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A mouse model for mucopolysaccharidosis type III A (Sanfilippo syndrome)
M Bhaumik1, V J Muller, T Rozaklis
1Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
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.
Insights
A new mouse model for Mucopolysaccharidosis type III A (Sanfilippo syndrome) exhibits key disease features, including heparan sulfate accumulation and reduced sulfamidase activity. This model is crucial for studying disease mechanisms and testing potential therapies.
Area of Science:
- Biochemistry
- Genetics
- Pathology
Background:
- Mucopolysaccharidosis type III A (MPS III A), also known as Sanfilippo syndrome, is a rare, autosomal recessive lysosomal storage disease.
- It is caused by a deficiency in the enzyme heparan N-sulfatase (sulfamidase), leading to the accumulation of heparan sulfate.
- This accumulation results in severe neurological and systemic manifestations.
Purpose of the Study:
- To describe a spontaneous mouse mutant that accurately models human MPS III A.
- To characterize the biochemical and pathological features of this MPS III A mouse model.
- To evaluate its utility for preclinical research and therapeutic development.
Main Methods:
- Characterization of a spontaneous mouse mutant exhibiting MPS III A features.
- Histopathological examination of brain and other tissues, focusing on lysosomal storage.
- Biochemical analysis of heparan sulfate levels and sulfamidase enzyme activity in affected tissues and urine.
- Assessment of other lysosomal hydrolase activities.
Main Results:
- The MPS III A mouse model displays neuronal lysosomal distension with characteristic storage material, including zebra bodies.
- Heparan sulfate accumulation was confirmed in various tissues and urine, with specific structural abnormalities.
- Affected mice showed significantly reduced sulfamidase activity in liver and brain extracts, consistent with MPS III A.
- The mice exhibited typical disease phenotypes, including premature death, bladder distension, and hepatosplenomegaly.
Conclusions:
- The described spontaneous mouse mutant serves as a robust preclinical model for Mucopolysaccharidosis type III A.
- This model facilitates the investigation of disease pathogenesis and the evaluation of novel therapeutic strategies.
- It is suitable for testing enzyme replacement, cell-based therapies, and gene therapy approaches for Sanfilippo syndrome.
