title: Caprine beta-D-mannosidosis: characterization of a model lysosomal storage disorder.
abstract: Interest in using caprine beta-D-mannosidosis as a model to evaluate bone marrow transplantation in the treatment of human lysosomal storage disorders provided the stimulus for characterization of beta-D-mannosidase in selected goat tissues and induction of hemopoietic chimerism in the goat. Total beta-D-mannosidase activity was measured with the use of 4-methylumbelliferyl beta-D-mannopyranoside as substrate. Residual activity in mutant liver was 52% of control but no activity was detectable in mutant kidney or brain tissue. Normal adult goat liver contained two forms of beta-D-mannosidase, a nonlysosomal form (52%) with a broad pH range for optimum activity (4.5-8.0) and a lysosomal form (48%) with a pH optimum of 5.5. Residual enzyme in mutant liver consisted entirely of the nonlysosomal form. Normal adult thyroid, kidney and brain contained two major lysosomal isoenzymes with pIs 5.5 and 5.9 and traces of a minor isoenzyme with pI 5.0. Normal liver contained three isoenzymes with similar pIs; however, an isoenzyme with pI 5.0 predominated. In 60-day fetal liver lysosomal isoenzymes predominated and only trace amounts of nonlysosomal isoenzyme were detectable. Total hepatic beta-D-mannosidase activity increased towards adult levels during the last 90 days of gestation as a result of increasing nonlysosomal isoenzyme activity. Intraperitoneal injection of fetal liver cells into 60-day goat fetuses resulted in sustained hemopoietic chimerism in surviving kids without evidence of graft-versus-host-disease. These results suggest that transplantation of normal fetal liver cells into preimmunocompetent goat fetuses affected with beta-D-mannosidosis is feasible and may provide an alternative strategy for evaluation of postnatal bone marrow transplantation in the treatment of human lysosomal storage disorders.
authors.affiliation: Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario.
authors.forename: R D
authors.initials: RD
authors.lastname: Pearce
authors.forename: J W
authors.initials: JW
authors.lastname: Callahan
authors.forename: P B
authors.initials: PB
authors.lastname: Little
authors.forename: L R
authors.initials: LR
authors.lastname: Klunder
authors.forename: J T
authors.initials: JT
authors.lastname: Clarke
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology*; D004195:Disease Models, Animal; D005333:Fetus / Q000201:enzymology; D015511:Goat Diseases / Q000201:enzymology*; D006041:Goats; D007668:Kidney / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008361:Mannosidases / Q000378:metabolism*; D013961:Thyroid Gland / Q000201:enzymology*; D008363:alpha-Mannosidosis / Q000201:enzymology / Q000662:veterinary*; D044902:beta-Mannosidase
chemical_list: D008361:Mannosidases; D044902:beta-Mannosidase