A mouse model for mucopolysaccharidosis type III A (Sanfilippo syndrome)

M Bhaumik, VJ Muller, T Rozaklis, J Linda… - …, 1999 - academic.oup.com
M Bhaumik, VJ Muller, T Rozaklis, J Linda, K Dobrenis, R Bhattacharyya, S Wurzelmann…
Glycobiology, 1999academic.oup.com
Abstract 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 …
Abstract
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.
Oxford University Press