeutic use of these compounds was evaluated in the feline model. Initially, in vitro studies were undertaken to deter mine if thiol-induced dimerization could enhance the MPS VI residual ASB activity in leukocytes and catabolize the accumulated substrate. Following incubation of fresh heparinized whole blood with DTT or cysteamine, the leuko cyte residual ASB activity was increased up to 11- and](https://iiif.wellcomecollection.org/image/b18027842_0077.JP2/full/800%2C/0/default.jpg)
