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

被引:153
作者
Bhaumik, M
Muller, VJ
Rozaklis, T
Johnson, L
Dobrenis, K
Bhattacharyya, R
Wurzelmann, S
Finamore, P
Hopwood, JJ
Walkley, SU
Stanley, P
机构
[1] Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA
[2] Yeshiva Univ Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA
[3] Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA
[4] Womens & Childrens Hosp, Lysosomal Dis Res Unit, Adelaide, SA 5006, Australia
关键词
MPS III A; mouse; pathogenesis; Sanfilippo syndrome;
D O I
10.1093/glycob/9.12.1389
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mucopolysaccharidosis type III A (MPS III A, Sanfilippo syndrome) is a Fare, 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 mere 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.
引用
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页码:1389 / 1396
页数:8
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