Abstract
Mucopolysaccharidosis (MPS) type IIIA, or Sanfilippo syndrome, is a neurodegenerative lysosomal storage disorder caused by a deficiency of the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH), involved in the catabolism of heparan sulfate. The clinical spectrum is broad and the age of symptom onset and the degree of preservation of cognitive and motor functions appears greatly influenced by genotype. To explore this further, we generated a conditional knockout (Sgsh KO) mouse model with ubiquitous Sgsh deletion, and compared the clinical and pathological phenotype with that of the spontaneous Sgsh D31N MPS-IIIA mouse model. Phenotypic deficits were noted in Sgsh KO mice prior to Sgsh D31N mice, however these outcomes did not correlate with any shift in the time of appearance nor rate of accumulation of primary (heparan sulfate) or secondary substrates (GM2/GM3 gangliosides). Other disease lesions (elevations in lysosomal integral membrane protein-II expression, reactive astrocytosis and appearance of ubiquitin-positive inclusions) were also comparable between affected mouse strains. This suggests that gross substrate storage and these neuropathological markers are neither primary determinants, nor good biomarkers/indicators of symptom generation, confirming similar observations made recently in MPS-IIIA patients. The Sgsh KO mouse will be a useful tool for elucidation of the neurological basis of disease and assessment of the clinical efficacy of new treatments for Sanfilippo syndrome.
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Acknowledgements
This work was supported by the Lysosomal Diseases Research Unit (SAHMRI, Australia). The Monash Gene Targeting Facility was contracted to generate the targeting construct and mice containing the targeted allele. We thank Meghan Setford and Andrew Shoubridge for assistance in genotyping and mouse husbandry; Lynn Garrard and staff at the Women’s and Children’s Health Network Animal Care Facility for care of the mice; Dr. Mark Corbett (Adelaide Neurogenetics Research Group; The University of Adelaide) for providing the CMV-Cre mice, Dr. Mark Adams (Evolutionary Biology Unit, South Australian Museum) for the allozyme electrophoresis and the Australian Genome Research Facility Ltd. for SNP genotyping.
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This work was supported by the Lysosomal Diseases Research Unit (SAHMRI, Australia).
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Communicated by: Carla E. Hollak
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Lau, A.A., King, B.M., Thorsen, C.L. et al. A novel conditional Sgsh knockout mouse model recapitulates phenotypic and neuropathic deficits of Sanfilippo syndrome. J Inherit Metab Dis 40, 715–724 (2017). https://doi.org/10.1007/s10545-017-0044-4
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DOI: https://doi.org/10.1007/s10545-017-0044-4