title: Caprine mucopolysaccharidosis-IIID: clinical, biochemical, morphological and immunohistochemical characteristics.
abstract: Several animal models have been developed for the mucopolysaccharidoses (MPSs), a group of lysosomal storage disorders caused by lysosomal hydrolase deficiencies that disrupt the catabolism of glycosaminoglycans (GAG). Among the MPS, the MPS-III (Sanfilippo) syndromes lacked an animal counterpart until recently. In this investigation of caprine MPS-IIID, the clinical, biochemical, morphological, and immunohistochemical studies revealed severe and mild phenotypes like those observed in human MPS III syndromes. Both forms of caprine MPS IIID result from a nonsense mutation and consequent deficiency of lysosomal N-acetylglucosamine 6-sulfatase (G6S) activity and are associated with tissue storage and urinary excretion of heparan sulfate (HS). Using special stains, immunohistochemistry, and electron microscopy, secondary lysosomes filled with GAG were identified in most tissues from affected goats. Primary neuronal accumulation of HS and the secondary storage of gangliosides were observed in the central nervous system (CNS) of these animals. In addition, morphological changes in the CNS such as neuritic expansions and other neuronal alterations that may have functional significance were also seen. The spectrum of lesions was greater in the severe form of caprine MPS IIID and included mild cartilaginous, bony, and corneal lesions. The more pronounced neurological deficits in the severe form were partly related to a greater extent of CNS dysmyelination. These findings demonstrate that caprine MPS IIID is a suitable animal model for the investigation of therapeutic strategies for MPS III syndromes.
authors.affiliation: Department of Pathology, Michigan State University, East Lansing 48824, USA.
authors.forename: M Z
authors.initials: MZ
authors.lastname: Jones
authors.forename: J
authors.initials: J
authors.lastname: Alroy
authors.forename: P J
authors.initials: PJ
authors.lastname: Boyer
authors.forename: K T
authors.initials: KT
authors.lastname: Cavanagh
authors.forename: K
authors.initials: K
authors.lastname: Johnson
authors.forename: D
authors.initials: D
authors.lastname: Gage
authors.forename: J
authors.initials: J
authors.lastname: Vorro
authors.forename: J A
authors.initials: JA
authors.lastname: Render
authors.forename: R S
authors.initials: RS
authors.lastname: Common
authors.forename: R A
authors.initials: RA
authors.lastname: Leedle
authors.forename: C
authors.initials: C
authors.lastname: Lowrie
authors.forename: P
authors.initials: P
authors.lastname: Sharp
authors.forename: S S
authors.initials: SS
authors.lastname: Liour
authors.forename: B
authors.initials: B
authors.lastname: Levene
authors.forename: H
authors.initials: H
authors.lastname: Hoard
authors.forename: R
authors.initials: R
authors.lastname: Lucas
authors.forename: J J
authors.initials: JJ
authors.lastname: Hopwood
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000737:chemistry; D004730:Endothelium, Vascular / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D005732:Gangliosides / Q000032:analysis*; D006025:Glycosaminoglycans / Q000378:metabolism; D015511:Goat Diseases; D006041:Goats; D006497:Heparan Sulfate / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D009084:Mucopolysaccharidosis III / Q000235:genetics / Q000473:pathology* / Q000662:veterinary*; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000648:ultrastructure; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D009439:Neuraminidase / Q000032:analysis; D009474:Neurons / Q000473:pathology; D017354:Point Mutation; D012077:Renal Artery / Q000473:pathology / Q000648:ultrastructure; D013116:Spinal Cord / Q000473:pathology*; D013429:Sulfatases / Q000235:genetics
chemical_list: D005732:Gangliosides; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D009439:Neuraminidase; D013429:Sulfatases; C018719:N-acetylglucosamine-6-sulfatase