A mouse model for mucopolysaccharidosis type III A (Sanfilippo syndrome).
Mucopolysaccharidosis type III A (MPS III A, Sanfilippo syndrome) is a rare, autosomal recessive, lysosomal storage disease characterized by accumulation of heparan sulfate secondary to defective function of the lysosomal enzyme heparan N- sulfatase (sulfamidase). Here we describe a spontaneous mouse mutant that replicates many of the features found in MPS III A in children. Brain sections revealed neurons with distended lysosomes filled with membranous and floccular materials with some having a classical zebra body morphology. Storage materials were also present in lysosomes of cells of many other tissues, and these often stained positively with periodic-acid Schiff reagent. Affected mice usually died at 7-10 months of age exhibiting a distended bladder and hepatosplenomegaly. Heparan sulfate isolated from urine and brain had nonreducing end glucosamine- N -sulfate residues that were digested with recombinant human sulfamidase. Enzyme assays of liver and brain extracts revealed a dramatic reduction in sulfamidase activity. Other lysosomal hydrolases that degrade heparan sulfate or other glycans and glycosaminoglycans were either normal, or were somewhat increased in specific activity. The MPS III A mouse provides an excellent model for evaluating pathogenic mechanisms of disease and for testing treatment strategies, including enzyme or cell replacement and gene therapy.
Bhaumik
M
M
Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
Muller
V J
VJ
Rozaklis
T
T
Johnson
L
L
Dobrenis
K
K
Bhattacharyya
R
R
Wurzelmann
S
S
Finamore
P
P
Hopwood
J J
JJ
Walkley
S U
SU
Stanley
P
P
D000818:Animals; D001921:Brain / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D006025:Glycosaminoglycans / Q000032:analysis / Q000652:urine; D006497:Heparan Sulfate / Q000652:urine; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D008099:Liver / Q000648:ultrastructure; D008247:Lysosomes / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009084:Mucopolysaccharidosis III / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D013154:Spleen / Q000648:ultrastructure; D001743:Urinary Bladder / Q000473:pathology
D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D006867:Hydrolases